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Banushi B, Collova J, Milroy H. Epigenetic Echoes: Bridging Nature, Nurture, and Healing Across Generations. Int J Mol Sci 2025; 26:3075. [PMID: 40243774 PMCID: PMC11989090 DOI: 10.3390/ijms26073075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Revised: 03/19/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
Trauma can impact individuals within a generation (intragenerational) and future generations (transgenerational) through a complex interplay of biological and environmental factors. This review explores the epigenetic mechanisms that have been correlated with the effects of trauma across generations, including DNA methylation, histone modifications, and non-coding RNAs. These mechanisms can regulate the expression of stress-related genes (such as the glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) gene), linking trauma to biological pathways that may affect long-term stress regulation and health outcomes. Although research using model organisms has elucidated potential epigenetic mechanisms underlying the intergenerational effects of trauma, applying these findings to human populations remains challenging due to confounding variables, methodological limitations, and ethical considerations. This complexity is compounded by difficulties in establishing causality and in disentangling epigenetic influences from shared environmental factors. Emerging therapies, such as psychedelic-assisted treatments and mind-body interventions, offer promising avenues to address both the psychological and potential epigenetic aspects of trauma. However, translating these findings into effective interventions will require interdisciplinary methods and culturally sensitive approaches. Enriched environments, cultural reconnection, and psychosocial interventions have shown the potential to mitigate trauma's impacts within and across generations. By integrating biological, social, and cultural perspectives, this review highlights the critical importance of interdisciplinary frameworks in breaking cycles of trauma, fostering resilience, and advancing comprehensive healing across generations.
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Affiliation(s)
- Blerida Banushi
- School of Indigenous Studies, The University of Western Australia, Crawley, WA 6009, Australia; (J.C.); (H.M.)
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Zeid D, Toussaint AB, Dressler C, Harbeck A, Karbalaei R, Cintrón Y, Pan A, Wimmer M. Extended abstinence from morphine alters sperm smRNA expression and prevents transmission of intergenerational phenotypes. ENVIRONMENTAL EPIGENETICS 2025; 11:dvaf006. [PMID: 40406632 PMCID: PMC12097204 DOI: 10.1093/eep/dvaf006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/17/2025] [Accepted: 03/19/2025] [Indexed: 05/26/2025]
Abstract
Paternal exposure to drugs of abuse can impact addiction-related behaviours in progeny via germline epigenome remodelling. Previously, we found that offspring of morphine-exposed male rats showed increased morphine-taking, diminished adolescent social play, and increased sensitivity to morphine-derived analgesia. Here, we first tested the impact of a 90-day paternal abstinence period following morphine self-administration on the transmission of the aforementioned phenotypes. The previously observed changes in morphine-related behaviours were no longer present in offspring of morphine-abstinent sires. We next compared small RNA (smRNA) content in sperm collected from four sire intravenous self-administration groups: morphine, saline, abstinent morphine, and abstinent saline. Two smRNAs (rno-miR-150-5p and an snoRNA annotated to Snora42/Noc3l) were differentially expressed specifically between morphine- and saline-treated sperm. No differential expression between abstinent morphine and saline sperm was observed. These data begin to delineate the temporal limits of heritable germline modifications associated with morphine exposure, in addition to identifying F0 germline factors coinciding with the manifestation of F1 multigenerational phenotypes. Furthermore, these data suggest that paternal abstinence at conception can prevent inheritance of germline factors that may alter offspring susceptibility to addiction-related endophenotypes.
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Affiliation(s)
- Dana Zeid
- Department of Psychology & Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, United States
| | - Andre B Toussaint
- Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, United States
| | - Carmen Dressler
- Department of Psychology & Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, United States
| | - Angela Harbeck
- Department of Psychology & Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, United States
| | - Reza Karbalaei
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, Baltimore 21205, United States
| | - Yandrés Cintrón
- Department of Psychology & Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, United States
| | - Andrew Pan
- Department of Psychology & Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, United States
| | - Mathieu Wimmer
- Department of Psychology & Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA 19122, United States
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Landa MS, Schuman ML, Aisicovich M, Peres Diaz LS, Gironacci MM, García SI, Pirola CJ. Valproate decreases transgenerationally blood pressure by affecting thyrotropin-releasing hormone promoter DNA methylation and gene expression in spontaneously hypertensive rat. Mol Cell Biochem 2025; 480:937-949. [PMID: 38630362 DOI: 10.1007/s11010-024-05001-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 03/25/2024] [Indexed: 02/19/2025]
Abstract
Central TRH, a neuropeptide, is involved in cardiovascular regulation. We demonstrated that the overexpression of diencephalic TRH (dTRH) in SHR rats can be prevented by antisense treatment, normalizing blood pressure (BP). Valproate (VPA) is an inhibitor of histone deacetylases (HDAC) which modulates gene expression through epigenetic modifications such as DNA methylation. AIMS Study the role of HDAC inhibition in the regulation of dTRH gene expression and its effect on the pathogenesis of hypertension. MAIN METHODS We treated 7-weeks-old male and female SHR and WKY rats with VPA for 10 weeks and evaluated BP, dTRH mRNA and methylation gene status. KEY FINDINGS VPA attenuated the elevated BP and dTRH mRNA expression characteristic of SHR. Indeed, we found a significant 62% reduction in dTRH mRNA expression in the SHR + VPA group compared to control SHR. The decrease TRH mRNA expression induced by VPA was confirmed "in vitro" in a primary neuron culture using trichostatin A. With methylation specific PCR we demonstrated a significant increase in TRH promoter DNA methylation level in SHR + VPA group compared to control SHR. After 2 weeks of treatment interruption, rats were mated. Although they did not receive any treatment, the offspring born from VPA-treated SHR parents showed similar changes in BP, dTRH expression and methylation status, implying a transgenerational inheritance. Our findings suggest that dTRH modulation by epigenetics mechanism affects BP and could be inherited by the next generation in SHR rats.
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Affiliation(s)
- María S Landa
- School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina
- Department of Molecular Cardiology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina
| | - Mariano L Schuman
- School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina
- Department of Molecular Cardiology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina
| | - Maia Aisicovich
- School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina
- Department of Molecular Cardiology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina
| | - Ludmila S Peres Diaz
- School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina
- Department of Molecular Cardiology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina
| | - Mariela M Gironacci
- Department of Biological Chemistry, Faculty of Pharmacy and Biochemistry, School of Pharmacy and Biochemistry (IQUIFIB), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina
| | - Silvia I García
- School of Medicine, Institute of Medical Research A. Lanari, Universidad de Buenos Aires, Combatientes de Malvinas 3150, 1427, Ciudad Autonoma de Buenos Aires, Argentina.
- Department of Molecular Cardiology, Institute of Medical Research (IDIM), National Scientific and Technical Research Council (CONICET), Universidad de Buenos Aires (UBA), Ciudad Autonoma de Buenos Aires, Argentina.
- Laboratory of Experimental Medicine, Hospital Alemán, Ciudad Autónoma de Buenos Aires, Argentina.
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, Center for Traslational Research in Health, Maimonides University, Hidalgo 775, 1405, Ciudad Autonoma de Buenos Aires, Argentina.
- National Scientific and Technical Research Council (CONICET), Ciudad Autonoma de Buenos Aires, Argentina.
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Martinez ME, Karaczyn A, Wu Z, Bennett CA, Matoin KL, Daigle HM, Hernandez A. Transgenerational epigenetic self-memory of Dio3 dosage is associated with Meg3 methylation and altered growth trajectories and neonatal hormones. Epigenetics 2024; 19:2376948. [PMID: 38991122 PMCID: PMC11244338 DOI: 10.1080/15592294.2024.2376948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 07/02/2024] [Indexed: 07/13/2024] Open
Abstract
Intergenerational and transgenerational epigenetic effects resulting from conditions in previous generations can contribute to environmental adaptation as well as disease susceptibility. Previous studies in rodent and human models have shown that abnormal developmental exposure to thyroid hormone affects endocrine function and thyroid hormone sensitivity in later generations. Since the imprinted type 3 deiodinase gene (Dio3) regulates sensitivity to thyroid hormones, we hypothesize its epigenetic regulation is altered in descendants of thyroid hormone overexposed individuals. Using DIO3-deficient mice as a model of developmental thyrotoxicosis, we investigated Dio3 total and allelic expression and growth and endocrine phenotypes in descendants. We observed that male and female developmental overexposure to thyroid hormone altered total and allelic Dio3 expression in genetically intact descendants in a tissue-specific manner. This was associated with abnormal growth and neonatal levels of thyroid hormone and leptin. Descendant mice also exhibited molecular abnormalities in the Dlk1-Dio3 imprinted domain, including increased methylation in Meg3 and altered foetal brain expression of other genes of the Dlk1-Dio3 imprinted domain. These molecular abnormalities were also observed in the tissues and germ line of DIO3-deficient ancestors originally overexposed to thyroid hormone in utero. Our results provide a novel paradigm of epigenetic self-memory by which Dio3 gene dosage in a given individual, and its dependent developmental exposure to thyroid hormone, influences its own expression in future generations. This mechanism of epigenetic self-correction of Dio3 expression in each generation may be instrumental in descendants for their adaptive programming of developmental growth and adult endocrine function.
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Affiliation(s)
- M. Elena Martinez
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
| | - Aldona Karaczyn
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
| | - Zhaofei Wu
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
| | - Christian A. Bennett
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
| | - Kassey L. Matoin
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
| | - Heather M. Daigle
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
| | - Arturo Hernandez
- Center for Molecular Medicine, MaineHealth Institute for Research, MaineHealth, Scarborough, ME, USA
- Graduate School for Biomedical Sciences and Engineering, University of Maine, Orono, ME, USA
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
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Xu W. Interrupting transgenerational programming of infant mortality risk: evidence from a multigeneration cohort study in Sweden. Am J Clin Nutr 2024; 120:1007-1008. [PMID: 39510721 DOI: 10.1016/j.ajcnut.2024.09.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 09/11/2024] [Indexed: 11/15/2024] Open
Affiliation(s)
- Wanghong Xu
- Department of Epidemiology, Fudan University School of Public Health, Shanghai, China.
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Diniz F, Edgington-Giordano F, Ngo NYN, Caspi G, El-Dahr SS, Tortelote GG. Morphometric analysis of the intergenerational effects of protein restriction on nephron endowment in mice. Heliyon 2024; 10:e39552. [PMID: 39498088 PMCID: PMC11533620 DOI: 10.1016/j.heliyon.2024.e39552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 10/15/2024] [Accepted: 10/17/2024] [Indexed: 11/07/2024] Open
Abstract
Background Parental nutritional status is crucial in shaping offspring's kidney development. However, the association between a protein-restrictive diet and its intergenerational impact on kidney development remains unclear. Methods We conducted multigenerational morphometric measurements to investigate the effects of parental protein deprivation on offspring kidney development across four generations. F0 mice were divided into two groups and fed a normal protein diet (NPD) or a low-protein diet (LPD) for three weeks before mating and continued these diets throughout gestation and lactation. Body weight (BW), kidney weight (KW), KW/BW ratio, nephron counts, and blood pressure were assessed in F1 pups. To examine paternal effects, we bred CD1 females on an NPD with males on an LPD. BW, KW, KW/BW, and nephron counts were measured at P20. To measure the transgenerational effect of parental LPD on kidney development, F1 offspring (from parents on LPD) were fed NPD upon weaning. These F1 offspring were bred at 6 weeks of age to produce F2, F3 and F4 generations. Kidney metrics were evaluated across generations. Results The average body weight of P0 pups from parents on NPD was 1.61g, while pups from parental LPD weighed an average of 0.869g, a decrease of 54 % (p = 6.9e-11, Wilcoxon test). F1 from parental LPD have significantly smaller kidneys than the control, with an average combined kidney weight of 0.0082g versus 0.0129g, a 37 % decrease (p = 3.2e-02, Wilcoxon test). P20 BW and KW remained low in LPD offspring. These effects persisted for 4 generations (F1 to F4) with an average glomerular count reduction of roughly 20 %. F3 and F4 showed wider variability in glomerular counts but were not statistically significant compared to controls. Conclusions Both maternal and paternal LPD significantly affected offspring nephron endowment. Our study underscores the complex nature of nutritional transgenerational effects on kidney development, emphasizing the importance of both maternal and paternal dietary impacts on kidney development and the developmental origin of adult disease.
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Affiliation(s)
- Fabiola Diniz
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Francesca Edgington-Giordano
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Nguyen Yen Nhi Ngo
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Gal Caspi
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Samir S. El-Dahr
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Giovane G. Tortelote
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA
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Haberman M, Menashe T, Cohen N, Kisliouk T, Yadid T, Marco A, Meiri N, Weller A. Paternal high-fat diet affects weight and DNA methylation of their offspring. Sci Rep 2024; 14:19874. [PMID: 39191806 DOI: 10.1038/s41598-024-70438-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 08/16/2024] [Indexed: 08/29/2024] Open
Abstract
Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.
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Affiliation(s)
- Michal Haberman
- Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel
- Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel
- Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel
| | - Tzlil Menashe
- Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel
- Department of Psychology, Bar Ilan University, Ramat-Gan, Israel
| | - Nir Cohen
- Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel
- Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel
- Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel
| | - Tatiana Kisliouk
- Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel
| | - Tam Yadid
- Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel
- Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Asaf Marco
- Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
| | - Noam Meiri
- Institute of Animal Science, Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel.
| | - Aron Weller
- Gonda Multidisciplinary Brain Research Center, Bar Ilan University, Ramat-Gan, Israel
- Department of Psychology, Bar Ilan University, Ramat-Gan, Israel
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Charrier M, Lumineau S, George I, Meurisse M, Georgelin M, Palme R, Angelier F, Coustham V, Nicolle C, Bertin A, Darmaillacq AS, Dickel L, Guémené D, Calandreau L, Houdelier C. Maternal stress effects across generations in a precocial bird. ROYAL SOCIETY OPEN SCIENCE 2024; 11:231826. [PMID: 39205998 PMCID: PMC11349446 DOI: 10.1098/rsos.231826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/24/2024] [Indexed: 09/04/2024]
Abstract
Prenatal maternal stress (PMS) is known to shape the phenotype of the first generation offspring (F1) but according to some studies, it could also shape the phenotype of the offspring of the following generations. We previously showed in the Japanese quail that PMS increased the emotional reactivity of F1 offspring in relation to (i) a variation in the levels of some histone post-translational modification (H3K27me3) in their brains and (ii) a modulation of the hormonal composition of the eggs from which they hatched. Here, we wondered whether PMS could also influence the behaviour of the second (F2) and third (F3) generation offspring due to the persistence of the specific marks we identified. Using a principal component analysis, we found that PMS influenced F2 and F3 quail profiles with subtle differences between generations. It increased F2 neophobia, F3 fearfulness and F3 neophobia but only in females. Interestingly, we did not find any variations in the level of histone post-translational modification in F3 brains and we observed inconsistent modulations of androstenedione levels in F1 and F2 eggs. Although they may vary over generations, our results demonstrate that PMS can have phenotypical effects into the third generation.
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Affiliation(s)
- Marion Charrier
- Univ Rennes, CNRS, Normandie Univ, EthoS (Éthologie animale et humaine), UMR 6552, Rennes, France
- CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
- SYSAAF, Centre INRAE Val de Loire, 37380 Nouzilly, France
| | - Sophie Lumineau
- Univ Rennes, CNRS, Normandie Univ, EthoS (Éthologie animale et humaine), UMR 6552, Rennes, France
| | - Isabelle George
- Univ Rennes, CNRS, Normandie Univ, EthoS (Éthologie animale et humaine), UMR 6552, Rennes, France
| | - Maryse Meurisse
- CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
| | - Marion Georgelin
- CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
| | - Rupert Palme
- Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Frédéric Angelier
- Centre d'Etudes Biologiques de Chizé, CNRS-LRU, UMR 7372, 79360 Villiers en Bois, France
| | - Vincent Coustham
- INRAE, Université de Tours, BOA, 37380 Nouzilly, France
- INRAE, Université de Pau et des Pays de l'Adour, E2S UPPA, NUMEA, 64310 Saint-Pée-sur-Nivelle, France
| | - Céline Nicolle
- Univ Rennes, CNRS, Normandie Univ, EthoS (Éthologie animale et humaine), UMR 6552, Rennes, France
| | - Aline Bertin
- CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
| | - Anne-Sophie Darmaillacq
- Normandie University, UNICAEN, University of Rennes, CNRS, EthoS (Éthologie animale et humaine), UMR 6552, 14000 Caen, France
| | - Ludovic Dickel
- Normandie University, UNICAEN, University of Rennes, CNRS, EthoS (Éthologie animale et humaine), UMR 6552, 14000 Caen, France
| | - Daniel Guémené
- SYSAAF, Centre INRAE Val de Loire, 37380 Nouzilly, France
- INRAE, Université de Tours, BOA, 37380 Nouzilly, France
| | | | - Cécilia Houdelier
- Univ Rennes, CNRS, Normandie Univ, EthoS (Éthologie animale et humaine), UMR 6552, Rennes, France
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Adeshina KA, Ibrahim KG, Abubakar MB, Imam MU. Transgenerational inheritance of insulin resistance in offspring of white rice-fed female fruit flies. SCIENTIFIC AFRICAN 2024; 24:e02208. [DOI: 10.1016/j.sciaf.2024.e02208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
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Skowronski AA, Leibel RL, LeDuc CA. Neurodevelopmental Programming of Adiposity: Contributions to Obesity Risk. Endocr Rev 2024; 45:253-280. [PMID: 37971140 PMCID: PMC10911958 DOI: 10.1210/endrev/bnad031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/29/2023] [Accepted: 10/19/2023] [Indexed: 11/19/2023]
Abstract
This review analyzes the published evidence regarding maternal factors that influence the developmental programming of long-term adiposity in humans and animals via the central nervous system (CNS). We describe the physiological outcomes of perinatal underfeeding and overfeeding and explore potential mechanisms that may mediate the impact of such exposures on the development of feeding circuits within the CNS-including the influences of metabolic hormones and epigenetic changes. The perinatal environment, reflective of maternal nutritional status, contributes to the programming of offspring adiposity. The in utero and early postnatal periods represent critically sensitive developmental windows during which the hormonal and metabolic milieu affects the maturation of the hypothalamus. Maternal hyperglycemia is associated with increased transfer of glucose to the fetus driving fetal hyperinsulinemia. Elevated fetal insulin causes increased adiposity and consequently higher fetal circulating leptin concentration. Mechanistic studies in animal models indicate important roles of leptin and insulin in central and peripheral programming of adiposity, and suggest that optimal concentrations of these hormones are critical during early life. Additionally, the environmental milieu during development may be conveyed to progeny through epigenetic marks and these can potentially be vertically transmitted to subsequent generations. Thus, nutritional and metabolic/endocrine signals during perinatal development can have lifelong (and possibly multigenerational) impacts on offspring body weight regulation.
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Affiliation(s)
- Alicja A Skowronski
- Division of Molecular Genetics, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Rudolph L Leibel
- Division of Molecular Genetics, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Charles A LeDuc
- Division of Molecular Genetics, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA
- Naomi Berrie Diabetes Center, Columbia University Irving Medical Center, New York, NY 10032, USA
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Elgazzaz M, Berdasco C, Garai J, Baddoo M, Lu S, Daoud H, Zabaleta J, Mauvais-Jarvis F, Lazartigues E. Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring. Mol Metab 2024; 80:101864. [PMID: 38159883 PMCID: PMC10806294 DOI: 10.1016/j.molmet.2023.101864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/04/2023] [Accepted: 12/22/2023] [Indexed: 01/03/2024] Open
Abstract
OBJECTIVE Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. METHODS C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses. RESULTS Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFβ2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFβ2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFβ receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss. CONCLUSIONS Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way.
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Affiliation(s)
- Mona Elgazzaz
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, 41522, Egypt
| | - Clara Berdasco
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA
| | - Jone Garai
- Department of Interdisciplinary Oncology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Melody Baddoo
- Department of Pathology and Laboratory Medicine/Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Shiping Lu
- Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Hisham Daoud
- School of Computer and Cyber Sciences, Augusta University, Augusta, GA 30901, USA
| | - Jovanny Zabaleta
- Department of Interdisciplinary Oncology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Franck Mauvais-Jarvis
- Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Department of Medicine, Section of Endocrinology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Eric Lazartigues
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Health Care System, New Orleans, LA 70119, USA; Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
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12
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Mohanan A, Harilal SL, Plakkot B, Pottakkat B, Kanakkaparambil R. Nutritional Epigenetics and Gut Microbiome. EPIGENETICS AND HUMAN HEALTH 2024:121-159. [DOI: 10.1007/978-3-031-54215-2_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Tompkins JD. Transgenerational Epigenetic DNA Methylation Editing and Human Disease. Biomolecules 2023; 13:1684. [PMID: 38136557 PMCID: PMC10742326 DOI: 10.3390/biom13121684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
During gestation, maternal (F0), embryonic (F1), and migrating primordial germ cell (F2) genomes can be simultaneously exposed to environmental influences. Accumulating evidence suggests that operating epi- or above the genetic DNA sequence, covalent DNA methylation (DNAme) can be recorded onto DNA in response to environmental insults, some sites which escape normal germline erasure. These appear to intrinsically regulate future disease propensity, even transgenerationally. Thus, an organism's genome can undergo epigenetic adjustment based on environmental influences experienced by prior generations. During the earliest stages of mammalian development, the three-dimensional presentation of the genome is dramatically changed, and DNAme is removed genome wide. Why, then, do some pathological DNAme patterns appear to be heritable? Are these correctable? In the following sections, I review concepts of transgenerational epigenetics and recent work towards programming transgenerational DNAme. A framework for editing heritable DNAme and challenges are discussed, and ethics in human research is introduced.
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Affiliation(s)
- Joshua D Tompkins
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
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14
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Yang J, Tang R, Chen S, Chen Y, Yuan K, Huang R, Wang L. Exposure to high-sugar diet induces transgenerational changes in sweet sensitivity and feeding behavior via H3K27me3 reprogramming. eLife 2023; 12:e85365. [PMID: 37698486 PMCID: PMC10558205 DOI: 10.7554/elife.85365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 09/11/2023] [Indexed: 09/13/2023] Open
Abstract
Human health is facing a host of new threats linked to unbalanced diets, including high-sugar diet (HSD), which contributes to the development of both metabolic and behavioral disorders. Studies have shown that diet-induced metabolic dysfunctions can be transmitted to multiple generations of offspring and exert long-lasting health burden. Meanwhile, whether and how diet-induced behavioral abnormalities can be transmitted to the offspring remains largely unclear. Here, we showed that ancestral HSD exposure suppressed sweet sensitivity and feeding behavior in the offspring in Drosophila. These behavioral deficits were transmitted through the maternal germline and companied by the enhancement of H3K27me3 modifications. PCL-PRC2 complex, a major driver of H3K27 trimethylation, was upregulated by ancestral HSD exposure, and disrupting its activity eliminated the transgenerational inheritance of sweet sensitivity and feeding behavior deficits. Elevated H3K27me3 inhibited the expression of a transcriptional factor Cad and suppressed sweet sensitivity of the sweet-sensing gustatory neurons, reshaping the sweet perception and feeding behavior of the offspring. Taken together, we uncovered a novel molecular mechanism underlying behavioral abnormalities spanning multiple generations of offspring upon ancestral HSD exposure, which would contribute to the further understanding of long-term health risk of unbalanced diet.
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Affiliation(s)
- Jie Yang
- Life Sciences Institute, Zhejiang UniversityHangzhouChina
| | - Ruijun Tang
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital, and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South UniversityChangshaChina
| | - Shiye Chen
- Life Sciences Institute, Zhejiang UniversityHangzhouChina
| | - Yinan Chen
- Life Sciences Institute, Zhejiang UniversityHangzhouChina
| | - Kai Yuan
- Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital, and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South UniversityChangshaChina
- The Biobank of Xiangya Hospital, Xiangya Hospital, Central South UniversityChangshaChina
| | - Rui Huang
- Center for Neurointelligence, School of Medicine, Chongqing UniversityChongqingChina
- Institute of Molecular Physiology, Shenzhen Bay LaboratoryShenzhenChina
| | - Liming Wang
- Institute of Molecular Physiology, Shenzhen Bay LaboratoryShenzhenChina
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15
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Cinquina V, Keimpema E, Pollak DD, Harkany T. Adverse effects of gestational ω-3 and ω-6 polyunsaturated fatty acid imbalance on the programming of fetal brain development. J Neuroendocrinol 2023; 35:e13320. [PMID: 37497857 PMCID: PMC10909496 DOI: 10.1111/jne.13320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 05/18/2023] [Accepted: 06/10/2023] [Indexed: 07/28/2023]
Abstract
Obesity is a key medical challenge of our time. The increasing number of children born to overweight or obese women is alarming. During pregnancy, the circulation of the mother and her fetus interact to maintain the uninterrupted availability of essential nutrients for fetal organ development. In doing so, the mother's dietary preference determines the amount and composition of nutrients reaching the fetus. In particular, the availability of polyunsaturated fatty acids (PUFAs), chiefly their ω-3 and ω-6 subclasses, can change when pregnant women choose a specific diet. Here, we provide a succinct overview of PUFA biochemistry, including exchange routes between ω-3 and ω-6 PUFAs, the phenotypes, and probable neurodevelopmental disease associations of offspring born to mothers consuming specific PUFAs, and their mechanistic study in experimental models to typify signaling pathways, transcriptional, and epigenetic mechanisms by which PUFAs can imprint long-lasting modifications to brain structure and function. We emphasize that the ratio, rather than the amount of individual ω-3 or ω-6 PUFAs, might underpin physiologically correct cellular differentiation programs, be these for neurons or glia, during pregnancy. Thereupon, the PUFA-driven programming of the brain is contextualized for childhood obesity, metabolic, and endocrine illnesses.
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Affiliation(s)
- Valentina Cinquina
- Department of Molecular NeurosciencesCenter for Brain Research, Medical University of ViennaViennaAustria
| | - Erik Keimpema
- Department of Molecular NeurosciencesCenter for Brain Research, Medical University of ViennaViennaAustria
| | - Daniela D. Pollak
- Department of Neurophysiology and NeuropharmacologyCenter for Physiology and Pharmacology, Medical University of ViennaViennaAustria
| | - Tibor Harkany
- Department of Molecular NeurosciencesCenter for Brain Research, Medical University of ViennaViennaAustria
- Deaprtment of NeuroscienceBiomedicum 7D, Karolinska InstitutetStockholmSweden
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16
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Naomi R, Teoh SH, Halim S, Embong H, Hasain Z, Bahari H, Kumar J. Unraveling Obesity: Transgenerational Inheritance, Treatment Side Effects, Flavonoids, Mechanisms, Microbiota, Redox Balance, and Bioavailability-A Narrative Review. Antioxidants (Basel) 2023; 12:1549. [PMID: 37627544 PMCID: PMC10451614 DOI: 10.3390/antiox12081549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/02/2023] [Accepted: 07/06/2023] [Indexed: 08/27/2023] Open
Abstract
Obesity is known as a transgenerational vicious cycle and has become a global burden due to its unavoidable complications. Modern approaches to obesity management often involve the use of pharmaceutical drugs and surgeries that have been associated with negative side effects. In contrast, natural antioxidants, such as flavonoids, have emerged as a promising alternative due to their potential health benefits and minimal side effects. Thus, this narrative review explores the potential protective role of flavonoids as a natural antioxidant in managing obesity. To identify recent in vivo studies on the efficiency of flavonoids in managing obesity, a comprehensive search was conducted on Wiley Online Library, Scopus, Nature, and ScienceDirect. The search was limited to the past 10 years; from the search, we identified 31 articles to be further reviewed. Based on the reviewed articles, we concluded that flavonoids offer novel therapeutic strategies for preventing obesity and its associated co-morbidities. This is because the appropriate dosage of flavonoid compounds is able to reduce adipose tissue mass, the formation of intracellular free radicals, enhance endogenous antioxidant defences, modulate the redox balance, and reduce inflammatory signalling pathways. Thus, this review provides an insight into the domain of a natural product therapeutic approach for managing obesity and recapitulates the transgenerational inheritance of obesity, the current available treatments to manage obesity and its side effects, flavonoids and their sources, the molecular mechanism involved, the modulation of gut microbiota in obesity, redox balance, and the bioavailability of flavonoids. In toto, although flavonoids show promising positive outcome in managing obesity, a more comprehensive understanding of the molecular mechanisms responsible for the advantageous impacts of flavonoids-achieved through translation to clinical trials-would provide a novel approach to inculcating flavonoids in managing obesity in the future as this review is limited to animal studies.
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Affiliation(s)
- Ruth Naomi
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia;
| | - Soo Huat Teoh
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Malaysia;
| | - Shariff Halim
- Faculty of Health Sciences, University Technology Mara (UiTM) Pulau Pinang, Bertam Campus, Kepala Batas 13200, Malaysia;
| | - Hashim Embong
- Department of Emergency Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia;
| | - Zubaidah Hasain
- Unit of Physiology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia, Kuala Lumpur 57000, Malaysia
| | - Hasnah Bahari
- Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang 43400, Malaysia;
| | - Jaya Kumar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia
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Olivieri F, Prattichizzo F, Lattanzio F, Bonfigli AR, Spazzafumo L. Antifragility and antiinflammaging: Can they play a role for a healthy longevity? Ageing Res Rev 2023; 84:101836. [PMID: 36574863 DOI: 10.1016/j.arr.2022.101836] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/14/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
One of the most exciting challenges of the research on aging is to explain how the environmental factors interact with the genetic background to modulate the chances to reach the extreme limit of human life in healthy conditions. The complex epigenetic mechanisms can explain both the interaction between DNA and environmental factors, and the long-distance persistence of lifestyle effects, due to the so called "epigenetic memory". One of the most extensively investigated theories on aging focuses on the inflammatory responses, suggesting that the age-related progression of low-grade and therefore for long time subclinical, chronic, systemic, inflammatory process, named "inflammaging", could be the most relevant risk factor for the development and progression of the most common age-related diseases and ultimately of death. The results of many studies on long-lived people, especially on centenarians, suggested that healthy old people can cope with inflammaging upregulating the antiinflammaging responses. Overall, a genetic make-up coding for a strong antiinflammaging response and an age-related ability to remodel key metabolic pathways to cope with a plethora of antigens and stressors seem to be the best ways for reach the extreme limit of human lifespan in health status. In this scenario, we wondered if the antifragility concept, recently developed in the framework of business and risk analysis, could add some information to disentangle the heterogeneous nature of the aging process in human. The antifragility is the property of the complex systems to increase their performances because of high stress. Based on this theory we were wondering if some subjects could be able to modulate faster than others their epigenome to cope with a plethora of stressors during life, probably modulating the inflammatory and anti-inflammatory responses. In this framework, antifragility could share some common mechanisms with anti-inflammaging, modulating the ability to restrain the inflammatory responses, so that antifragility and antiinflammaging could be viewed as different pieces of the same puzzle, both impinging upon the chances to travel along the healthy aging trajectory.
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Affiliation(s)
- Fabiola Olivieri
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica Delle Marche, Ancona, Italy; Clinica di Medicina di Laboratorio e di Precisione, IRCCS INRCA, Ancona, Italy.
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18
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Švorcová J. Transgenerational Epigenetic Inheritance of Traumatic Experience in Mammals. Genes (Basel) 2023; 14:120. [PMID: 36672861 PMCID: PMC9859285 DOI: 10.3390/genes14010120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/04/2023] Open
Abstract
In recent years, we have seen an increasing amount of evidence pointing to the existence of a non-genetic heredity of the effects of events such as separation from parents, threat to life, or other traumatising experiences such as famine. This heredity is often mediated by epigenetic regulations of gene expression and may be transferred even across several generations. In this review, we focus on studies which involve transgenerational epigenetic inheritance (TEI), with a short detour to intergenerational studies focused on the inheritance of trauma or stressful experiences. The reviewed studies show a plethora of universal changes which stress exposure initiates on multiple levels of organisation ranging from hormonal production and the hypothalamic-pituitary-adrenal (HPA) axis modulation all the way to cognition, behaviour, or propensity to certain psychiatric or metabolic disorders. This review will also provide an overview of relevant methodology and difficulties linked to implementation of epigenetic studies. A better understanding of these processes may help us elucidate the evolutionary pathways which are at work in the course of emergence of the diseases and disorders associated with exposure to trauma, either direct or in a previous generation.
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Affiliation(s)
- Jana Švorcová
- Department of Philosophy and History of Science, Faculty of Science, Charles University, 128 00 Prague, Czech Republic
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19
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Verdikt R, Armstrong AA, Allard P. Transgenerational inheritance and its modulation by environmental cues. Curr Top Dev Biol 2022; 152:31-76. [PMID: 36707214 PMCID: PMC9940302 DOI: 10.1016/bs.ctdb.2022.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The epigenome plays an important role in shaping phenotypes. However, whether the environment can alter an organism's phenotype across several generations through epigenetic remodeling in the germline is still a highly debated topic. In this chapter, we briefly review the mechanisms of epigenetic inheritance and their connection with germline development before highlighting specific developmental windows of susceptibility to environmental cues. We further discuss the evidence of transgenerational inheritance to a range of different environmental cues, both epidemiological in humans and experimental in rodent models. Doing so, we pinpoint the current challenges in demonstrating transgenerational inheritance to environmental cues and offer insight in how recent technological advances may help deciphering the epigenetic mechanisms at play. Together, we draw a detailed picture of how our environment can influence our epigenomes, ultimately reshaping our phenotypes, in an extended theory of inheritance.
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Affiliation(s)
- Roxane Verdikt
- Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
| | - Abigail A Armstrong
- Department of Obstetrics/Gynecology and Division of Reproductive Endocrinology and Infertility, University of California, Los Angeles, CA, United States
| | - Patrick Allard
- Institute for Society and Genetics, University of California, Los Angeles, Los Angeles, CA, United States; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States.
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20
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Sheth VG, Sharma N, Kabeer SW, Tikoo K. Lactobacillus rhamnosus supplementation ameliorates high fat diet-induced epigenetic alterations and prevents its intergenerational inheritance. Life Sci 2022; 311:121151. [DOI: 10.1016/j.lfs.2022.121151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/20/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022]
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21
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Rajamoorthi A, LeDuc CA, Thaker VV. The metabolic conditioning of obesity: A review of the pathogenesis of obesity and the epigenetic pathways that "program" obesity from conception. Front Endocrinol (Lausanne) 2022; 13:1032491. [PMID: 36329895 PMCID: PMC9622759 DOI: 10.3389/fendo.2022.1032491] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
Understanding the developmental origins of health and disease is integral to overcome the global tide of obesity and its metabolic consequences, including atherosclerotic cardiovascular disease, type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease. The rising prevalence of obesity has been attributed, in part, to environmental factors including the globalization of the western diet and unhealthy lifestyle choices. In this review we argue that how and when such exposures come into play from conception significantly impact overall risk of obesity and later health outcomes. While the laws of thermodynamics dictate that obesity is caused by an imbalance between caloric intake and energy expenditure, the drivers of each of these may be laid down before the manifestation of the phenotype. We present evidence over the last half-century that suggests that the temporospatial evolution of obesity from intrauterine life and beyond is, in part, due to the conditioning of physiological processes at critical developmental periods that results in maladaptive responses to obesogenic exposures later in life. We begin the review by introducing studies that describe an association between perinatal factors and later risk of obesity. After a brief discussion of the pathogenesis of obesity, including the systemic regulation of appetite, adiposity, and basal metabolic rate, we delve into the mechanics of how intrauterine, postnatal and early childhood metabolic environments may contribute to adult obesity risk through the process of metabolic conditioning. Finally, we detail the specific epigenetic pathways identified both in preclinical and clinical studies that synergistically "program" obesity.
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Affiliation(s)
- Ananthi Rajamoorthi
- Department of Pediatrics, Columbia University Medical Center, New York, NY, United States
| | - Charles A. LeDuc
- Department of Pediatrics, Columbia University Medical Center, New York, NY, United States
- The Naomi Berrie Diabetes Center, Columbia University IRVING Medical Center, New York, NY, United States
| | - Vidhu V. Thaker
- Department of Pediatrics, Columbia University Medical Center, New York, NY, United States
- The Naomi Berrie Diabetes Center, Columbia University IRVING Medical Center, New York, NY, United States
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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22
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Magierecka A, Aristeidou A, Papaevripidou M, Gibson JK, Sloman KA, Metcalfe NB. Timing of reproduction modifies transgenerational effects of chronic exposure to stressors in an annual vertebrate. Proc Biol Sci 2022; 289:20221462. [PMID: 36476008 PMCID: PMC9554732 DOI: 10.1098/rspb.2022.1462] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Stressful environmental conditions can shape both an individual's phenotype and that of its offspring. However, little is known about transgenerational effects of chronic (as opposed to acute) stressors, nor whether these vary across the breeding lifespan of the parent. We exposed adult female (F0 generation) three-spined sticklebacks (Gasterosteus aculeatus) to chronic environmental stressors and compared their reproductive allocation with that of non-exposed controls across early, middle and late clutches produced within the single breeding season of this annual population. There was a seasonal trend (but no treatment difference) in F0 reproductive allocation, with increases in egg mass and fry size in late clutches. We then tested for transgenerational effects in the non-exposed F1 and F2 generations. Exposure of F0 females to stressors resulted in phenotypic change in their offspring and grandoffspring that were produced late in their breeding lifespan: F1 offspring produced from the late-season clutches of stressor-exposed F0 females had higher early life survival, and subsequently produced heavier eggs and F2 fry that were larger at hatching. Changed maternal allocation due to a combination of seasonal factors and environmental stressors can thus have a transgenerational effect by influencing the reproductive allocation of daughters, especially those born late in life.
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Affiliation(s)
- Agnieszka Magierecka
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow G12 8QQ, UK
| | - Antreas Aristeidou
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow G12 8QQ, UK
| | - Maria Papaevripidou
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow G12 8QQ, UK
| | - John K. Gibson
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow G12 8QQ, UK
| | - Katherine A. Sloman
- Institute for Biomedical and Environmental Health Research, University of the West of Scotland, Lanarkshire G72 0LH, UK
| | - Neil B. Metcalfe
- School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow G12 8QQ, UK
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23
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Inada A, Inada O. Differences in long-term effects of standard rodent diets on blood glucose and body weight of offspring. Diabetol Int 2022; 13:615-623. [PMID: 36117929 PMCID: PMC9477981 DOI: 10.1007/s13340-022-00578-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 03/10/2022] [Indexed: 01/03/2023]
Abstract
Standard rodent diets are similar and contain well-balanced components, such as crude protein, fat, fiber, and ash. However, it is not clear whether there are differences in their long-term effects on metabolism. Here, we investigated the effects of long-term feeding of major standard diets, CRF-1, CE-2, and FR-1 to wild-type (WT) C57BL/6 mice on the blood glucose levels and body weight gain of their offspring, which were raised on the same diet and in the same environment as the mothers. The offspring have been influenced by the maternal diet during the fetal and neonatal stages, and were maintained on the same diet thereafter (until 60 weeks of age). In the CE-2 group, the offspring showed stable blood glucose levels and had the lowest body weight. The FR1 group showed the lowest blood glucose level, but body weight was increased significantly compared to the CE-2 group. In the CRF-1 group, higher blood glucose levels were seen from the neonatal stage and body weight increased more rapidly than in the other groups. Next, to determine the effects of blood glucose level and housing pattern on food and water consumption, severely diabetic (hyperglycemic) inducible cAMP early repressor (ICER) transgenic (Tg) mice and littermate WT mice (normoglycemic) were fed CE-2 diet and housed individually or in groups. Food and water consumption of WT mice was independent of housing pattern, whereas Tg mice showed significantly increased food and water consumption when housed individually, compared to group housing, and this did not change at different ages. Thus, the selection of standard diet and rearing method can have a marked impact on experimental outcomes in experiments using mice and presumably mouse cells, especially in studies of metabolism, diabetes, and obesity.
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Affiliation(s)
- Akari Inada
- grid.177174.30000 0001 2242 4849Diabetes and Genes, Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- grid.417982.10000 0004 0623 246XPresent Address: Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation (IBRI), 6-3-7 Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan
| | - Oogi Inada
- grid.177174.30000 0001 2242 4849Diabetes and Genes, Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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MacKay H, Gunasekara CJ, Yam KY, Srisai D, Yalamanchili HK, Li Y, Chen R, Coarfa C, Waterland RA. Sex-specific epigenetic development in the mouse hypothalamic arcuate nucleus pinpoints human genomic regions associated with body mass index. SCIENCE ADVANCES 2022; 8:eabo3991. [PMID: 36170368 PMCID: PMC9519050 DOI: 10.1126/sciadv.abo3991] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 08/10/2022] [Indexed: 06/16/2023]
Abstract
Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and occurs in genomic regions enriched for heritability of body mass index in humans. Our results offer a potential explanation for both the limited ontogenic windows for and sex differences in sensitivity to developmental programming of obesity and provide a rich resource for epigenetic analyses of developmental programming of energy balance.
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Affiliation(s)
- Harry MacKay
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Chathura J. Gunasekara
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Kit-Yi Yam
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Dollada Srisai
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Hari Krishna Yalamanchili
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA
| | - Yumei Li
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Rui Chen
- Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Cristian Coarfa
- Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Robert A. Waterland
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
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25
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Aizawa S, Tochihara A, Yamamuro Y. Paternal high-fat diet alters triglyceride metabolism-related gene expression in liver and white adipose tissue of male mouse offspring. Biochem Biophys Rep 2022; 31:101330. [PMID: 35990577 PMCID: PMC9388883 DOI: 10.1016/j.bbrep.2022.101330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/03/2022] [Accepted: 08/11/2022] [Indexed: 11/24/2022] Open
Abstract
Obesity is a major public health problem, and its prevalence is progressively increasing worldwide. In addition, accumulating evidence suggests that diverse nutritional and metabolic disturbances including obesity can be transmitted from parents to offspring via transgenerational epigenetic inheritance. The previous reports have shown that paternal obesity has profound impacts on the development and metabolic health of their progeny. However, little information is available concerning the effects of paternal high-fat diet (HFD) exposure on triglyceride metabolism in the offspring. Therefore, we investigated the effects of paternal HFD on triglyceride metabolism and related gene expression in male mouse offspring. We found that paternal HFD exposure significantly increased the body weight, liver and epididymal white adipose tissue (eWAT) weights, and liver triglyceride content in male offspring, despite consuming control diet. In addition, paternal HFD exposure had induced changes in the mRNA expression of genes involved in lipid and triglyceride metabolism in the liver and eWAT. These findings indicate transgenerational inheritance from the paternal metabolic disturbance of triglyceride and support the effects of paternal lifestyle choices on offspring development and health later in life.
Paternal HFD exposure increased body weight, liver, and eWAT weights in male offspring. Paternal HFD exposure induced triglyceride metabolism disturbance in male offspring. Triglyceride metabolism-related gene expression in the offspring liver and eWAT was altered by paternal HFD exposure.
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26
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Low miR-92a-3p in oocytes mediates the multigenerational and transgenerational inheritance of poor cartilage quality in rat induced by prenatal dexamethasone exposure. Biochem Pharmacol 2022; 203:115196. [DOI: 10.1016/j.bcp.2022.115196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/23/2022] [Accepted: 07/26/2022] [Indexed: 11/18/2022]
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Tocantins C, Diniz MS, Grilo LF, Pereira SP. The birth of cardiac disease: Mechanisms linking gestational diabetes mellitus and early onset of cardiovascular disease in offspring. WIREs Mech Dis 2022; 14:e1555. [PMID: 35304833 DOI: 10.1002/wsbm.1555] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 02/10/2022] [Accepted: 03/09/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease (CVD) is the biggest killer worldwide, composing a major economic burden for health care systems. Obesity and diabetes are dual epidemics on the rise and major risk factors predisposing for CVD. Increased obesity- and diabetes-related incidence is now observed among children, adolescents, and young adults. Gestational diabetes mellitus (GDM) is the most common metabolic pregnancy disorder, and its prevalence is rapidly increasing. During pregnancies complicated by GDM, the offspring are exposed to a compromised intrauterine environment characterized by hyperglycemic periods. Unfavorable in utero conditions at critical periods of fetal cardiac development can produce developmental adaptations that remodel the cardiovascular system in a way that can contribute to adult-onset of heart disease due to the programming during fetal life. Epidemiological studies have reported increased cardiovascular complications among GDM-descendants, highlighting the urgent need to investigate and understand the mechanisms modulated during fetal development of in utero GDM-exposed offspring that predispose an individual to increased CVD during life. In this manuscript, we overview previous studies in this area and gather evidence linking GDM and CVD development in the offspring, providing new insights on novel mechanisms contributing to offspring CVD programming by GDM, from the role of maternal-fetal interactions to their impact on fetal cardiovascular development, how the perpetuation of cardiac programming is maintained in postnatal life, and advance the intergenerational implications contributing to increased CVD premature origin. Understanding the perpetuation of CVD can be the first step to manage and reverse this leading cause of morbidity and mortality. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Cardiovascular Diseases > Molecular and Cellular Physiology Metabolic Diseases > Genetics/Genomics/Epigenetics.
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Affiliation(s)
- Carolina Tocantins
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Mariana S Diniz
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Luís F Grilo
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Susana P Pereira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,Laboratory of Metabolism and Exercise (LametEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sport, University of Porto, Porto, Portugal
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28
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Gangisetty O, Chaudhary S, Palagani A, Sarkar DK. Transgenerational inheritance of fetal alcohol effects on proopiomelanocortin gene expression and methylation, cortisol response to stress, and anxiety-like behaviors in offspring for three generations in rats: Evidence for male germline transmission. PLoS One 2022; 17:e0263340. [PMID: 35143549 PMCID: PMC8830645 DOI: 10.1371/journal.pone.0263340] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/23/2021] [Indexed: 12/03/2022] Open
Abstract
Previously it has been shown that fetal alcohol exposure increases the stress response partly due to lowering stress regulatory proopiomelanocortin (Pomc) gene expression in the hypothalamus via epigenetic mechanisms for multiple generations in mixed-breed rats. In this study we assess the induction of heritable epigenetic changes of Pomc-related variants by fetal alcohol exposure in isogenic Fischer 344 rats. Using transgenerational breeding models and fetal alcohol exposure procedures, we determined changes in hypothalamic Pomc gene expression and its methylation levels, plasma corticosterone hormone response to restraint stress, and anxiety-like behaviors using elevated plus maze tests in fetal alcohol-exposed offspring for multiple generations in isogenic Fischer rats. Fetal alcohol-exposed male and female rat offspring showed significant deficits in POMC neuronal functions with increased Pomc gene methylation and reduced expression. These changes in POMC neuronal functions were associated with increased plasma corticosterone response to restraint stress and increased anxiety-like behavior. These effects of fetal alcohol exposure persisted in the F1, F2, and F3 progeny of the male germline but not of the female germline. These data suggest that fetal alcohol exposure induces heritable changes in Pomc-related variants involving stress hyperresponsiveness and anxiety-like behaviors which perpetuate into subsequent generations through the male germline via epigenetic modifications.
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Affiliation(s)
- Omkaram Gangisetty
- Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Shaista Chaudhary
- Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Ajay Palagani
- Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey, United States of America
| | - Dipak K. Sarkar
- Rutgers Endocrine Research Program, Department of Animal Sciences, Rutgers University, New Brunswick, New Jersey, United States of America
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Svoboda LK, Ishikawa T, Dolinoy DC. Developmental toxicant exposures and sex-specific effects on epigenetic programming and cardiovascular health across generations. ENVIRONMENTAL EPIGENETICS 2022; 8:dvac017. [PMID: 36325489 PMCID: PMC9600458 DOI: 10.1093/eep/dvac017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/12/2022] [Accepted: 10/01/2022] [Indexed: 05/15/2023]
Abstract
Despite substantial strides in diagnosis and treatment, cardiovascular diseases (CVDs) continue to represent the leading cause of death in the USA and around the world, resulting in significant morbidity and loss of productive years of life. It is increasingly evident that environmental exposures during early development can influence CVD risk across the life course. CVDs exhibit marked sexual dimorphism, but how sex interacts with environmental exposures to affect cardiovascular health is a critical and understudied area of environmental health. Emerging evidence suggests that developmental exposures may have multi- and transgenerational effects on cardiovascular health, with potential sex differences; however, further research in this important area is urgently needed. Lead (Pb), phthalate plasticizers, and perfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with numerous adverse human health effects. Notably, recent evidence suggests that developmental exposure to each of these toxicants has sex-specific effects on cardiovascular outcomes, but the underlying mechanisms, and their effects on future generations, require further investigation. This review article will highlight the role for the developmental environment in influencing cardiovascular health across generations, with a particular emphasis on sex differences and epigenetic mechanisms. In particular, we will focus on the current evidence for adverse multi and transgenerational effects of developmental exposures to Pb, phthalates, and PFAS and highlight areas where further research is needed.
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Affiliation(s)
- Laurie K Svoboda
- *Correspondence address. Environmental Health Sciences, University of Michigan, School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA. Tel: +734-764-2032; E-mail:
| | - Tomoko Ishikawa
- Environmental Health Sciences, University of Michigan, School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
| | - Dana C Dolinoy
- Environmental Health Sciences, University of Michigan, School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
- Nutritional Sciences, University of Michigan, School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA
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30
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Pool KR, Chazal F, Smith JT, Blache D. Estrogenic Pastures: A Source of Endocrine Disruption in Sheep Reproduction. Front Endocrinol (Lausanne) 2022; 13:880861. [PMID: 35574027 PMCID: PMC9097266 DOI: 10.3389/fendo.2022.880861] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Phytoestrogens can impact on reproductive health due to their structural similarity to estradiol. Initially identified in sheep consuming estrogenic pasture, phytoestrogens are known to influence reproductive capacity in numerous species. Estrogenic pastures continue to persist in sheep production systems, yet there has been little headway in our understanding of the underlying mechanisms that link phytoestrogens with compromised reproduction in sheep. Here we review the known and postulated actions of phytoestrogens on reproduction, with particular focus on competitive binding with nuclear and non-nuclear estrogen receptors, modifications to the epigenome, and the downstream impacts on normal physiological function. The review examines the evidence that phytoestrogens cause reproductive dysfunction in both the sexes, and that outcomes depend on the developmental period when an individual is exposed to phytoestrogen.
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31
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Anwer H, Morris MJ, Noble DWA, Nakagawa S, Lagisz M. Transgenerational effects of obesogenic diets in rodents: A meta-analysis. Obes Rev 2022; 23:e13342. [PMID: 34595817 DOI: 10.1111/obr.13342] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 12/22/2022]
Abstract
Obesity is a major health condition that affects millions worldwide. There is an increased interest in understanding the adverse outcomes associated with obesogenic diets. A multitude of studies have investigated the transgenerational impacts of maternal and parental obesogenic diets on subsequent generations of offspring, but results have largely been mixed. We conducted a systematic review and meta-analysis on rodent studies to elucidate how obesogenic diets impact the mean and variance of grand-offspring traits. Our study focused on transgenerational effects (i.e., F2 and F3 generations) in one-off and multigenerational exposure studies. From 33 included articles, we obtained 407 effect sizes representing pairwise comparisons of control and treatment grand-offspring groups pertaining to measures of body weight, adiposity, glucose, insulin, leptin, and triglycerides. We found evidence that male and female grand-offspring descended from grandparents exposed to an obesogenic diet displayed phenotypes consistent with metabolic syndrome, especially in cases where the obesogenic diet was continued across generations. Further, we found stronger evidence for the effects of grand-maternal than grand-paternal exposure on grand-offspring traits. A high-fat diet in one-off exposure studies did not seem to impact phenotypic variation, whereas in multigenerational exposure studies it reduced variation in several traits.
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Affiliation(s)
- Hamza Anwer
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Margaret J Morris
- School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Daniel W A Noble
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
- Division of Ecology and Evolution, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Shinichi Nakagawa
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Malgorzata Lagisz
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
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32
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Brown SG, Brenman-Suttner DB, McInnes AG, Lew K, Moehring AJ, Bauer JH, Simon AF. Inheritance of pheromone profiles from aged D. melanogaster. MICROPUBLICATION BIOLOGY 2021; 2021:10.17912/micropub.biology.000459. [PMID: 34723148 PMCID: PMC8553430 DOI: 10.17912/micropub.biology.000459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 12/02/2022]
Abstract
Through aging, D. melanogaster males and females change their social spacing. Flies are initially more social, but reduce sociability as they grow older. This preferred social space is inherited in their progeny. Here, we report that in females, the profiles of cuticular hydrocarbons (CHC), which are known to promote social interaction between individuals, similarly are affected by age. Importantly, for a subset of those CHC, the progeny's CHC levels are comparable to those of their parents, suggesting that parental age influences offspring CHC expression. Those data establish a foundation to identify the relationship between CHC levels and social spacing, and to understand the mechanisms of the inheritance of complex traits.
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Affiliation(s)
- Samuel G Brown
- Department of Chemistry, California State University Sacramento, CA, USA
| | - Dova B Brenman-Suttner
- Current: Department of Biology, York University, Toronto, ON, Canada,
Department of Biology, University of Western Ontario, London, ON, Canada
| | - Abigail G McInnes
- Department of Chemistry, California State University Sacramento, CA, USA
| | - Katlynn Lew
- Department of Chemistry, California State University Sacramento, CA, USA
| | - Amanda J Moehring
- Department of Biology, University of Western Ontario, London, ON, Canada
| | - Johannes H Bauer
- Department of Chemistry, California State University Sacramento, CA, USA
| | - Anne F Simon
- Department of Biology, University of Western Ontario, London, ON, Canada,
Correspondence to: Anne F Simon ()
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33
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Cai S, Quan S, Yang G, Chen M, Ye Q, Wang G, Yu H, Wang Y, Qiao S, Zeng X. Nutritional Status Impacts Epigenetic Regulation in Early Embryo Development: A Scoping Review. Adv Nutr 2021; 12:1877-1892. [PMID: 33873200 PMCID: PMC8483970 DOI: 10.1093/advances/nmab038] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 02/03/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
With the increasing maternal age and the use of assisted reproductive technology in various countries worldwide, the influence of epigenetic modification on embryonic development is increasingly notable and prominent. Epigenetic modification disorders caused by various nutritional imbalance would cause embryonic development abnormalities and even have an indelible impact on health in adulthood. In this scoping review, we summarize the main epigenetic modifications in mammals and the synergies among different epigenetic modifications, especially DNA methylation, histone acetylation, and histone methylation. We performed an in-depth analysis of the regulation of various epigenetic modifications on mammals from zygote formation to cleavage stage and blastocyst stage, and reviewed the modifications of key sites and their potential molecular mechanisms. In addition, we discuss the effects of nutrition (protein, lipids, and one-carbon metabolism) on epigenetic modification in embryos and emphasize the importance of various nutrients in embryonic development and epigenetics during pregnancy. Failures in epigenetic regulation have been implicated in mammalian and human early embryo loss and disease. With the use of reproductive technologies, it is becoming even more important to establish developmentally competent embryos. Therefore, it is essential to evaluate the extent to which embryos are sensitive to these epigenetic modifications and nutrition status. Understanding the epigenetic regulation of early embryo development will help us make better use of reproductive technologies and nutrition regulation to improve reproductive health in mammals.
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Affiliation(s)
- Shuang Cai
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Shuang Quan
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Guangxin Yang
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Meixia Chen
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Qianhong Ye
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Gang Wang
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Haitao Yu
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Yuming Wang
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Shiyan Qiao
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
| | - Xiangfang Zeng
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Beijing Key Laboratory of Bio-feed Additives, China Agricultural University, Beijing, China
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Lee K, Hardy DB. Metabolic Consequences of Gestational Cannabinoid Exposure. Int J Mol Sci 2021; 22:9528. [PMID: 34502436 PMCID: PMC8430813 DOI: 10.3390/ijms22179528] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 12/20/2022] Open
Abstract
Up to 20% of pregnant women ages 18-24 consume cannabis during pregnancy. Moreover, clinical studies indicate that cannabis consumption during pregnancy leads to fetal growth restriction (FGR), which is associated with an increased risk of obesity, type II diabetes (T2D), and cardiovascular disease in the offspring. This is of great concern considering that the concentration of Δ9- tetrahydrocannabinol (Δ9-THC), a major psychoactive component of cannabis, has doubled over the last decade and can readily cross the placenta and enter fetal circulation, with the potential to negatively impact fetal development via the endocannabinoid (eCB) system. Cannabis exposure in utero could also lead to FGR via placental insufficiency. In this review, we aim to examine current pre-clinical and clinical findings on the direct effects of exposure to cannabis and its constituents on fetal development as well as indirect effects, namely placental insufficiency, on postnatal metabolic diseases.
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Affiliation(s)
- Kendrick Lee
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5C1, Canada;
- The Children’s Health Research Institute, The Lawson Health Research Institute, London, ON N6A 5C1, Canada
| | - Daniel B. Hardy
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5C1, Canada;
- The Children’s Health Research Institute, The Lawson Health Research Institute, London, ON N6A 5C1, Canada
- Department of Obstetrics and Gynaecology, Schulich School of Medicine and Dentistry, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5C1, Canada
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35
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Gawliński D, Gawlińska K, Smaga I. Maternal High-Fat Diet Modulates Cnr1 Gene Expression in Male Rat Offspring. Nutrients 2021; 13:nu13082885. [PMID: 34445045 PMCID: PMC8402185 DOI: 10.3390/nu13082885] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/13/2021] [Accepted: 08/20/2021] [Indexed: 01/07/2023] Open
Abstract
In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring’s brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype.
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36
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Pankey CL, Odhiambo JF, Smith AM, Ford SP. Effects of maternal obesity in an ovine model on metabolic outcomes in F2 adults and F3 neonates. Domest Anim Endocrinol 2021; 76:106628. [PMID: 33895699 PMCID: PMC8169583 DOI: 10.1016/j.domaniend.2021.106628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 10/21/2022]
Abstract
Accumulating evidence suggests that indications of metabolic syndrome can be inherited through the germline as a result of maternal obesity. We hypothesized that diet-induced maternal obesity during gestation would program metabolic consequences for multiple generations of offspring, even when first, second, and third generation offspring (F1, F2, F3, respectively) were fed only to requirements. Control (CON) and obese (OB) ewes (generation 0; F0) were bred to a single ram to produce the first generation of offspring (F1). From 60 d prior to conception through term, CONF0 ate 100% National Research Council recommendations (NRC), while OBF0 ewes ate 150% NRC. All F1, F2, and F3 ate 100% NRC after weaning. All mature F1 ewes were bred to a single ram to generate CONF2 (n = 6) and OBF2 (n = 10). All mature F2 ewes were bred to a single ram to produce CONF3 (n = 6) and OBF3 (n = 10). OBF2 ewes exhibited greater (P < 0.0001) plasma cortisol than CONF2 throughout gestation. A glucose tolerance test at 90% gestation revealed OBF2 ewes had higher (P < 0.05) insulin response with similar glucose, resulting in greater (P < 0.05) insulin resistance. OBF3 neonates had similar weight, lean mass, and body fat mass to CONF3 neonates. These data suggest that multigenerational programming of adverse metabolic phenotypes occur in association with F0 maternal obesity, yet adiposity may return to CON levels in F3 neonates.
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Affiliation(s)
- C L Pankey
- Department of Biomedical Science, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA; Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA.
| | - J F Odhiambo
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA; College of Agriculture and Food Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL, USA
| | - A M Smith
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA
| | - S P Ford
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA
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37
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Breton CV, Landon R, Kahn LG, Enlow MB, Peterson AK, Bastain T, Braun J, Comstock SS, Duarte CS, Hipwell A, Ji H, LaSalle JM, Miller RL, Musci R, Posner J, Schmidt R, Suglia SF, Tung I, Weisenberger D, Zhu Y, Fry R. Exploring the evidence for epigenetic regulation of environmental influences on child health across generations. Commun Biol 2021; 4:769. [PMID: 34158610 PMCID: PMC8219763 DOI: 10.1038/s42003-021-02316-6] [Citation(s) in RCA: 94] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 06/03/2021] [Indexed: 02/08/2023] Open
Abstract
Environmental exposures, psychosocial stressors and nutrition are all potentially important influences that may impact health outcomes directly or via interactions with the genome or epigenome over generations. While there have been clear successes in large-scale human genetic studies in recent decades, there is still a substantial amount of missing heritability to be elucidated for complex childhood disorders. Mounting evidence, primarily in animals, suggests environmental exposures may generate or perpetuate altered health outcomes across one or more generations. One putative mechanism for these environmental health effects is via altered epigenetic regulation. This review highlights the current epidemiologic literature and supporting animal studies that describe intergenerational and transgenerational health effects of environmental exposures. Both maternal and paternal exposures and transmission patterns are considered, with attention paid to the attendant ethical, legal and social implications.
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Affiliation(s)
- Carrie V Breton
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Remy Landon
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Linda G Kahn
- Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, USA
| | - Michelle Bosquet Enlow
- Department of Psychiatry, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Alicia K Peterson
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Theresa Bastain
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Joseph Braun
- Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA
| | - Sarah S Comstock
- Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI, USA
| | - Cristiane S Duarte
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, NY, USA
| | - Alison Hipwell
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hong Ji
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, California National Primate Research Center, University of California, Davis, Davis, CA, USA
| | - Janine M LaSalle
- Department of Medical Microbiology and Immunology, MIND Institute, Genome Center, University of California, Davis, Davis, CA, USA
| | | | - Rashelle Musci
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Jonathan Posner
- Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, NY, USA
| | - Rebecca Schmidt
- Department of Public Health Sciences, UC Davis School of Medicine, Davis, CA, USA
| | | | - Irene Tung
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Daniel Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
| | - Yeyi Zhu
- Division of Research, Kaiser Permanente Northern California and Department of Epidemiology and Biostatistics, University of California, San Francisco, Oakland, CA, USA
| | - Rebecca Fry
- Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, UNC Chapel Hill, Chapel Hill, NC, USA
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Lecoutre S, Maqdasy S, Breton C. Maternal obesity as a risk factor for developing diabetes in offspring: An epigenetic point of view. World J Diabetes 2021; 12:366-382. [PMID: 33889285 PMCID: PMC8040079 DOI: 10.4239/wjd.v12.i4.366] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 01/30/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
According to the developmental origin of health and disease concept, the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. In particular, maternal obesity and neonatal accelerated growth predispose offspring to overweight and type 2 diabetes (T2D) in adulthood. This concept mainly relies on the developmental plasticity of adipose tissue and pancreatic β-cell programming in response to suboptimal milieu during the perinatal period. These changes result in unhealthy hypertrophic adipocytes with decreased capacity to store fat, low-grade inflammation and loss of insulin-producing pancreatic β-cells. Over the past years, many efforts have been made to understand how maternal obesity induces long-lasting adipose tissue and pancreatic β-cell dysfunction in offspring and what are the molecular basis of the transgenerational inheritance of T2D. In particular, rodent studies have shed light on the role of epigenetic mechanisms in linking maternal nutritional manipulations to the risk for T2D in adulthood. In this review, we discuss epigenetic adipocyte and β-cell remodeling during development in the progeny of obese mothers and the persistence of these marks as a basis of obesity and T2D predisposition.
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Affiliation(s)
- Simon Lecoutre
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141-86, Sweden
- University of Lille, EA4489, Maternal Malnutrition and Programming of Metabolic Diseases, Lille 59000, France
| | - Salwan Maqdasy
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141-86, Sweden
- Clermont-Ferrand CHU, Department of Endocrinology, Diabetology and Metabolic Diseases, Clermont-Ferrand 63003, France
| | - Christophe Breton
- University of Lille, EA4489, Maternal Malnutrition and Programming of Metabolic Diseases, Lille 59000, France
- U1283-UMR8199-EGID, University of Lille, Institut National de la Santé Et de la Recherche Médicale, Centre National de la Recherche Scientifique, Lille 59000, France
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Hossin MZ, Falkstedt D, Allebeck P, Mishra G, Koupil I. Early life programming of adult ischemic heart disease within and across generations: The role of the socioeconomic context. Soc Sci Med 2021; 275:113811. [PMID: 33713928 DOI: 10.1016/j.socscimed.2021.113811] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 01/22/2021] [Accepted: 02/27/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND The developmental origins of ischemic heart disease (IHD) have been widely documented but little is known about their persistence across more than one generation. This study aimed to investigate whether the effects of early life disadvantages on adult IHD have changed between generations and are mediated by adult socioeconomic circumstances, and further explore the transgenerational effects of grandparental and parental exposures to disadvantaged circumstances on adult offspring's IHD. METHODS We used register-based data from the Uppsala Multigenerational Study, Sweden. The study populations were the parents born 1915-1929 and their offspring born 1932-1972 with available obstetric data. The offspring were further linked to grandparents who had their socioeconomic and demographic data recorded. The outcome was incident IHD assessed at ages 32-75 during a follow-up from January 1, 1964 till December 31, 2008. The exposures included birthweight standardized-for-gestational age, ponderal index, gestational length, and parental socioeconomic position (SEP). Education and income were analyzed as mediators. Potential transgenerational associations were explored by linking offspring IHD to parents' standardized birthweight and gestational length, grandparental SEP, and to grandmothers' age, parity, and marital status at parental birth. All associations were examined in Cox proportional hazard regression models. RESULTS Lower standardized birthweight and lower parental SEP were found to be associated with higher IHD rates in both generations, with no evidence of effect modification by generation. Education and income did not mediate the association between standardized birthweight and IHD. Disadvantaged grandparental SEP, younger and older childbearing ages of grandmothers, and paternal preterm birth affected offspring's IHD independent of parental education, income, or IHD history. CONCLUSIONS The findings point to similar magnitudes of IHD inequalities by early life disadvantages across two historical periods and the existence of transgenerational effects on IHD. Epigenetic dysregulation involving the germline is a plausible candidate mechanism underlying the transgenerational associations that warrant further research.
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Affiliation(s)
| | - Daniel Falkstedt
- Department of Global Public Health, Karolinska Institute, Stockholm, Sweden.
| | - Peter Allebeck
- Department of Global Public Health, Karolinska Institute, Stockholm, Sweden.
| | - Gita Mishra
- School of Public Health, The University of Queensland, Herston, Australia.
| | - Ilona Koupil
- Department of Global Public Health, Karolinska Institute, Stockholm, Sweden; Department of Public Health Sciences, Stockholm University, Stockholm, Sweden.
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40
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Peleg-Raibstein D. Understanding the Link Between Maternal Overnutrition, Cardio-Metabolic Dysfunction and Cognitive Aging. Front Neurosci 2021; 15:645569. [PMID: 33716660 PMCID: PMC7953988 DOI: 10.3389/fnins.2021.645569] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/10/2021] [Indexed: 12/16/2022] Open
Abstract
Obesity has long been identified as a global epidemic with major health implications such as diabetes and cardiovascular disease. Maternal overnutrition leads to significant health issues in industrial countries and is one of the risk factors for the development of obesity and related disorders in the progeny. The wide accessibility of junk food in recent years is one of the major causes of obesity, as it is low in nutrient content and usually high in salt, sugar, fat, and calories. An excess of nutrients during fetal life not only has immediate effects on the fetus, including increased growth and fat deposition in utero, but also has long-term health consequences. Based on human studies, it is difficult to discern between genetic and environmental contributions to the risk of disease in future generations. Consequently, animal models are essential for studying the impact of maternal overnutrition on the developing offspring. Recently, animal models provided some insight into the physiological mechanisms that underlie developmental programming. Most of the studies employed thus far have focused only on obesity and metabolic dysfunctions in the offspring. These studies have advanced our understanding of how maternal overnutrition in the form of high-fat diet exposure can lead to an increased risk of obesity in the offspring, but many questions remain open. How maternal overnutrition may increase the risk of developing brain pathology such as cognitive disabilities in the offspring and increase the risk to develop metabolic disorders later in life? Further, does maternal overnutrition exacerbate cognitive- and cardio-metabolic aging in the offspring?
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Affiliation(s)
- Daria Peleg-Raibstein
- Laboratory of Neurobehavioural Dynamics, Institute for Neuroscience, Department of Health Sciences and Technology, ETH Zürich, Zurich, Switzerland
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41
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De Serrano AR, Hughes KA, Rodd FH. Paternal exposure to a common pharmaceutical (Ritalin) has transgenerational effects on the behaviour of Trinidadian guppies. Sci Rep 2021; 11:3985. [PMID: 33597600 PMCID: PMC7889922 DOI: 10.1038/s41598-021-83448-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 02/02/2021] [Indexed: 01/04/2023] Open
Abstract
Evidence is emerging that paternal effects, the nongenetic influence of fathers on their offspring, can be transgenerational, spanning several generations. Methylphenidate hydrochloride (MPH; e.g. Ritalin) is a dopaminergic drug that is highly prescribed to adolescent males for the treatment of Attention-deficit/hyperactivity disorder. It has been suggested that MPH could cause transgenerational effects because MPH can affect the male germline in rodents and because paternal effects have been observed in individuals taking similar drugs (e.g. cocaine). Despite these concerns, the transgenerational effects of paternal MPH exposure are unknown. Therefore, we exposed male and female Trinidadian guppies (Poecilia reticulata) to a low, chronic dose of MPH and observed that MPH affected the anxiety/exploratory behaviour of males, but not females. Because of this male-specific effect, we investigated the transgenerational effects of MPH through the paternal line. We observed behavioural effects of paternal MPH exposure on offspring and great-grandoffspring that were not directly administered the drug, making this the first study to demonstrate that paternal MPH exposure can affect descendants. These effects were not due to differential mortality or fecundity between control and MPH lines. These results highlight the transgenerational potential of MPH.
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Affiliation(s)
- Alex R De Serrano
- Department of Ecology and Evolutionary Biology, University of Toronto, 25 Willcocks St, Toronto, ON, M5S 3B2, Canada.
| | - Kimberly A Hughes
- Department of Biological Science, Florida State University, 319 Stadium Dr, Tallahassee, FL, 32304, USA
| | - F Helen Rodd
- Department of Ecology and Evolutionary Biology, University of Toronto, 25 Willcocks St, Toronto, ON, M5S 3B2, Canada
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42
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Barański M, Średnicka-Tober D, Rempelos L, Hasanaliyeva G, Gromadzka-Ostrowska J, Skwarło-Sońta K, Królikowski T, Rembiałkowska E, Hajslova J, Schulzova V, Cakmak I, Ozturk L, Hallmann E, Seal C, Iversen PO, Vigar V, Leifert C. Feed Composition Differences Resulting from Organic and Conventional Farming Practices Affect Physiological Parameters in Wistar Rats-Results from a Factorial, Two-Generation Dietary Intervention Trial. Nutrients 2021; 13:377. [PMID: 33530419 PMCID: PMC7911726 DOI: 10.3390/nu13020377] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/15/2021] [Accepted: 01/21/2021] [Indexed: 12/18/2022] Open
Abstract
Recent human cohort studies reported positive associations between organic food consumption and a lower incidence of obesity, cancer, and several other diseases. However, there are very few animal and human dietary intervention studies that provide supporting evidence or a mechanistic understanding of these associations. Here we report results from a two-generation, dietary intervention study with male Wistar rats to identify the effects of feeds made from organic and conventional crops on growth, hormonal, and immune system parameters that are known to affect the risk of a number of chronic, non-communicable diseases in animals and humans. A 2 × 2 factorial design was used to separate the effects of contrasting crop protection methods (use or non-use of synthetic chemical pesticides) and fertilizers (mineral nitrogen, phosphorus and potassium (NPK) fertilizers vs. manure use) applied in conventional and organic crop production. Conventional, pesticide-based crop protection resulted in significantly lower fiber, polyphenol, flavonoid, and lutein, but higher lipid, aldicarb, and diquat concentrations in animal feeds. Conventional, mineral NPK-based fertilization resulted in significantly lower polyphenol, but higher cadmium and protein concentrations in feeds. Feed composition differences resulting from the use of pesticides and/or mineral NPK-fertilizer had a significant effect on feed intake, weight gain, plasma hormone, and immunoglobulin concentrations, and lymphocyte proliferation in both generations of rats and in the second generation also on the body weight at weaning. Results suggest that relatively small changes in dietary intakes of (a) protein, lipids, and fiber, (b) toxic and/or endocrine-disrupting pesticides and metals, and (c) polyphenols and other antioxidants (resulting from pesticide and/or mineral NPK-fertilizer use) had complex and often interactive effects on endocrine, immune systems and growth parameters in rats. However, the physiological responses to contrasting feed composition/intake profiles differed substantially between the first and second generations of rats. This may indicate epigenetic programming and/or the generation of "adaptive" phenotypes and should be investigated further.
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Affiliation(s)
- Marcin Barański
- Department of Animal Physiology, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland
- Laboratory of Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warsaw, Poland
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland
- Nafferton Ecological Farming Group, Food and Rural Development, School of Agriculture, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK
| | - Dominika Średnicka-Tober
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland
- Nafferton Ecological Farming Group, Food and Rural Development, School of Agriculture, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK
| | - Leonidas Rempelos
- Nafferton Ecological Farming Group, Food and Rural Development, School of Agriculture, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK
| | - Gultakin Hasanaliyeva
- Nafferton Ecological Farming Group, Food and Rural Development, School of Agriculture, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK
- Department of Sustainable Crop and Food Protection, Food and Environmental Sciences, Faculty of Agriculture, Universita Catollica del Sacro Cuore, I-29122 Piacenza, Italy
| | - Joanna Gromadzka-Ostrowska
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland
| | - Krystyna Skwarło-Sońta
- Department of Animal Physiology, Faculty of Biology, University of Warsaw, 02-096 Warsaw, Poland
| | - Tomasz Królikowski
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland
| | - Ewa Rembiałkowska
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland
| | - Jana Hajslova
- Department of Food Analysis and Nutrition, Institute of Chemical Technology, UCT Prague, 166 28 Prague, Czech Republic
| | - Vera Schulzova
- Department of Food Analysis and Nutrition, Institute of Chemical Technology, UCT Prague, 166 28 Prague, Czech Republic
| | - Ismail Cakmak
- Faculty of Engineering and Natural Sciences, Sabanci University, 34956 Istanbul, Turkey
| | - Levent Ozturk
- Faculty of Engineering and Natural Sciences, Sabanci University, 34956 Istanbul, Turkey
| | - Ewelina Hallmann
- Institute of Human Nutrition Sciences, Warsaw University of Life Sciences, Nowoursynowska 159c, 02-776 Warsaw, Poland
| | - Chris Seal
- Human Nutrition Research Centre, Institute of Cellular Medicine, Newcastle upon Tyne NE2 4HH, UK
| | - Per Ole Iversen
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway
- Department of Haematology, Oslo University Hospital, 0424 Oslo, Norway
| | - Vanessa Vigar
- NatMed, Southern Cross University, Military Rd., Lismore, NSW 2480, Australia
| | - Carlo Leifert
- Nafferton Ecological Farming Group, Food and Rural Development, School of Agriculture, Newcastle University, Newcastle upon Tyne, Tyne and Wear NE1 7RU, UK
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway
- SCU Plant Science, Southern Cross University, Military Rd., Lismore, NSW 2480, Australia
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Pant R, Firmal P, Shah VK, Alam A, Chattopadhyay S. Epigenetic Regulation of Adipogenesis in Development of Metabolic Syndrome. Front Cell Dev Biol 2021; 8:619888. [PMID: 33511131 PMCID: PMC7835429 DOI: 10.3389/fcell.2020.619888] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. Pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. In this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. Impairment in the adipocyte function occurs due to individuals' genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. Moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. Therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.
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Affiliation(s)
- Richa Pant
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Priyanka Firmal
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Vibhuti Kumar Shah
- National Centre for Cell Science, SP Pune University Campus, Pune, India
| | - Aftab Alam
- Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Samit Chattopadhyay
- National Centre for Cell Science, SP Pune University Campus, Pune, India.,Department of Biological Sciences, BITS Pilani, Goa, India
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44
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Lin C, Lin Y, Luo J, Yu J, Cheng Y, Wu X, Lin L, Lin Y. Maternal High-Fat Diet Multigenerationally Impairs Hippocampal Synaptic Plasticity and Memory in Male Rat Offspring. Endocrinology 2021; 162:bqaa214. [PMID: 33211807 DOI: 10.1210/endocr/bqaa214] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Indexed: 12/14/2022]
Abstract
As advances are made in the field of developmental origins of health and disease, there is an emphasis on long-term influence of maternal environmental factors on offspring health. Maternal high-fat diet (HFD) consumption has been suggested to exert detrimental effects on cognitive function in offspring, but whether HFD-dependent brain remodeling can be transmitted to the next generations is still unclear. This study tested the hypothesis that HFD consumption during rat pregnancy and lactation multigenerationally influences male offspring hippocampal synaptic plasticity and cognitive function. We observed that hippocampus-dependent learning and memory was impaired in 3 generations from HFD-fed maternal ancestors (referred as F1-F3), as assessed by novel object recognition and Morris water maze tests. Moreover, maternal HFD exposure also affected electrophysiological and ultrastructure measures of hippocampal synaptic plasticity across generations. We observed that intranasal insulin replacement partially rescued hippocampal synaptic plasticity and cognitive deficits in F3 rats, suggesting central insulin resistance may play an important role in maternal diet-induced neuroplasticity impairment. Furthermore, maternal HFD exposure enhanced the palmitoylation of GluA1 critically involved in long-term potentiation induction, while palmitoylation inhibitor 2-bromopalmitate counteracts GluA1 hyperpalmitoylation and partially abolishes the detrimental effects of maternal diet on learning and memory in F3 offspring. Importantly, maternal HFD-dependent GluA1 hyperpalmitoylation was reversed by insulin replacement. Taken together, our data suggest that maternal HFD exposure multigenerationally influences adult male offspring hippocampal synaptic plasticity and cognitive performance, and central insulin resistance may serve as the cross-talk between maternal diet and cognitive impairment across generations.
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Affiliation(s)
- Cheng Lin
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - YanYan Lin
- Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ji Luo
- Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - JunRu Yu
- Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Neurology, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - YaNi Cheng
- Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - XiaoYun Wu
- Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Lin Lin
- Department of Gynecology and Obstetrics, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, China
| | - YuanShao Lin
- Department of Neurology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Zatecka E, Bohuslavova R, Valaskova E, Margaryan H, Elzeinova F, Kubatova A, Hylmarova S, Peknicova J, Pavlinkova G. The Transgenerational Transmission of the Paternal Type 2 Diabetes-Induced Subfertility Phenotype. Front Endocrinol (Lausanne) 2021; 12:763863. [PMID: 34803926 PMCID: PMC8602877 DOI: 10.3389/fendo.2021.763863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/20/2021] [Indexed: 12/26/2022] Open
Abstract
Diabetes is a chronic metabolic disorder characterized by hyperglycemia and associated with many health complications due to the long-term damage and dysfunction of various organs. A consequential complication of diabetes in men is reproductive dysfunction, reduced fertility, and poor reproductive outcomes. However, the molecular mechanisms responsible for diabetic environment-induced sperm damage and overall decreased reproductive outcomes are not fully established. We evaluated the effects of type 2 diabetes exposure on the reproductive system and the reproductive outcomes of males and their male offspring, using a mouse model. We demonstrate that paternal exposure to type 2 diabetes mediates intergenerational and transgenerational effects on the reproductive health of the offspring, especially on sperm quality, and on metabolic characteristics. Given the transgenerational impairment of reproductive and metabolic parameters through two generations, these changes likely take the form of inherited epigenetic marks through the germline. Our results emphasize the importance of improving metabolic health not only in women of reproductive age, but also in potential fathers, in order to reduce the negative impacts of diabetes on subsequent generations.
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Affiliation(s)
- Eva Zatecka
- Laboratory of Reproductive Biology, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Romana Bohuslavova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Eliska Valaskova
- Laboratory of Reproductive Biology, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Hasmik Margaryan
- Laboratory of Reproductive Biology, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Fatima Elzeinova
- Laboratory of Reproductive Biology, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Alena Kubatova
- Laboratory of Reproductive Biology, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Simona Hylmarova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
- Department of Internal Medicine, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czechia
| | - Jana Peknicova
- Laboratory of Reproductive Biology, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
| | - Gabriela Pavlinkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology Czech Academy of Sciences (CAS), Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec (BIOCEV), Vestec, Czechia
- *Correspondence: Gabriela Pavlinkova,
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Eberle C, Kirchner MF, Herden R, Stichling S. Paternal metabolic and cardiovascular programming of their offspring: A systematic scoping review. PLoS One 2020; 15:e0244826. [PMID: 33382823 PMCID: PMC7775047 DOI: 10.1371/journal.pone.0244826] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND There is lots of evidence that maternal peri-gestational metabolic, genomic and environmental conditions are closely linked to metabolic and cardiovascular outcomes in their offspring later in life. Moreover, there is also lotsof evidence that underlining mechanisms, such as molecular as well as epigenetic changes may alter the intrauterine environment leading to cardio-metabolic diseases in their offspring postnatal. But, there is also increasing evidence that cardio-metabolic diseases may be closely linked to their paternal metabolic risk factors, such as obesity, Type 2 Diabetes and other risk factors. OBJECTIVE To analyse the evidence as well as specific risk factors of paternal trans-generational programming of cardio-metabolic diseases in their offspring. METHODS Within a systematic scoping review, we performed a literature search in MEDLINE (PubMed) and EMBASE databases in August 2020 considering original research articles (2000-2020) that examined the impact of paternal programming on metabolic and cardiovascular offspring health. Epidemiological, clinical and experimental studies as well as human and animal model studies were included. RESULTS From n = 3.199 citations, n = 66 eligible studies were included. We selected n = 45 epidemiological as well as clinical studies and n = 21 experimental studies. In brief, pre-conceptional paternal risk factors, such as obesity, own birth weight, high-fat and low-protein diet, undernutrition, diabetes mellitus, hyperglycaemia, advanced age, smoking as well as environmental chemical exposure affect clearly metabolic and cardiovascular health of their offspring later in life. CONCLUSIONS There is emerging evidence that paternal risk factors, such as paternal obesity, diabetes mellitus, nutritional habits, advanced age and exposure to environmental chemicals or cigarette smoke, are clearly associated with adverse effects in metabolic and cardiovascular health in their offspring. Compared to maternal programming, pre-conceptional paternal factors might also have also a substantial effect in the sense of trans-generational programming of their offspring and need further research.
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Affiliation(s)
- Claudia Eberle
- Medicine with Specialization in Internal Medicine and General Medicine, Hochschule Fulda–University of Applied Sciences, Fulda, Germany
| | - Michaela F. Kirchner
- Medicine with Specialization in Internal Medicine and General Medicine, Hochschule Fulda–University of Applied Sciences, Fulda, Germany
| | - Raphaela Herden
- Medicine with Specialization in Internal Medicine and General Medicine, Hochschule Fulda–University of Applied Sciences, Fulda, Germany
| | - Stefanie Stichling
- Medicine with Specialization in Internal Medicine and General Medicine, Hochschule Fulda–University of Applied Sciences, Fulda, Germany
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Hellmann JK, Bukhari SA, Deno J, Bell AM. Sex-specific plasticity across generations I: Maternal and paternal effects on sons and daughters. J Anim Ecol 2020; 89:2788-2799. [PMID: 33191518 PMCID: PMC7902357 DOI: 10.1111/1365-2656.13364] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
Intergenerational plasticity or parental effects-when parental environments alter the phenotype of future generations-can influence how organisms cope with environmental change. An intriguing, underexplored possibility is that sex-of both the parent and the offspring-plays an important role in driving the evolution of intergenerational plasticity in both adaptive and non-adaptive ways. Here, we evaluate the potential for sex-specific parental effects in a freshwater population of three-spined sticklebacks Gasterosteus aculeatus by independently and jointly manipulating maternal and paternal experiences and separately evaluating their phenotypic effects in sons versus daughters. We tested the adaptive hypothesis that daughters are more responsive to cues from their mother, whereas sons are more responsive to cues from their father. We exposed mothers, fathers or both parents to visual cues of predation risk and measured offspring antipredator traits and brain gene expression. Predator-exposed fathers produced sons that were more risk-prone, whereas predator-exposed mothers produced more anxious sons and daughters. Furthermore, maternal and paternal effects on offspring survival were non-additive: offspring with a predator-exposed father, but not two predator-exposed parents, had lower survival against live predators. There were also strong sex-specific effects on brain gene expression: exposing mothers versus fathers to predation risk activated different transcriptional profiles in their offspring, and sons and daughters strongly differed in the ways in which their brain gene expression profiles were influenced by parental experience. We found little evidence to support the hypothesis that offspring prioritize their same-sex parent's experience. Parental effects varied with both the sex of the parent and the offspring in complicated and non-additive ways. Failing to account for these sex-specific patterns (e.g. by pooling sons and daughters) would have underestimated the magnitude of parental effects. Altogether, these results draw attention to the potential for sex to influence patterns of intergenerational plasticity and raise new questions about the interface between intergenerational plasticity and sex-specific selective pressures, sexual conflict and sexual selection.
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Affiliation(s)
- Jennifer K Hellmann
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
| | - Syed Abbas Bukhari
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
| | - Jack Deno
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
| | - Alison M Bell
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
- Program in Ecology, Evolution and Conservation, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
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48
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Hellmann JK, Carlson ER, Bell AM. Sex-specific plasticity across generations II: Grandpaternal effects are lineage specific and sex specific. J Anim Ecol 2020; 89:2800-2812. [PMID: 33191513 PMCID: PMC7902365 DOI: 10.1111/1365-2656.13365] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 07/07/2020] [Indexed: 12/31/2022]
Abstract
Transgenerational plasticity (TGP) occurs when the environment encountered by one generation (F0) alters the phenotypes of one or more future generations (e.g. F1 and F2). Sex selective TGP, via specific lineages or to only male or female descendants, has been underexplored in natural systems, and may be adaptive if it allows past generations to fine-tune the phenotypes of future generations in response to sex-specific life-history strategies. We sought to understand if exposing males to predation risk can influence grandoffspring via sperm in three-spined stickleback Gasterosteus aculeatus. We specifically tested the hypothesis that grandparental effects are transmitted in a sex-specific way down the male lineage, from paternal grandfathers to F2 males. We reared F1 offspring of unexposed and predator-exposed F0 males under 'control' conditions and used them to generate F2s with control grandfathers, a predator-exposed maternal grandfather (i.e. predator-exposed F0 males to F1 daughters to F2s), a predator-exposed paternal grandfather (i.e. predator-exposed F0 males to F1 sons to F2s) or two predator-exposed grandfathers. We then assayed male and female F2s for a variety of traits related to antipredator defence. We found little evidence that transgenerational effects were mediated to only male descendants via the paternal lineage. Instead, grandpaternal effects depended on lineage and were mediated largely across sexes, from F1 males to F2 females and from F1 females to F2 males. When their paternal grandfather was exposed to predation risk, female F2s were heavier and showed a reduced change in behaviour in response to a simulated predator attack relative to grandoffspring of control, unexposed grandparents. In contrast, male F2s showed reduced antipredator behaviour when their maternal grandfather was exposed to predation risk. However, these patterns were only evident when one grandfather, but not both grandfathers, was exposed to predation risk, suggesting the potential for non-additive interactions across lineages. If sex-specific and lineage effects are common, then grandparental effects are likely underestimated in the literature. These results draw attention to the importance of sex-selective inheritance of environmental effects and raise new questions about the proximate and ultimate causes of selective transmission across generations.
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Affiliation(s)
- Jennifer K Hellmann
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
| | - Erika R Carlson
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
| | - Alison M Bell
- Department of Evolution, Ecology and Behavior, School of Integrative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
- Program in Ecology, Evolution and Conservation, University of Illinois Urbana-Champaign, Urbana, Illinois, USA, 61801
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49
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Møller Johansen L, Gerra MC, Arendt-Nielsen L. Time course of DNA methylation in pain conditions: From experimental models to humans. Eur J Pain 2020; 25:296-312. [PMID: 33063322 DOI: 10.1002/ejp.1674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVE Throughout the last decade, research has uncovered associations between pain and epigenetic alterations caused by environmental factors. Specifically, studies have demonstrated correlations between pain conditions and altered DNA methylation patterns. Thus, DNA methylation has been revealed as a possible modulator or contributor to pain conditions, providing a potential therapeutic target for treatment by DNA methylation modification. To develop such treatments, it is necessary to clarify a wide number of aspects on how DNA methylation affects pain perception; first and foremost, the temporal dynamics. The objective of the present review is to provide an overview of current knowledge on temporal dynamics of DNA methylation in response to pain, and to investigate if a timeframe can be established based on the data of currently published studies. DATABASES AND DATA TREATMENT PubMed, MEDLINE, Google Scholar and Embase were searched comprehensively for studies of DNA methylation in neuropathic, inflammatory and alternative animal pain models, and in chronic pain patients including Complex Regional Pain Syndrome, chronic postsurgical pain, chronic widespread pain, fibromyalgia and Crohn's disease. RESULTS We identified 34 articles highlighting variations in temporal dynamics of DNA methylation across species and between different types of pain. These studies represent a starting point to uncover new insights in the DNA methylation time course in pain. CONCLUSIONS No timeframe can currently be made for the DNA methylation response to pain in any of the reviewed conditions, highlighting an important focus area for future research.
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Affiliation(s)
- Lonnie Møller Johansen
- Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, Aalborg, Denmark
| | - Maria Carla Gerra
- Center for Neuroplasticity and Pain (CNAP), SMI®, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
| | - Lars Arendt-Nielsen
- Center for Neuroplasticity and Pain (CNAP), SMI®, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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Ben Maamar M, Beck D, Nilsson E, McCarrey JR, Skinner MK. Developmental origins of transgenerational sperm histone retention following ancestral exposures. Dev Biol 2020; 465:31-45. [PMID: 32628935 PMCID: PMC7484192 DOI: 10.1016/j.ydbio.2020.06.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 12/16/2022]
Abstract
Numerous environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. Alterations in the germline epigenome are necessary to transmit transgenerational phenotypes. In previous studies, the pesticide DDT (dichlorodiphenyltrichloroethane) and the agricultural fungicide vinclozolin were shown to promote the transgenerational inheritance of sperm differential DNA methylation regions, non-coding RNAs and histone retention, which are termed epimutations. These epimutations are able to mediate this epigenetic inheritance of disease and phenotypic variation. The current study was designed to investigate the developmental origins of the transgenerational differential histone retention sites (called DHRs) during gametogenesis of the sperm. Vinclozolin and DDT were independently used to promote the epigenetic transgenerational inheritance of these DHRs. Male control lineage, DDT lineage and vinclozolin lineage F3 generation rats were used to isolate round spermatids, caput epididymal spermatozoa, and caudal sperm. The DHRs distinguishing the control versus DDT lineage or vinclozolin lineage samples were determined at these three developmental stages. DHRs and a reproducible core of histone H3 retention sites were observed using an H3 chromatin immunoprecipitation-sequencing (ChIP-Seq) analysis in each of the germ cell populations. The chromosomal locations and genomic features of the DHRs were analyzed. A cascade of epigenetic histone retention site alterations was found to be initiated in the round spermatids and then further modified during epididymal sperm maturation. Observations show that in addition to alterations in sperm DNA methylation and ncRNA expression previously identified, the induction of differential histone retention sites (DHRs) in the later stages of spermatogenesis also occurs. This novel component of epigenetic programming during spermatogenesis can be environmentally altered and transmitted to subsequent generations through epigenetic transgenerational inheritance.
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Affiliation(s)
- Millissia Ben Maamar
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA
| | - Daniel Beck
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA
| | - Eric Nilsson
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA
| | - John R McCarrey
- Department of Biology, University of Texas at San Antonio, San Antonio, TX, 78249, USA
| | - Michael K Skinner
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA, 99164-4236, USA.
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