While genetic studies have provided insights into essential hypertension (EH, defined by high blood pressure ≥140/90 mmHg), investigation through epigenetics may address gaps in understanding its heritability. This study focused on African Brazilian populations in Vale do Ribeira River region, due to their high hypertension prevalence. We aimed to determine if DNA methylation is linked to hypertension susceptibility, through a genome-wide evaluation of 80 peripheral blood samples from normotensive (39) and hypertensive (41) individuals, with Infinium Methylation EPIC BeadChip platform. Data were analyzed using ChAMP package and cross-referenced with information from databases such as EWAS Atlas, GWAS catalog, GeneCards, literature, and tools such as VarElect and EWAS Toolkit. The comparison between hypertensive and normotensive revealed 190 differentially methylated CpG positions (DMPs) and 46 differentially methylated regions (DMRs), both with p-value ≤0.05. Among the DMPs, 27 were found to have a plausible role in blood pressure. Among the DMRs, those mapped to ABAT, BLCAP, CERS3, EIF4E, FMN1, GABBR1, HLA-DQB2, HOXA5, IL5RA, KCNH2, MIR487B, MIR539, MIR886, MKRN3, NUDT12, PON3, RNF39, RWDD3, and TSHBS1 were highlighted because of their lowest p-values, current literature, and/or VarElect prioritization. Our findings suggest that differences in methylation contribute to the high susceptibility to essential hypertension in these populations.

Maternal undernutrition during pregnancy is associated with adverse effects in the offspring during adulthood and contributes to the risk of developing a number of chronic diseases. Historical events, such as famines, allow us to study the effects that food deprivation in utero has on the offspring's health. In particular, the Dutch Hunger Winter (1944-1945) and the Great Chinese Famine (1959-1961) have been extensively analysed, and it has been shown that prenatal exposure to starvation increases the risk of cardiometabolic, mental and kidney disease in adult life. More importantly, the risk can be transmitted to future generations. However, not all studies agree on the thresholds of risk of exposed subjects or on the timing of starvation during foetal life that could be held responsible for these deleterious lifelong consequences. Gender differences complicate the picture. In this narrative review, we discuss similarities and differences between the two famines and compare the available data, seeking to determine what can be learned from these tragedies.

Metabolic disease, including obesity and type 2 diabetes, are amongst the most significant health issues facing women of reproductive age. To date, no antenatal weight management tools have reduced the risk of adverse health outcomes for women with obesity and their offspring, resulting in a shift in focus to the pre-conception period. Although not yet recognised in most international weight management guidelines, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are being increasingly used for weight management prior to conception.

A literature search of PubMed, Medline, and Embase databases identified relevant articles describing the use of GLP-1 RAs prior to and during pregnancy. Papers were selected based on relevance and originality, with clinical trials, large observational studies and meta-analyses being preferentially included.

This narrative review summarises the mechanism of action of GLP-1 RAs and the clinical effects observed in non-pregnant adults. It synthesises the available data from human and animal studies regarding the safety and efficacy of GLP-1 RAs prior to pregnancy, and the consequences of inadvertent drug exposure in early pregnancy. In considering the need to balance the risks of metabolic disease with the risks posed by inadvertent drug exposure, it highlights the areas where further research is needed to guide clinical decision-making.

GLP-1 RAs may have a role in facilitating weight loss and improving the metabolic health of women prior to pregnancy. However, there is currently insufficient evidence to demonstrate that the use of this class of drugs prior to pregnancy improves pregnancy outcomes.

Environmental influences on traits and associated transgenerational epigenetic inheritance have widespread implications but remain controversial and underlying mechanisms poorly understood. We introduce long-term environmental induction experiments on alternative diets in Pristionchus pacificus, a nematode exhibiting mouth-form plasticity including predation, by propagating 110 isogenic lines for 101 generations with associated food-reversal experiments. We found dietary induction and subsequent transgenerational inheritance of the predatory morph and identified a role of ubiquitin ligase EBAX-1/ZSWIM8 in this process. Ppa-ebax-1 mutants are transgenerational inheritance defective, and Ppa-EBAX-1 destabilizes the clustered microRNA family miR-2235a/miR-35. Deletions of a cluster of 44 identical miR-2235a copies resulted in precocious and extended transgenerational inheritance of the predatory morph. These findings indicate that EBAX-1/ZSWIM8 destabilizes miRNAs, resulting in transgenerational inheritance, suggesting a role for target-directed miRNA degradation.

Receptors of insulin and insulin-like growth factors (IGFs) are receptor tyrosine kinases whose signalling controls multiple aspects of animal physiology throughout life. In addition to regulating metabolism and growth, insulin-IGF receptor signalling has recently been linked to a variety of new, cell type-specific functions. In the last century, key questions have focused on how structural differences of insulin and IGFs affect receptor activation, and how insulin-IGF receptor signalling translates into pleiotropic biological functions. Technological advances such as cryo-electron microscopy have provided a detailed understanding of how native and engineered ligands activate insulin-IGF receptors. In this Review, we highlight recent structural and functional insights into the activation of insulin-IGF receptors, and summarize new agonists and antagonists developed for intervening in the activation of insulin-IGF receptor signalling. Furthermore, we discuss recently identified regulatory mechanisms beyond ligand-receptor interactions and functions of insulin-IGF receptor signalling in diseases.

Slavery, legal segregation, and ongoing discrimination have exacted an unfathomable toll on the black population in the United States, particularly with respect to the impact on health outcomes. In recent years, various researchers and activists have suggested that racial disparities in the modern era can be attributed directly to the trauma of slavery, postulating that these unspeakable traumas led to epigenetic changes in slaves-changes that have since been passed down to subsequent generations. Investigating those claims in this paper, we comprise a review of previous literature that considers the potential for transgenerational epigenetic transmission of trauma in humans. However, we find that there is little evidence to indicate the presence of transgenerational epigenetic transmission of trauma in humans. We find no prior evidence that supports (or is relevant to) the notion that the black-white health gap stems from the inherited trauma of slavery. We conclude that, given the ongoing traumas black Americans are exposed to in modern America, it is much more likely that present-day racial health disparities are due to more direct and current mechanisms than transgenerational transmission of slavery-era trauma.

The study of women exposures and child outcomes occurring in the first 1,000 days of life since conception enhances understanding of the relationships between environmental factors, epigenetic changes, and disease development, extending beyond childhood and spanning the entire lifespan. Generation Gemelli is a recently launched case-control study that enrolls mother-newborns pairs in one of the largest university hospitals in Italy, in order to examine the association between maternal environmental exposures and intrauterine growth restriction (IUGR) and the risk of premature birth. The study will also evaluate the association of maternal exposures and the health and growth of infants and children up to 24 months of age.

The study entails the set-up of a case-control study within a birth cohort. With approximately 4,000 annual deliveries, we aim to enroll 140 cases (newborns with IUGR and premature birth) and 280 controls per year, from September 2022. A comprehensive questionnaire will be used to gather information about various types of maternal environmental exposures before and during pregnancy. We will collect biological samples from both mothers and newborns (including vaginal swab, placenta sample, blood, saliva, meconium, and bronchoalveolar lavage fluid) at birth and within the early hours of the newborn's life. We will perform laboratory examinations including dosage of heavy metals and essential elements, investigation of placental distress and fetal brain damage of biomarkers, analysis of microbiota and of DNA methylation profile. We will conduct clinical follow-up assessments in both cases and controls at months 12 and 24 and we will collect anthropometric data, feeding types with particular reference to breastfeeding and its duration, pediatric emergency room visits, hospitalizations, medication usage, known allergies, and neuropsychological development.

The Generation Gemelli case-control study holds the promise of significantly enhancing our comprehension of how maternal environmental exposures relate to the health of children and the broader population. The study of the exposome will provide insights into the relationships between environmental exposures, epigenetic changes and health outcomes during the first 1000 days of life and onward.

Intrauterine growth restriction (IUGR) is a risk factor for postnatal cardiovascular, metabolic, and psychiatric disorders. In most IUGR models, placental dysfunction that causes reduced 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) activity, which degrades glucocorticoids (GCs) in the placenta, resulting in fetal GC overexposure. This overexposure to GCs continues to affect not only intrauterine fetal development itself, but also the metabolic status and neural activity in adulthood through epigenetic changes such as microRNA change, histone modification, and DNA methylation. We have shown that the IUGR model induced DNA hypomethylation in the paraventricular nucleus (PVN) in the brain, which in turn activates sympathetic activities, the renin-angiotensin system (RAS), contributing to the development of salt-sensitive hypertension. Even in adulthood, strong stress and/or exogenous steroids have been shown to induce epigenetic changes in the brain. Furthermore, DNA hypomethylation in the PVN is also observed in other hypertensive rat models, which suggests that it contributes significantly to the origins of elevated blood pressure. These findings suggest that if we can alter epigenetic changes in the brain, we can treat or prevent hypertension.

Few investigations have been made to determine whether pharmaceutical drugs cause any generational effects. These effects can be divided into intergenerational and transgenerational effects. In insects, the F1 offspring of exposed individuals are considered to show intergenerational effects (as they have been exposed as germ cells or early embryos), while the F2 generation is fully non-exposed and considered to show transgenerational effects. Here, the common over-the-counter (OTC) drug, paracetamol, is investigated for genotype-specific responses and effects across generations on three life-history traits: fecundity, longevity, and spontaneous locomotor activity levels in the model species Drosophila melanogaster. Seven isofemale D. melanogaster lines were exposed to a high and intermediate dose of paracetamol determined by a dose-response curve. NMR investigations verified the long-term presence of paracetamol in the food substrate. Phenotypic effects of paracetamol ingestion were investigated on flies exposed to the drug and in their offspring and grand-offspring. The dose-response curve indicated genotype-specific responses to paracetamol. In the following experiment, all traits investigated displayed significant effects of paracetamol ingestion for at least one of the seven isofemale lines, and we detected strong genotype-specific responses to paracetamol. Fecundity tended to increase in individuals directly exposed to the drug whereas fecundity in the F2 generation was reduced (transgenerational). Longevity generally decreased in directly exposed individuals but tended to increase in F1 offspring (intergenerational). Paracetamol effects on spontaneous locomotor activity were primarily detected as transgenerational effects and were rarely seen in directly exposed individuals. However, across lines, no clear overall trend could be determined for any trait. The generational effects and marked genotype-specific response to paracetamol warrants further investigation of both genotype-specific responses and generational effects in general.

Internal and external factors can change an individual's phenotype. A significant external threat to humans and livestock is environmental heat load, a combination of high ambient temperatures and humidity. A heat stress response occurs when an endothermal animal is exposed to a heat load that challenges its' thermoregulation capacity. With the ongoing climate change trends, the incidence of chronically elevated temperatures causing heat stress is expected to rise, posing an even greater risk to the health and survival of all species. Heat stress is generally related to adverse effects on food intake, health, and performance in mammal livestock species and humans. Evidence from epidemiological and experimental studies of humans and livestock demonstrated that exposing pregnant females to heat stress affects the phenotype of the newborn in various ways. For instance, in utero heat stress is related to lower BW at birth and changes in metabolic and immune functions in the newborn. In cows, the effects of heat stress on the performance of the offspring last for three or four generations, suggesting intergenerational effects. The molecular mechanism orchestrating these effects of heat stress may be epigenetic regulation, as various epigenetic mechanisms control genome reprogramming. Epigenetic modifications are attached to DNA and histone proteins and can influence how specific genes are expressed, resulting in phenotypic changes. Epigenetic modifications can be triggered in response to environmental heat stress without altering the DNA sequence. Heat stress insults during critical periods of organ development (i.e., fetal exposure) can trigger epigenetic modifications that impact health and productivity across generations. Thus, epigenetic changes caused by extreme temperatures can be passed down to the offspring if the mother is exposed to the insult during pregnancy. Understanding the phenotypic and molecular consequences of maternal heat stress, including the carry-over lingering effects on the resulting progeny, is necessary to develop effective mitigation strategies and gain translational knowledge about the fundamental processes leading to intergenerational and transgenerational inheritance. This review examines the phenotypic and molecular evidence of how maternal exposure to extreme heat can affect future generations in several species, including humans, swine, sheep, goats, and cattle. The current knowledge of the molecular mechanisms involved in intergenerational and transgenerational epigenetic inheritance will also be presented and discussed.

Adult health inequalities are a persistent public health problem. Explanations are usually sought in behaviours and environments in adulthood, despite evidence on the importance of early life conditions for life course outcomes. We review evidence from a broad range of fields to unravel to what extent, and how, socioeconomic health inequalities are intergenerationally transmitted.We find that transmission of socioeconomic and associated health (dis)advantages from parents to offspring, and its underlying structural determinants, contributes substantially to socioeconomic inequalities in adult health. In the first two decades of life-from conception to early adulthood-parental socioeconomic position (SEP) and parental health strongly influence offspring adult SEP and health. Socioeconomic and health (dis)advantages are largely transmitted through the same broad mechanisms. Socioeconomic inequalities in the fetal environment contribute to inequalities in fetal development and birth outcomes, with lifelong socioeconomic and health consequences. Inequalities in the postnatal environment-especially the psychosocial and learning environment, physical exposures and socialisation-result in inequalities in child and adolescent health, development and behavioural habits, with health and socioeconomic consequences tracking into adulthood. Structural factors shape these mechanisms in a socioeconomically patterned and time-specific and place-specific way, leading to distinct birth-cohort patterns in health inequality.Adult health inequalities are for an important part intergenerationally transmitted. Effective health inequality reduction requires addressing intergenerational transmission of (dis)advantage by creating societal circumstances that allow all children to develop to their full potential.

According to the Developmental Origins of Health and Disease hypothesis, exposure to certain environmental influences during early life may be a key determinant of fetal development and short- and long-term offspring health. Indeed, adverse conditions encountered during the fetal, perinatal, and early childhood stages can alter normal development and growth, as well as put the offspring at elevated risk of developing long-term health conditions in adulthood, including chronic kidney disease and cardiovascular diseases. Of relevance in understanding the mechanistic basis of these long-term health conditions are previous findings showing low glomerular number in human intrauterine growth restriction and low birth weight-indicators of a suboptimal intrauterine environment. In different animal models, the main suboptimal intrauterine conditions studied relate to maternal dietary manipulations, poor micronutrient intake, prenatal ethanol exposure, maternal diabetes, glucocorticoid and chemical exposure, hypoxia, and placental insufficiency. These studies have demonstrated changes in kidney structure, glomerular endowment, and expression of key genes and signaling pathways controlling endocrine, excretion, and filtration function of the offspring. This review aims to summarize those studies to uncover the effects and mechanisms by which adverse gestational environments impact offspring renal and vascular health in adulthood. This is important for identifying agents and interventions that can prevent and mitigate the long-term consequences of an adverse intrauterine environment on the subsequent generation.NEW & NOTEWORTHY Human data and experimental animal data show that suboptimal environments during fetal development increase the risk of renal and vascular diseases in adult-life. This is related to permanent changes in kidney structure, function, and expression of genes and signaling pathways controlling filtration, excretion, and endocrine function. Uncovering the mechanisms by which offspring renal development and function is impacted is important for identifying ways to mitigate the development of diseases that strain health care services worldwide.

In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to a hypertrophic growth that is accompanied by the development of inflammation and metabolic dysfunction. However, the molecular mechanisms underlying the fine-tuned regulation of adipose tissue expansion are far from being understood.

We analyzed by mass spectrometry-based proteomics visceral white adipose tissue (vWAT) samples collected from C57BL6 mice fed with a HFD for 8 weeks. A subset of these mice, called low inflammation (Low-INFL), showed reduced adipose tissue inflammation, as opposed to those developing the expected inflammatory response (Hi-INFL). We identified the discriminants between Low-INFL and Hi-INFL vWAT samples and explored their function in Adipose-Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes.

vWAT proteomics allowed us to quantify 6051 proteins. Among the candidates that most differentiate Low-INFL from Hi-INFL vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in Low-INFL, as compared to Hi-INFL. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was so far unknown, was another top-scored hit. SMYD3 expression was significantly higher in Low-INFL vWAT, as confirmed by western blot analysis. Using AD-hMSCs in culture, we found that SMYD3 mRNA and protein levels decrease rapidly during the adipocyte differentiation. Moreover, SMYD3 knock-down before adipocyte differentiation resulted in reduced H3K4me3 and decreased cell proliferation, thus limiting the number of cells available for adipogenesis.

Our study describes an important role of SMYD3 as a newly discovered regulator of adipocyte precursor proliferation during the early steps of adipogenesis.

Numerous examples of different phenotypic outcomes in response to varying environmental conditions have been described across phyla, from plants to mammals. Here, we examine the impact of the environment on different developmental traits, focusing in particular on one key environmental variable, nutrient availability. We present advances in our understanding of developmental plasticity in response to food variation using the nematode Caenorhabditis elegans, which provides a near-isogenic context while permitting lab-controlled environments and analysis of wild isolates. We discuss how this model has allowed investigators not only to describe developmental plasticity events at the organismal level but also to zoom in on the tissues involved in translating changes in the environment into a plastic response, as well as the underlying molecular pathways, and sometimes associated changes in behaviour. Lastly, we also discuss how early life starvation experiences can be logged to later impact adult physiological traits, and how such memory could be wired.

Both breast cancer and obesity can regulate epigenetic changes or be regulated by epigenetic changes. Due to the well-established link between obesity and an increased risk of developing breast cancer, understanding how obesity-mediated epigenetic changes affect breast cancer pathogenesis is critical. Researchers have described how obesity and breast cancer modulate the epigenome individually and synergistically. In this review, the epigenetic alterations that occur in obesity, including DNA methylation, histone, and chromatin modification, accelerated epigenetic age, carcinogenesis, metastasis, and tumor microenvironment modulation, are discussed. Delineating the relationship between obesity and epigenetic regulation is vital to furthering our understanding of breast cancer pathogenesis.

Congenital malformations are functional and structural alterations in embryonic or foetal development resulting from a variety of factors including maternal health status. This study aimed to investigate the association between maternal birth weight (MBW) and the prevalence of congenital malformations in offspring using data from a nationwide birth cohort study in Japan including 103,060 pregnancies. A binary logistic regression model with adjustment for various covariates revealed that an MBW of <2500 g (low MBW) was associated with an increased risk of congenital heart disease (adjusted odds ratio: 1.388, [95% confidence interval: 1.075-1.792]), angioma (1.491 [1.079-2.059]), and inguinal hernia (1.746, [1.189-2.565]), while those with an MBW of ≥4000 g (high MBW) were associated with congenital anomalies of the urinary tract (2.194, [1.261-3.819]) and arrhythmia (1.775, [1.157-2.725]) compared with those with an MBW of 3000-3499 g. Low MBW was associated with cleft lip and/or palate (1.473, [1.052-2.064]), congenital heart disease (1.615, [1.119-2.332]), genital organs (1.648, [1.130-2.405]), hypospadias (1.804, [1.130-2.881]), and inguinal hernia (1.484, [1.189-1.851]) in male infants and CAKUT (1.619, [1.154-2.273]) in female infants, whereas high MBW was associated with congenital heart disease (1.745, [1.058-2.877]) and CAKUT (2.470, [1.350-4.517]) in male infants. The present study is the first to demonstrate a link between MBW and congenital malformations in Japanese children. While these results must be interpreted with caution, MBW should be considered a major predictor of congenital malformation risk.

Tangential growth of the human cerebral cortex is driven by cell proliferation during the first and second trimester of pregnancy. Fetal growth peaks in mid-gestation. Here, we explore how genes associated with fetal growth relate to cortical growth. We find that both maternal and fetal genetic variants associated with higher birthweight predict larger cortical surface area. The relative dominance of the maternal vs. fetal variants in these associations show striking variations across birth years (1943 to 1966). The birth-year patterns vary as a function of the epigenetic status near genes differentially methylated in individuals exposed (or not) to famine during the Dutch Winter of 1944/1945. Thus, it appears that the two sets of molecular processes contribute to early cortical development to a different degree in times of food scarcity or its abundance.

The radiation protection community has been particularly attentive to the risks of delayed effects on offspring from low dose or low dose-rate exposures to ionizing radiation. Despite this, the current epidemiologic studies and scientific data are still insufficient to provide the necessary evidence for improving risk assessment guidelines. This literature review aims to inform future studies on multigenerational and transgenerational effects. It primarily focuses on animal studies involving in utero exposure and discusses crucial elements for interpreting the results. These elements include in utero exposure scenarios relative to the developmental stages of the embryo/fetus, and the primary biological mechanisms responsible for transmitting heritable or hereditary effects to future generations. The review addresses several issues within the contexts of both multigenerational and transgenerational effects, with a focus on hereditary perspectives.

Knowledge consolidation in the field of Developmental Origins of Health and Disease (DOHaD) has led us to propose a new study strategy. This strategy aims to address the transgenerational effects of in utero exposure to low dose and low dose-rate radiation. Within this concept, there is a possibility that disruption of epigenetic programming in embryonic and fetal cells may occur. This disruption could lead to metabolic dysfunction, which in turn may cause abnormal responses to future environmental challenges, consequently increasing disease risk. Lastly, we discuss methodological limitations in our studies. These limitations are related to cohort size, follow-up time, model radiosensitivity, and analytical techniques. We propose scientific and analytical strategies for future research in this field.

While reports on the generational inheritance of a parental response to stress have been widely reported in animals, the molecular mechanisms behind this phenomenon have only recently emerged. The booming interest in epigenetic inheritance has been facilitated in part by the discovery that small non-coding RNAs are one of its principal conduits. Discovered 30 years ago in the Caenorhabditis elegans nematode, these small molecules have since cemented their critical roles in regulating virtually all aspects of eukaryotic development. Here, we provide an overview on the current understanding of epigenetic inheritance in animals, including mice and C. elegans, as it pertains to stresses such as temperature, nutritional, and pathogenic encounters. We focus on C. elegans to address the mechanistic complexity of how small RNAs target their cohort mRNAs to effect gene expression and how they govern the propagation or termination of generational perdurance in epigenetic inheritance. Presently, while a great amount has been learned regarding the heritability of gene expression states, many more questions remain unanswered and warrant further investigation.

The first 1000 days of life is a critical period that contributes significantly to the programming of an individual's future health. Among the many changes that occur during this period early in life, there is growing evidence that the establishment of healthy gut microbiota plays an important role in the prevention of both short- and long-term health problems. Numerous publications suggest that the quality of the gut microbiota colonisation depends on several dietary factors, including breastfeeding. In this respect, a relationship between breastfeeding and the risk of inflammatory bowel disease (IBD) has been suggested. IBDs are chronic intestinal diseases, and perinatal factors may be partly responsible for their onset. We review the existence of links between breastfeeding and IBD based on experimental and clinical studies. Overall, despite encouraging experimental data in rodents, the association between breastfeeding and the development of IBD remains controversial in humans, partly due to the considerable heterogeneity between clinical studies. The duration of exclusive breastfeeding is probably decisive for its lasting effect on IBD. Thus, specific improvements in our knowledge could support dietary interventions targeting the gut microbiome, such as the early use of prebiotics, probiotics or postbiotics, in order to prevent the disease.

The concept of Developmental Origin of Health and Disease (DOHaD) postulates that adult-onset metabolic disorders may originate from suboptimal conditions during critical embryonic and fetal programming windows. In particular, nutritional disturbance during key developmental stages may program the set point of adiposity and its associated metabolic diseases later in life. Numerous studies in mammals have reported that maternal obesity and the resulting accelerated growth in neonates may affect adipocyte development, resulting in persistent alterations in adipose tissue plasticity (i.e., adipocyte proliferation and storage) and adipocyte function (i.e., insulin resistance, impaired adipokine secretion, reduced thermogenesis, and higher inflammation) in a sex- and depot-specific manner. Over recent years, adipose progenitor cells (APCs) have been shown to play a crucial role in adipose tissue plasticity, essential for its development, maintenance, and expansion. In this review, we aim to provide insights into the developmental timeline of lineage commitment and differentiation of APCs and their role in predisposing individuals to obesity and metabolic diseases. We present data supporting the possible implication of dysregulated APCs and aberrant perinatal adipogenesis through epigenetic mechanisms as a primary mechanism responsible for long-lasting adipose tissue dysfunction in offspring born to obese mothers.

The current decline in dairy cattle fertility has resulted in significant financial losses for dairy farmers. In the past, most efforts to improve dairy cattle fertility have been focused on either management or genetics, while epigenetics have received less attention. In this study, 12 bulls were selected from a provided 100 bull list and studied (High daughter fertility = 6, Low daughter fertility = 6) for Enzymatic methylation sequencing in the Illumina HiSeq platform according to the Canadian daughter fertility index (DFI), sires with high and low daughter fertility have average DFI of 92 and 112.6, respectively. And the bull list provided shows a mean DFI of 103.4. 252 CpGs with methylation differences greater than 20% (q < 0.01) were identified, as well as the top 10 promising DMRs with a 15% methylation difference (q < 1.1e-26). Interestingly, the DMCs and DMRs were found to be distributed more on the X chromosome than on the autosome, and they were covered by gene clusters linked to germ cell formation and development. In conclusion, these findings could enhance our ability to make informed decisions when deciding on superior bulls and advance our understanding of paternal epigenetic inheritance.

Prenatal ethanol exposure (PEE) (mainly through maternal alcohol consumption) has become widespread. However, studies suggest that it can cause intrauterine growth retardation (IUGR) and multi-organ developmental toxicity in offspring, and susceptibility to various chronic diseases (such as neuropsychiatric diseases, metabolic syndrome, and related diseases) in adults. Through ethanol's direct effects and its indirect effects mediated by maternal-derived glucocorticoids, PEE alters epigenetic modifications and organ developmental programming during fetal development, which damages the offspring health and increases susceptibility to various chronic diseases after birth. Ethanol directly leads to the developmental toxicity of multiple tissues and organs in many ways. Regarding maternal-derived glucocorticoid-mediated IUGR, developmental programming, and susceptibility to multiple conditions after birth, ethanol induces programmed changes in the neuroendocrine axes of offspring, such as the hypothalamus-pituitary-adrenal (HPA) and glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axes. In addition, the differences in ethanol metabolic enzymes, placental glucocorticoid barrier function, and the sensitivity to glucocorticoids in various tissues and organs mediate the severity and sex differences in the developmental toxicity of ethanol exposure during pregnancy. Offspring exposed to ethanol during pregnancy have a "thrifty phenotype" in the fetal period, and show "catch-up growth" in the case of abundant nutrition after birth; when encountering adverse environments, these offspring are more likely to develop diseases. Here, we review the developmental toxicity, functional alterations in multiple organs, and neuroendocrine metabolic programming mechanisms induced by PEE based on our research and that of other investigators. This should provide new perspectives for the effective prevention and treatment of ethanol developmental toxicity and the early prevention of related fetal-originated diseases.

The concept of the inheritance of acquired traits, a foundational principle of Lamarck's evolutionary theory, has garnered renewed attention in recent years. Evidence for this phenomenon remained limited for decades but gained prominence with the Överkalix cohort study in 2002. This study revealed a link between cardiovascular disease incidence and the food availability experienced by individuals' grandparents during their slow growth periods, reigniting interest in the inheritance of acquired traits, particularly in the context of non-communicable diseases. This scientometric analysis and systematic review comprehensively explores the current landscape of paternally transmitted acquired metabolic traits.

Utilizing Scopus Advanced search and meticulous screening, we included mammalian studies that document the inheritance or modification of metabolic traits in subsequent generations of unexposed descendants. Our inclusive criteria encompass intergenerational and transgenerational studies, as well as multigenerational exposures. Predominantly, this field has been driven by a select group of researchers, potentially shaping the design and focus of existing studies. Consequently, the literature primarily comprises transgenerational rodent investigations into the effects of ancestral exposure to environmental pollutants on sperm DNA methylation. The complexity and volume of data often lead to multiple or redundant publications. This practice, while understandable, may obscure the true extent of the impact of ancestral exposures on the health of non-exposed descendants. In addition to DNA methylation, studies have illuminated the role of sperm RNAs and histone marks in paternally acquired metabolic disorders, expanding our understanding of the mechanisms underlying epigenetic inheritance.

This review serves as a comprehensive resource, shedding light on the current state of research in this critical area of science, and underscores the need for continued exploration to uncover the full spectrum of paternally mediated metabolic inheritance.

Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD.

Obesity is a complex multifactorial condition that often manifests in early life with a lifelong burden on metabolic health. Diet, including pre-pregnancy maternal diet, in utero nutrition and dietary patterns in early and late life, can shape obesity development. Growing evidence suggests that epigenetic modifications, specifically DNA methylation, might mediate or accompany these effects across life stages and generations. By reviewing human observational and intervention studies conducted over the past 10 years, this work provides a comprehensive overview of the evidence linking nutrition to DNA methylation and its association with obesity across different age periods, spanning from preconception to adulthood and identify future research directions in the field.

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the m6,2A and BUD-23/BUD23 as the m7G methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.

Recent decades provide mounting evidence for the continual increase in global temperatures, now termed "global warming," to the point of drastic worldwide change in the climate. Climatic change is a long-term shift in temperatures and weather patterns, including increased frequency and intensity of extreme environmental events such as heat waves accompanied by extreme temperatures and high humidity. Climate change and global warming put several challenges to the livestock industry by directly affecting the animal's production, reproduction, health, and welfare. The broad impact of global warming, and in particular heat stress, on-farm animals' performance has been comprehensively studied. It has been estimated that the US livestock industry's loss caused by heat stress is up to $2.4 billion annually. However, the long-term intergenerational and transgenerational effects of climatic change and global warming on farm animals are sparse. Transgenerational effects, which are mediated by epigenetic mechanisms, can affect the animal's performance regardless of its immediate environment by altering its phenotypic expression to fit its ancestors' environment. In many animal species, environmental effects are epigenetically encoded within a narrow time interval during the organism's gametogenesis, and these epigenetic modifications can then be intergenerationally transmitted. Several epigenetic mechanisms mediate intergenerational transmission of environmental effects, typically in a parent-dependent manner. Therefore, exposure of the animal to an extreme climatic event and other environmental stressors during gametogenesis can undergo epigenetic stabilization in the germline and be passed to the offspring. As a result, the offspring might express a phenotype adjusted to fit the stressors experienced by their ancestors, regardless of their direct environment. The purpose of this perspective is to review current evidence for intergenerational and transgenerational transmission of environmental stress effects, specifically in the context of global warming and climate change, and to offer viewpoints on the possible impacts on the livestock industry.

Environmental exposures produce heritable traits that can linger in the population for one or two generations. Millions of individuals consume substances such as artificial sweeteners daily that are declared safe by regulatory agencies without evaluation of their potential heritable effects. We show that consumption of aspartame, an FDA-approved artificial sweetener, daily for up to 16-weeks at doses equivalent to only 7-15% of the FDA recommended maximum daily intake value (equivalent to 2-4 small, 8 oz diet soda drinks per day) produces significant spatial learning and memory deficits in mice. Moreover, the cognitive deficits are transmitted to male and female descendants along the paternal lineage suggesting that aspartame's adverse cognitive effects are heritable, and that they are more pervasive than current estimates, which consider effects in the directly exposed individuals only. Traditionally, deleterious environmental exposures of pregnant and nursing women are viewed as risk factors for the health of future generations. Environmental exposures of men are not considered to pose similar risks. Our findings suggest that environmental exposures of men can produce adverse impact on cognitive function in future generations and demonstrate the need for considering heritable effects via the paternal lineage as part of the regulatory evaluations of artificial sweeteners.

We discuss pathological epigenetic events that are reversible (PEERs). A recent study by Poganik and colleagues showed that severe stress in mice and humans transiently elevates biological age of several tissues, and this transient age increase is reversible when the stress is removed. These studies suggest new strategies for reversing normal aging. However, it is important to note that developmental origin of health and disease studies have shown that developmental exposure to toxic chemicals such as lead causes permanent changes in neuron shape, connectivity and cellular hyperplasia of organs such as the heart and liver. In this review, the PEER hypothesis speculates that the hallmarks of aging and the hallmarks of developmental origin of health and disease intersect at PEERs.

Famine is a risk factor for non-communicable chronic diseases (NCDs), which account for over 80% of deaths in China. The effect of famine on the prevalence of NCDs in terms of various age groups, time periods and cohorts is currently poorly understood.

This study aims to explore long-term trends in the impact of China's Great Famine (1959-1961) on NCDs in China.

This study used data from the 2010-2020 China Family Panel Longitudinal Survey across 25 provinces in China. The subjects were aged 18-85 years, and the total number of subjects was 174,894. The prevalence of NCDs was derived from the China Family Panel Studies database (CFPS). An age-period-cohort (APC) model was used to estimate the age, period and cohort effects of NCDs in 2010-2020 and the effect of famine on the risk of NCDs in terms of cohort effects.

The prevalence of NCDs increased with age. Additionally, the prevalence did not clearly decrease over the survey period. Regarding the cohort effect, people born in the years adjacent to the famine period had a higher risk of NCDs; additionally, females, those born in rural areas, and those who lived in provinces with severe famine and post-famine had a higher likelihood of NCDs.

Experiencing famine at an early age or the experience of famine in a close relative's generation (births after the onset of famine) are associated with an increased risk of NCDs. Additionally, more severe famine is associated with a higher risk of NCDs.

The health of parents prior to conception, a woman's health during pregnancy and the infant's environment across their first months and years collectively have profound effects on the child's health across the lifespan. Since there are very few cohort studies in early pregnancy, gaps remain in our understanding of the mechanisms underpinning these relationships, and how health may be optimised. 'BABY1000', a pilot prospective longitudinal birth cohort study, aims to (1) identify factors before and during pregnancy and early life that impact longer-term health and (2) assess the feasibility and acceptability of study design to inform future research.

Participants were based in Sydney, Australia. Women were recruited at preconception or 12 weeks' gestation, and data were collected from them throughout pregnancy and postpartum, their children until the age of 2 years, and dietary information from a partner (if able) at the last study visit. The pilot aimed to recruit 250 women. However, recruitment ceased earlier than planned secondary to limitations from the COVID-19 pandemic and the final number of subjects was 225.

Biosamples, clinical measurements and sociodemographic/psychosocial measures were collected using validated tools and questionnaires. Data analysis and 24-month follow-up assessments for children are ongoing. Key early findings presented include participant demographics and dietary adequacy during pregnancy. The COVID-19 pandemic and associated public health and research restrictions affected recruitment of participants, follow-up assessments and data completeness.

The BABY1000 study will provide further insight into the developmental origins of health and disease and inform design and implementation of future cohort and intervention studies in the field. Since the BABY1000 pilot was conducted across the COVID-19 pandemic, it also provides unique insight into the early impacts of the pandemic on families, which may have effects on health across the lifespan.

Cardiovascular disease (CVD) is a leading cause of death globally, with the prevalence projected to keep rising. Risk factors for adult CVD emerge at least as early as the prenatal period. Alterations in stress-responsive hormones in the prenatal period are hypothesized to contribute to CVD in adulthood, but little is known about relations between prenatal stress-responsive hormones and early precursors of CVD, such as cardiometabolic risk and health behaviors. The current review presents a theoretical model of the relation between prenatal stress-responsive hormones and adult CVD through cardiometabolic risk markers (e.g., rapid catch-up growth, high BMI/adiposity, high blood pressure, and altered blood glucose, lipids, and metabolic hormones) and health behaviors (e.g., substance use, poor sleep, poor diet and eating behaviors, and low physical activity levels). Emerging evidence in human and non-human animal literatures suggest that altered stress-responsive hormones during gestation predict higher cardiometabolic risk and poorer health behaviors in offspring. This review additionally highlights limitations of the current literature (e.g., lack of racial/ethnic diversity, lack of examination of sex differences), and discusses future directions for this promising area of research.

Historical and demographical human cohorts of populations exposed to famine, as well as animal studies, revealed that exposure to food deprivation is associated to lasting health-related effects for the exposed individuals, as well as transgenerational effects in their offspring that affect their diseases' risk and overall longevity. Autophagy, an evolutionary conserved catabolic process, serves as cellular response to cope with nutrient starvation, allowing the mobilization of an internal source of stored nutrients and the production of energy. We review the evidence obtained in multiple model organisms that support the idea that autophagy induction, including through dietary regimes based on reduced food intake, is in fact associated to improved health span and extended lifespan. Thereafter, we expose autophagy-induced chromatin remodeling, such as DNA methylation and histone posttranslational modifications that are known heritable epigenetic marks, as a plausible mechanism for transgenerational epigenetic inheritance of hunger.

Exposure to adverse nutritional and metabolic environments during critical periods of development can exert long-lasting effects on health outcomes of an individual and its descendants. Although such metabolic programming has been observed in multiple species and in response to distinct nutritional stressors, conclusive insights into signaling pathways and mechanisms responsible for initiating, mediating, and manifesting changes to metabolism and behavior across generations remain scarce. By using a starvation paradigm in Caenorhabditis elegans, we show that starvation-induced changes in dauer formation-16/forkhead box transcription factor class O (DAF-16/FoxO) activity, the main downstream target of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling, are responsible for metabolic programming phenotypes. Tissue-specific depletion of DAF-16/FoxO during distinct developmental time points demonstrates that DAF-16/FoxO acts in somatic tissues, but not directly in the germline, to both initiate and manifest metabolic programming. In conclusion, our study deciphers multifaceted and critical roles of highly conserved insulin/IGF-1 receptor signaling in determining health outcomes and behavior across generations.

Evidence from human and animal studies has shown that maternal overnutrition and/or obesity are linked with neurobehavioral changes in the offspring. This fetal programming is characterized by adaptive responses to changes in the nutritional state during early life. In the past decade, an association has been made between overconsumption of highly-palatable food by the mother during fetal development and abnormal behaviors resembling addiction in the offspring. Maternal overnutrition can lead to alterations in the offspring's brain reward circuitry leading to hyperresponsiveness of this circuit following exposure to calorie-dense foods later in life. Given the accumulating evidence indicating that the central nervous system plays a pivotal role in regulating food intake, energy balance, and the motivation to seek food, a dysfunction in the reward circuitry may contribute to the addiction-like behaviors observed in the offspring. However, the underlying mechanisms leading to these alterations in the reward circuitry during fetal development and their relevance to the increased risk for the offspring to later develop addictive-like behaviors is still unclear. Here, we review the most relevant scientific reports about the impact of food overconsumption during fetal development and its effect on addictive-like behaviors of the offspring in the context of eating disorders and obesity.

Over the twentieth century, male reproductive health has suffered a substantial decline, as evidenced by decreases in sperm counts and testosterone levels and increases in reproductive pathologies. At the same time, the prevalence of chronic diseases such as obesity, diabetes, and metabolic syndrome has risen dramatically. Metabolic and reproductive health are highly interconnected, suggesting that their respective trends are intertwined and, given the timeframe of such trends, environmental and not genetic factors are most likely to be the primary causes. Industrialization, which began in Europe in the mid-eighteenth century, has resulted in profound changes to our diet, lifestyle, and environment, many of which are causal factors in the rise in chronic diseases. Industrialization results in a nutrition transition from an agricultural unprocessed to a modern processed diet, incorporating increases in sugar, vegetable oils, ultra-processed foods, linoleic acid, trans-fats, and total energy. This dietary shift has incurred numerous adverse effects on metabolic and reproductive health, characterized by chronic inflammation, oxidative stress, and insulin resistance. Moreover, these effects appear to multiply across subsequent generations via epigenetic inheritance. Men's fertility is markedly affected by obesity and diabetes, with an increase in total energy via processed food intake arguably being the key factor driving the diabesity pandemic. In contrast, wholefoods rich in micronutrients and phytonutrients support male fertility and a healthy body weight. Therefore, men wanting to maximize their fertility should consider making positive dietary changes, such as replacing processed foods with unprocessed foods that support metabolic and reproductive health.

Inorganic arsenic (iAs) is one of the largest toxic exposures to impact humanity worldwide. Exposure to iAs during pregnancy may disrupt the proper remodeling of the epigenome of F1 developing offspring and potentially their F2 grand-offspring via disruption of fetal primordial germ cells (PGCs). There is a limited understanding between the correlation of disease phenotype and methylation profile within offspring of both generations and whether it persists to adulthood. Our study aims to understand the intergenerational effects of in utero iAs exposure on the epigenetic profile and onset of disease phenotypes within F1 and F2 adult offspring, despite the lifelong absence of direct arsenic exposure within these generations. We exposed F0 female mice (C57BL6/J) to the following doses of iAs in drinking water 2 weeks before pregnancy until the birth of the F1 offspring: 1, 10, 245, and 2300 ppb. We found sex- and dose-specific changes in weight and body composition that persist from early time to adulthood within both generations. Fasting blood glucose challenge suggests iAs exposure causes dysregulation of glucose metabolism, revealing generational, exposure, and sex-specific differences. Toward understanding the mechanism, genome-wide DNA methylation data highlights exposure-specific patterns in liver, finding dysregulation within genes associated with cancer, T2D, and obesity. We also identified regions containing persistently differentially methylated CpG sites between F1 and F2 generations. Our results indicate the F1 developing embryos and their PGCs, which will result in F2 progeny, retain epigenetic damage established during the prenatal period and are associated with adult metabolic dysfunction.

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.

We examine multi-generational impacts of positive in utero health interventions using a new research design that exploits sharp increases in prenatal Medicaid eligibility that occurred in some states. Our analyses are based on U.S. Vital Statistics Natality files, which enables linkages between individuals' early life Medicaid exposure and the next generation's health at birth. We find evidence that the health benefits associated with treated generations' early life program exposure extend to later offspring. Our results suggest that the returns on early life health investments may be substantively underestimated.

The aim of this study was to investigate the transgenerational associations between exposure to famine in early life and obesity.

This study used the longitudinal data from the China Health and Nutrition Survey from 1989 to 2015. A total of 1113 fathers and 1207 mothers (946 mother-father pairs) born in 1955 to 1966 and 1895 adult offspring were included. Offspring were classified into subgroups according to the famine exposure of their parents (unexposed, maternal exposed, paternal exposed, parental exposed) and exposure timing (during fetal development, childhood).

Maternal exposure to famine in early life was associated with elevated levels of BMI, waist circumference, overweight, and central obesity of their children, whereas paternal exposure was inversely associated with these measurements. Compared with children of unexposed parents (P0M0), the maternal exposed group (P0M1) had higher mean BMI, by 1.3 kg/m² (95% CI: 0.3 to 2.4); waist circumference, by 1.5 cm (-1.0 to 3.9); overweight (odds ratio [OR] [95% CI]: 3.1 [1.6 to 6.1]); and central obesity (OR [95% CI]: 1.9 [1.02 to 3.7]). No significant heterogeneity was observed in the associations by sex of offspring.

Fetal and early childhood exposure to famine in parents may be associated with their children's risk of obesity during adulthood. A better understanding of the transgenerational associations is important for developing strategies to reduce obesity risk in future generations.