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England-Mason G, MacEachern SJ, Amador K, Soomro MH, Reardon AJF, MacDonald AM, Kinniburgh DW, Letourneau N, Giesbrecht GF, Martin JW, Forkert ND, Dewey D. Using machine learning to investigate the influence of the prenatal chemical exposome on neurodevelopment of young children. Neurotoxicology 2025; 108:218-230. [PMID: 40222479 DOI: 10.1016/j.neuro.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/15/2025]
Abstract
Research investigating the prenatal chemical exposome and child neurodevelopment has typically focused on a limited number of chemical exposures and controlled for sociodemographic factors and maternal mental health. Emerging machine learning approaches may facilitate more comprehensive examinations of the contributions of chemical exposures, sociodemographic factors, and maternal mental health to child neurodevelopment. A machine learning pipeline that utilized feature selection and ranking was applied to investigate which common prenatal chemical exposures and sociodemographic factors best predict neurodevelopmental outcomes in young children. Data from 406 maternal-child pairs enrolled in the APrON study were used. Maternal concentrations of 32 environmental chemical exposures (i.e., phthalates, bisphenols, per- and polyfluoroalkyl substances (PFAS), metals, trace elements) measured during pregnancy and 11 sociodemographic factors, as well as measures of maternal mental health and urinary creatinine were entered into the machine learning pipeline. The pipeline, which consisted of a RReliefF variable selection algorithm and support vector machine regression model, was used to identify and rank the best subset of variables predictive of cognitive, language, and motor development outcomes on the Bayley Scales of Infant Development-Third Edition (Bayley-III) at 2 years of age. Bayley-III cognitive scores were best predicted using 29 variables, resulting in a correlation coefficient of r = 0.27 (R2=0.07). For language outcomes, 45 variables led to the best result (r = 0.30; R2=0.09), whereas for motor outcomes 33 variables led to the best result (r = 0.28, R2=0.09). Environmental chemicals, sociodemographic factors, and maternal mental health were found to be highly ranked predictors of cognitive, language, and motor development in young children. Our findings demonstrate the potential of machine learning approaches to identify and determine the relative importance of different predictors of child neurodevelopmental outcomes. Future developmental neurotoxicology research should consider the prenatal chemical exposome as well as sample characteristics such as sociodemographic factors and maternal mental health as important predictors of child neurodevelopment.
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Affiliation(s)
- Gillian England-Mason
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Sarah J MacEachern
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Department of Psychology, Faculty of Arts, University of Calgary, Calgary, Alberta
| | - Kimberly Amador
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada; Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Munawar Hussain Soomro
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Anthony J F Reardon
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Amy M MacDonald
- Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada
| | - David W Kinniburgh
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada; Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada
| | - Nicole Letourneau
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Faculty of Nursing, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada; Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gerald F Giesbrecht
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Department of Psychology, Faculty of Arts, University of Calgary, Calgary, Alberta; Department of Community Health Sciences, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada
| | - Jonathan W Martin
- Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm, Sweden
| | - Nils D Forkert
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Deborah Dewey
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine University of Calgary, Calgary, Alberta, Canada.
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Buoso E, Masi M, Limosani RV, Oliviero C, Saeed S, Iulini M, Passoni FC, Racchi M, Corsini E. Endocrine Disrupting Toxicity of Bisphenol A and Its Analogs: Implications in the Neuro-Immune Milieu. J Xenobiot 2025; 15:13. [PMID: 39846545 PMCID: PMC11755641 DOI: 10.3390/jox15010013] [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: 10/23/2024] [Revised: 12/22/2024] [Accepted: 01/15/2025] [Indexed: 01/24/2025] Open
Abstract
Endocrine-disrupting chemicals (EDCs) are natural or synthetic substances that are able to interfere with hormonal systems and alter their physiological signaling. EDCs have been recognized as a public health issue due to their widespread use, environmental persistence and the potential levels of long-term exposure with implications in multiple pathological conditions. Their reported adverse effects pose critical concerns about their use, warranting their strict regulation. This is the case of bisphenol A (BPA), a well-known EDC whose tolerable daily intake (TDI) was re-evaluated in 2023 by the European Food Safety Authority (EFSA), and the immune system has been identified as the most sensitive to BPA exposure. Increasing scientific evidence indicates that EDCs can interfere with several hormone receptors, pathways and interacting proteins, resulting in a complex, cell context-dependent response that may differ among tissues. In this regard, the neuronal and immune systems are important targets of hormonal signaling and are now emerging as critical players in endocrine disruption. Here, we use BPA and its analogs as proof-of-concept EDCs to address their detrimental effects on the immune and nervous systems and to highlight complex interrelationships within the immune-neuroendocrine network (INEN). Finally, we propose that Receptor for Activated C Kinase 1 (RACK1), an important target for EDCs and a valuable screening tool, could serve as a central hub in our toxicology model to explain bisphenol-mediated adverse effects on the INEN.
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Affiliation(s)
- Erica Buoso
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy; (R.V.L.); (C.O.); (S.S.); (M.R.)
- Department of Pharmacology, Physiology & Biophysics, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02215, USA
| | - Mirco Masi
- Computational and Chemical Biology, Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy;
| | - Roberta Valeria Limosani
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy; (R.V.L.); (C.O.); (S.S.); (M.R.)
| | - Chiara Oliviero
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy; (R.V.L.); (C.O.); (S.S.); (M.R.)
| | - Sabrina Saeed
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy; (R.V.L.); (C.O.); (S.S.); (M.R.)
| | - Martina Iulini
- Laboratory of Toxicology, Department of Pharmacological and Biomolecular Science, University of Milan, Via Balzaretti 9, 20133 Milan, Italy; (M.I.); (F.C.P.); (E.C.)
| | - Francesca Carlotta Passoni
- Laboratory of Toxicology, Department of Pharmacological and Biomolecular Science, University of Milan, Via Balzaretti 9, 20133 Milan, Italy; (M.I.); (F.C.P.); (E.C.)
| | - Marco Racchi
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Via Taramelli 12/14, 27100 Pavia, Italy; (R.V.L.); (C.O.); (S.S.); (M.R.)
| | - Emanuela Corsini
- Laboratory of Toxicology, Department of Pharmacological and Biomolecular Science, University of Milan, Via Balzaretti 9, 20133 Milan, Italy; (M.I.); (F.C.P.); (E.C.)
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Ma Q, Yang Z, Yang C, Lin M, Gong M, Deng P, He M, Lu Y, Zhang K, Pi H, Qu M, Yu Z, Zhou Z, Chen C. A single-cell transcriptomic landscape of cadmium-hindered brain development in mice. Commun Biol 2024; 7:997. [PMID: 39147853 PMCID: PMC11327346 DOI: 10.1038/s42003-024-06685-6] [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: 11/26/2023] [Accepted: 08/06/2024] [Indexed: 08/17/2024] Open
Abstract
The effects of neurotoxicant cadmium (Cd) exposure on brain development have not been well elucidated. To investigate this, we have herein subjected pregnant mice to low-dose Cd throughout gestation. Using single-cell RNA sequencing (scRNA-seq), we explored the cellular responses in the embryonic brain to Cd exposure, and identified 18 distinct cell subpopulations that exhibited varied responses to Cd. Typically, Cd exposure impeded the development and maturation of cells in the brain, especially progenitor cells such as neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). It also caused significant cell subpopulation shifts in almost all the types of cells in the brain. Additionally, Cd exposure reduced the dendritic sophistication of cortical neurons in the offspring. Importantly, these changes led to aberrant Ca2+ activity in the cortex and neural behavior changes in mature offspring. These data contribute to our understanding of the effects and mechanisms of Cd exposure on brain development and highlight the importance of controlling environmental neurotoxicant exposure at the population level.
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Affiliation(s)
- Qinlong Ma
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhiqi Yang
- Brain Research Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Chuanyan Yang
- Brain Research Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Min Lin
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Mingyue Gong
- Brain Research Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Ping Deng
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Mindi He
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Yonghui Lu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Kuan Zhang
- Brain Research Center, Army Medical University (Third Military Medical University), Chongqing, China
| | - Huifeng Pi
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Mingyue Qu
- The PLA Rocket Force Characteristic Medical Center, Beijing, China
| | - Zhengping Yu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China
| | - Zhou Zhou
- Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing, China.
| | - Chunhai Chen
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, China.
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England-Mason G, Merrill SM, Liu J, Martin JW, MacDonald AM, Kinniburgh DW, Gladish N, MacIsaac JL, Giesbrecht GF, Letourneau N, Kobor MS, Dewey D. Sex-Specific Associations between Prenatal Exposure to Bisphenols and Phthalates and Infant Epigenetic Age Acceleration. EPIGENOMES 2024; 8:31. [PMID: 39189257 PMCID: PMC11348373 DOI: 10.3390/epigenomes8030031] [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: 06/06/2024] [Revised: 07/19/2024] [Accepted: 08/07/2024] [Indexed: 08/28/2024] Open
Abstract
We examined whether prenatal exposure to two classes of endocrine-disrupting chemicals (EDCs) was associated with infant epigenetic age acceleration (EAA), a DNA methylation biomarker of aging. Participants included 224 maternal-infant pairs from a Canadian pregnancy cohort study. Two bisphenols and 12 phthalate metabolites were measured in maternal second trimester urines. Buccal epithelial cell cheek swabs were collected from 3 month old infants and DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The Pediatric-Buccal-Epigenetic tool was used to estimate EAA. Sex-stratified robust regressions examined individual chemical associations with EAA, and Bayesian kernel machine regression (BKMR) examined chemical mixture effects. Adjusted robust models showed that in female infants, prenatal exposure to total bisphenol A (BPA) was positively associated with EAA (B = 0.72, 95% CI: 0.21, 1.24), and multiple phthalate metabolites were inversely associated with EAA (Bs from -0.36 to -0.66, 95% CIs from -1.28 to -0.02). BKMR showed that prenatal BPA was the most important chemical in the mixture and was positively associated with EAA in both sexes. No overall chemical mixture effects or male-specific associations were noted. These findings indicate that prenatal EDC exposures are associated with sex-specific deviations in biological aging, which may have lasting implications for child health and development.
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Affiliation(s)
- Gillian England-Mason
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Owerko Centre, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Sarah M. Merrill
- Department of Psychiatry and Human Behavior, The Warren Alpert Medical School at Brown University, Providence, RI 02903, USA
- Department of Medical Genetics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Centre for Molecular Medicine and Therapeutics, Vancouver, BC V6H 0B3, Canada
| | - Jiaying Liu
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Jonathan W. Martin
- Science for Life Laboratory, Department of Environmental Science, Stockholm University, 114 19 Stockholm, Sweden
| | - Amy M. MacDonald
- Alberta Centre for Toxicology, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - David W. Kinniburgh
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Alberta Centre for Toxicology, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Nicole Gladish
- Department of Medical Genetics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Centre for Molecular Medicine and Therapeutics, Vancouver, BC V6H 0B3, Canada
| | - Julia L. MacIsaac
- Department of Medical Genetics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Centre for Molecular Medicine and Therapeutics, Vancouver, BC V6H 0B3, Canada
| | - Gerald F. Giesbrecht
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Owerko Centre, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
- Department of Psychology, Faculty of Arts, University of Calgary, Calgary, AB T2N 1N4, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
| | - Nicole Letourneau
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Owerko Centre, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Faculty of Nursing, University of Calgary, Calgary, AB T2N 1N4, Canada
- Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Hotchkiss Brain Institute, Calgary, AB T2N 4N1, Canada
| | - Michael S. Kobor
- Department of Medical Genetics, British Columbia Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
- Centre for Molecular Medicine and Therapeutics, Vancouver, BC V6H 0B3, Canada
- Program in Child and Brain Development, Canadian Institute for Advanced Research (CIFAR), Toronto, ON M5G 1M1, Canada
| | - Deborah Dewey
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Owerko Centre, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
- Hotchkiss Brain Institute, Calgary, AB T2N 4N1, Canada
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Lei X, Ao J, Li J, Gao Y, Zhang J, Tian Y. Maternal concentrations of environmental phenols during early pregnancy and behavioral problems in children aged 4 years from the Shanghai Birth Cohort. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 933:172985. [PMID: 38705299 DOI: 10.1016/j.scitotenv.2024.172985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/01/2024] [Accepted: 05/02/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND Prenatal exposure to environmental phenols such as bisphenol (BPs), paraben (PBs), benzophenone (BzPs), and triclosan (TCS) is ubiquitous and occurs in mixtures. Although some of them have been suspected to impact child behavioral development, evidence is still insufficient, and their mixed effects remain unclear. OBJECTIVES To explore the association of prenatal exposure to multiple phenols with child behavioral problems. METHOD In a sample of 600 mother-child pairs from the Shanghai Birth Cohort, we quantified 18 phenols (6 PBs, 7 BPs, 4 BzPs, and TCS) in urine samples collected during early pregnancy. Parent-reported Strengths and Difficulties Questionnaires were utilized to evaluate child behavioral difficulties across four subscales, namely conduct, hyperactivity/inattention, emotion, and peer relationship problems, at 4 years of age. Multivariable linear regression was conducted to estimate the relationships between single phenolic compounds and behavioral problems. Additionally, weighted quantile sum (WQS) regression was employed to examine the overall effects of the phenol mixture. Sex-stratified analyses were also performed. RESULTS Our population was extensively exposed to 10 phenols (direction rates >50 %), with low median concentrations (1.00 × 10-3-6.89 ng/mL). Among them, single chemical analyses revealed that 2,4-dihydroxy benzophenone (BP1), TCS, and methyl 4-hydroxybenzoate (MeP) were associated with increased behavior problems, including hyperactivity/inattention (BP1: β = 0.16; 95 % confidence interval [CI]: 0.04, 0.30), emotional problems (BP1: β = 0.11; 95 % CI: 0.02, 0.20; TCS: β = 0.08; 95 % CI: 0.02, 0.14), and peer problems (MeP: β = 0.10; 95 % CI: 0.02, 0.18); however, we did not identify any significant association with conduct problems. Further phenol mixture analyses in the WQS model yielded similar results. Stratification for child sex showed stronger positive associations in boys. CONCLUSION Our findings indicated that maternal phenol levels during early pregnancy, specifically BP1, TCS, and MeP, are associated with high behavioral problem scores in 4-year-old children.
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Affiliation(s)
- Xiaoning Lei
- MOE-Shanghai Key Laboratory of Children's Environmental Health, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, PR China; Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, PR China.
| | - Junjie Ao
- MOE-Shanghai Key Laboratory of Children's Environmental Health, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, PR China
| | - Jingjing Li
- Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, PR China
| | - Yu Gao
- Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, PR China
| | - Jun Zhang
- MOE-Shanghai Key Laboratory of Children's Environmental Health, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, PR China
| | - Ying Tian
- MOE-Shanghai Key Laboratory of Children's Environmental Health, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, 200092 Shanghai, PR China; Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, PR China.
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Yesildemir O, Celik MN. Association between pre- and postnatal exposure to endocrine-disrupting chemicals and birth and neurodevelopmental outcomes: an extensive review. Clin Exp Pediatr 2024; 67:328-346. [PMID: 37986566 PMCID: PMC11222910 DOI: 10.3345/cep.2023.00941] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 07/13/2023] [Accepted: 08/14/2023] [Indexed: 11/22/2023] Open
Abstract
Endocrine-disrupting chemicals (EDCs) are natural or synthetic chemicals that mimic, block, or interfere with the hormones in the body. The most common and well- studied EDCs are bisphenol A, phthalates, and persistent organic pollutants including polychlorinated biphenyls, polybrominated diphenyl ethers, per- and polyfluoroalkyl substances, other brominated flame retardants, organochlorine pesticides, dioxins, and furans. Starting in embryonic life, humans are constantly exposed to EDCs through air, diet, skin, and water. Fetuses and newborns undergo crucial developmental processes that allow adaptation to the environment throughout life. As developing organisms, they are extremely sensitive to low doses of EDCs. Many EDCs can cross the placental barrier and reach the developing fetal organs. In addition, newborns can be exposed to EDCs through breastfeeding or formula feeding. Pre- and postnatal exposure to EDCs may increase the risk of childhood diseases by disrupting the hormone-mediated processes critical for growth and development during gestation and infancy. This review discusses evidence of the relationship between pre- and postnatal exposure to several EDCs, childbirth, and neurodevelopmental outcomes. Available evidence suggests that pre- and postnatal exposure to certain EDCs causes fetal growth restriction, preterm birth, low birth weight, and neurodevelopmental problems through various mechanisms of action. Given the adverse effects of EDCs on child development, further studies are required to clarify the overall associations.
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Affiliation(s)
- Ozge Yesildemir
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Bursa Uludag University, Bursa, Turkey
| | - Mensure Nur Celik
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Ondokuz Mayıs University, Samsun, Turkey
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Morales-Grahl E, Hilz EN, Gore AC. Regrettable Substitutes and the Brain: What Animal Models and Human Studies Tell Us about the Neurodevelopmental Effects of Bisphenol, Per- and Polyfluoroalkyl Substances, and Phthalate Replacements. Int J Mol Sci 2024; 25:6887. [PMID: 38999997 PMCID: PMC11241431 DOI: 10.3390/ijms25136887] [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: 04/26/2024] [Revised: 06/14/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
In recent decades, emerging evidence has identified endocrine and neurologic health concerns related to exposure to endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), certain per- and polyfluoroalkyl compounds (PFASs), and phthalates. This has resulted in consumer pressure to remove these chemicals from the market, especially in food-contact materials and personal care products, driving their replacement with structurally or functionally similar substitutes. However, these "new-generation" chemicals may be just as or more harmful than their predecessors and some have not received adequate testing. This review discusses the research on early-life exposures to new-generation bisphenols, PFASs, and phthalates and their links to neurodevelopmental and behavioral alterations in zebrafish, rodents, and humans. As a whole, the evidence suggests that BPA alternatives, especially BPAF, and newer PFASs, such as GenX, can have significant effects on neurodevelopment. The need for further research, especially regarding phthalate replacements and bio-based alternatives, is briefly discussed.
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Affiliation(s)
| | | | - Andrea C. Gore
- Division of Pharmacology and Toxicology, The University of Texas at Austin, Austin, TX 78712, USA; (E.M.-G.); (E.N.H.)
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Nayan NM, Kadir SHSA, Husin A, Siran R. Neurodevelopmental effects of prenatal Bisphenol A exposure on the role of microRNA regulating NMDA receptor subunits in the male rat hippocampus. Physiol Behav 2024; 280:114546. [PMID: 38583549 DOI: 10.1016/j.physbeh.2024.114546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/22/2024] [Accepted: 04/05/2024] [Indexed: 04/09/2024]
Abstract
Maternal bisphenol A (BPA) exposure has been reported to cause learning and memory deficits in born offspring. However, little is known that this impairment is potentially caused by epigenetic modulation on the development of NMDA receptor subunits. This study investigates the effect of prenatal BPA exposure on the hippocampal miR-19a and miR-539, which are responsible for regulating NMDA receptor subunits as well as learning and memory functions. Pregnant Sprague Dawley rats were orally administered with 5 mg/kg/day of BPA from pregnancy day 1 (PD1) until gestation day 21 (GD21), while control mothers received no BPA. The mothers were observed daily until GD21 for either a cesarean section or spontaneous delivery. The male offspring were sacrificed when reaching GD21 (fetus), postnatal days 7, 14, 21 (PND7, 14, 21) and adolescent age 35 (AD35) where their hippocampi were dissected from the brain. The expression of targeted miR-19a, miR-539, GRIN2A, and GRIN2B were determined by qRT-PCR while the level of GluN2A and GluN2B were estimated by western blot. At AD35, the rats were assessed with neurobehavioral tests to evaluate their learning and memory function. The findings showed that prenatal BPA exposure at 5 mg/kg/day significantly reduces the expression of miR-19a, miR-539, GRIN2A, and GRIN2B genes in the male rat hippocampus at all ages. The level of GluN2A and GluN2B proteins is also significantly reduced when reaching adolescent age. Consequently, the rats showed spatial and fear memory impairments when reaching AD35. In conclusion, prenatal BPA exposure disrupts the role of miR-19a and miR-539 in regulating the NMDA receptor subunit in the hippocampus which may be one of the causes of memory and learning impairment in adolescent rats.
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Affiliation(s)
- Norazirah Mat Nayan
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA 47000, Sungai Buloh, Selangor, Malaysia; Laboratory Animal Care Unit (LACU), Faculty of Medicine, Universiti Teknologi MARA 47000, Sungai Buloh, Selangor, Malaysia; Institute for Molecular Medicine and Biotechnology (IMMB) Faculty of Medicine, Universiti Teknologi MARA 47000, Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abd Kadir
- Institute for Molecular Medicine and Biotechnology (IMMB) Faculty of Medicine, Universiti Teknologi MARA 47000, Sungai Buloh, Selangor, Malaysia
| | - Andrean Husin
- Faculty of Dentistry, Universiti Teknologi MARA 47000, Sungai Buloh, Selangor, Malaysia; Neuroscience Research Group (NRG), Faculty of Medicine, Universiti Teknologi MARA, 47000, Sungai Buloh, Selangor, Malaysia
| | - Rosfaiizah Siran
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA 47000, Sungai Buloh, Selangor, Malaysia; Neuroscience Research Group (NRG), Faculty of Medicine, Universiti Teknologi MARA, 47000, Sungai Buloh, Selangor, Malaysia..
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9
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Cao Z, Yang M, Gong H, Feng X, Hu L, Li R, Xu S, Wang Y, Xiao H, Zhou A. Association between prenatal exposure to rare earth elements and the neurodevelopment of children at 24-months of age: A prospective cohort study. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 343:123201. [PMID: 38135135 DOI: 10.1016/j.envpol.2023.123201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 12/18/2023] [Accepted: 12/19/2023] [Indexed: 12/24/2023]
Abstract
The increasing consumption of rare earth elements (REEs) has resulted in a considerable risk of environmental exposure. However, the adverse effects of prenatal REEs exposure on children's neurodevelopment are not yet fully recognized. Therefore, we investigated the individual and joint effects of prenatal exposure to 13 REEs on children's neurocognitive development based on 809 mother-child pairs from a large birth cohort in Wuhan, China. Maternal urinary concentrations of 13 REEs were repeatedly measured by inductively coupled plasma mass spectrometry. Children's neurodevelopment [e.g., mental and psychomotor development index (MDI/PDI)] at 24-months was assessed using Bayley Scales of Infant Development of Chinese Revision. GEE and BKMR models were applied to estimate the individual and joint effects of prenatal REE exposure on child neurodevelopment level. After controlling for typical confounders, we observed that exposure to 9 REEs during the first trimester were significantly associated with decreased MDI scores [βs and 95% confidence intervals (CIs) ranging from -2.24 (-3.86 ∼ -0.63) to -1.44 (-2.26∼ -0.26)], and 7 REEs during third trimester were significantly associated decreased PDI scores [β and 95% CIs ranging from -1.95 (-3.19 ∼ -0.71) to -1.25 (-2.34 ∼ -0.16)]. Higher quantiles of REE mixture in first and third trimester were associated with decreased MDI and PDI score. Thulium, erbium in the first trimester and cerium, lanthanum in the third trimester accounted most importance to joint effects on MDI and PDI, respectively. In conclusion, prenatal exposure to higher concentrations of REEs during the first and third trimester were negative associated with children's neurodevelopment.
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Affiliation(s)
- Zhongqiang Cao
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Meng Yang
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Hongjian Gong
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xiaoyuan Feng
- Medical Center of Cardiovascular Ultrasound, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Liqin Hu
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Ruizhen Li
- Department of Child Healthcare, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Shunqing Xu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Youjie Wang
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Han Xiao
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Aifen Zhou
- Institute of Maternal and Children Health, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
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10
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Dou L, Sun S, Chen L, Lv L, Chen C, Huang Z, Zhang A, He H, Tao H, Yu M, Zhu M, Zhang C, Hao J. The association between prenatal bisphenol F exposure and infant neurodevelopment: The mediating role of placental estradiol. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 271:116009. [PMID: 38277971 DOI: 10.1016/j.ecoenv.2024.116009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/19/2024] [Accepted: 01/21/2024] [Indexed: 01/28/2024]
Abstract
BACKGROUND There are limited population studies on the neurodevelopmental effects of bisphenol F (BPF), a substitute for bisphenol A. Furthermore, the role of placental estradiol as a potential mediator linking these two factors remains unclear. OBJECTIVE To examine the association between maternal prenatal BPF exposure and infant neurodevelopment in a prospective cohort study and to explore the mediating effects of placental estradiol between BPF exposure and neurodevelopment in a nested case-control study. METHODS The prospective cohort study included 1077 mother-neonate pairs from the Wuhu city cohort study in China. Maternal BPF was determined using the liquid/liquid extraction and Ultra-performance liquid chromatography tandem mass spectrometry method. Children's neurodevelopment was assessed at ages 3, 6, and 12 months using Ages and Stages Questionnaires. The nested case-control study included 150 neurodevelopmental delay cases and 150 healthy controls. Placental estradiol levels were measured using enzyme-linked immunosorbent assay kits. Generalized estimating equation models and robust Poisson regression models were used to examine the associations between BPF exposure and children's neurodevelopment. In the nested case-control study, causal mediation analysis was conducted to assess the role of placental estradiol as a mediator in multivariate models. RESULTS In the prospective cohort study, the pregnancy-average BPF concentration was positively associated with developmental delays in gross-motor, fine-motor, and problem-solving ( ORtotal ASQ: 1.14(1.05, 1.25), ORgross-motor: 1.22(1.10, 1.36), ORfine-motor: 1.19(1.07, 1.31), ORproblem-solving: 1.11(1.01, 1.23)). After sex-stratified analyses, pregnancy-average BPF concentration was associated with an increased risk of neurodevelopmental delays in the gross-motor (ORgross-motor:1.30(1.12, 1.51)) and fine-motor (ORfine-motor: 1.22(1.06, 1.40)) domains in boys. In the nested case-control study, placental estradiol mediated 16.6% (95%CI: 4.4%, 35.0%) of the effects of prenatal BPF exposure on developmental delay. CONCLUSIONS Our study supports an inverse relationship between prenatal BPF exposure and child neurodevelopment in infancy, particularly in boys. Decreased placental estradiol may be an underlying biological pathway linking prenatal BPF exposure to neurodevelopmental delay in offspring.
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Affiliation(s)
- Lianjie Dou
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China
| | - Shu Sun
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China
| | - Lan Chen
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China
| | - Lanxing Lv
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China
| | - Chen Chen
- Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China
| | - Zhaohui Huang
- Anhui Provincial Center for Women and Children's Health, Hefei, Anhui Province, China
| | - Anhui Zhang
- Wuhu Maternal and Child Health (MCH) Center, Wuhu, Anhui Province, China
| | - Haiyan He
- Wuhu Maternal and Child Health (MCH) Center, Wuhu, Anhui Province, China
| | - Hong Tao
- Wuhu Maternal and Child Health (MCH) Center, Wuhu, Anhui Province, China
| | - Min Yu
- Wuhu Maternal and Child Health (MCH) Center, Wuhu, Anhui Province, China
| | - Min Zhu
- Wuhu Maternal and Child Health (MCH) Center, Wuhu, Anhui Province, China
| | - Chao Zhang
- Key Laboratory of Population Health Across Life Cycle (Anhui Medical University),Ministry of Education of the People's Republic of China, Hefei, Anhui Province, China; Department of Health Promotion and Behavioral Sciences, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China.
| | - Jiahu Hao
- Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China; Department of Maternal, Child & Adolescent Health, School of Public Health, Anhui Medical University, Hefei, Anhui Province, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University),Ministry of Education of the People's Republic of China, Hefei, Anhui Province, China; NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Hefei, Anhui Province, China.
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11
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Costa HE, Cairrao E. Effect of bisphenol A on the neurological system: a review update. Arch Toxicol 2024; 98:1-73. [PMID: 37855918 PMCID: PMC10761478 DOI: 10.1007/s00204-023-03614-0] [Citation(s) in RCA: 48] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/27/2023] [Indexed: 10/20/2023]
Abstract
Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) and one of the most produced synthetic compounds worldwide. BPA can be found in epoxy resins and polycarbonate plastics, which are frequently used in food storage and baby bottles. However, BPA can bind mainly to estrogen receptors, interfering with various neurologic functions, its use is a topic of significant concern. Nonetheless, the neurotoxicity of BPA has not been fully understood despite numerous investigations on its disruptive effects. Therefore, this review aims to highlight the most recent studies on the implications of BPA on the neurologic system. Our findings suggest that BPA exposure impairs various structural and molecular brain changes, promoting oxidative stress, changing expression levels of several crucial genes and proteins, destructive effects on neurotransmitters, excitotoxicity and neuroinflammation, damaged blood-brain barrier function, neuronal damage, apoptosis effects, disruption of intracellular Ca2+ homeostasis, increase in reactive oxygen species, promoted apoptosis and intracellular lactate dehydrogenase release, a decrease of axon length, microglial DNA damage, astrogliosis, and significantly reduced myelination. Moreover, BPA exposure increases the risk of developing neurologic diseases, including neurovascular (e.g. stroke) and neurodegenerative (e.g. Alzheimer's and Parkinson's) diseases. Furthermore, epidemiological studies showed that the adverse effects of BPA on neurodevelopment in children contributed to the emergence of serious neurological diseases like attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, emotional problems, anxiety, and cognitive disorders. In summary, BPA exposure compromises human health, promoting the development and progression of neurologic disorders. More research is required to fully understand how BPA-induced neurotoxicity affects human health.
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Affiliation(s)
- Henrique Eloi Costa
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
- FCS-UBI, Faculty of Health Sciences, University of Beira Interior, 6200-506, Covilhã, Portugal
| | - Elisa Cairrao
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal.
- FCS-UBI, Faculty of Health Sciences, University of Beira Interior, 6200-506, Covilhã, Portugal.
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12
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Wang X, Luo ZC, Du O, Zhang HJ, Fan P, Ma R, Chen Y, Wang W, Zhang J, Ouyang F. The association between maternal urinary Bisphenol A levels and neurodevelopment at age 2 years in Chinese boys and girls: A prospective cohort study. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 264:115413. [PMID: 37651794 DOI: 10.1016/j.ecoenv.2023.115413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/22/2023] [Accepted: 08/25/2023] [Indexed: 09/02/2023]
Abstract
The impact of maternal exposure to Bisphenol A on child cognitive development as well as its sex dimorphism remains uncertain. This study used data of 215 mothers and their children from a birth cohort in Shanghai. Urinary BPA were measured in spot urine samples of mothers at late pregnancy and children at age 2 years. Cognitive development was evaluated by Ages & Stages Questionnaires, Third Edition (ASQ-3) at age 2 years. Urinary BPA was detectable in 98.9% of mothers (geometric mean, GM: 2.6 μg/g. creatinine) and 99.8% children (GM: 3.4 μg/g. creatinine). Relative to the low and medium BPA tertiles, high tertile of maternal urinary BPA concentrations were associated with 4.8 points lower (95% CI: -8.3, -1.2) in gross motor and 3.7 points lower (95% CI: -7.4, -0.1) in problem-solving domain in girls only, with adjustment for maternal age, maternal education, pre-pregnancy BMI, passive smoking during pregnancy, parity, delivery mode, birth-weight for gestational age, child age at ASQ-3 test. This negative association remained with additional adjustment for child urinary BPA concentrations at age 2 years. No association was observed in boys. These results suggested the sex-dimorphism on the associations of maternal BPA exposure with gross motor and problem-solving domains in children at age 2 years. This study also indicated that optimal early child development should start with a healthy BPA-free "in utero" environment.
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Affiliation(s)
- Xia Wang
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Neonatology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhong-Cheng Luo
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Obstetrics and Gynecology, Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Institute of Health Policy, Management and Evaluation, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Ouyang Du
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Electrical and Systems Engineering, McKelvey School of Engineering at Washington University in St. Louis, USA
| | - Hui-Juan Zhang
- Department of Pathology, The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Pianpian Fan
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui Ma
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuanzhi Chen
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiye Wang
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fengxiu Ouyang
- Ministry of Education and Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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13
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Mustieles V, Rolland M, Pin I, Thomsen C, Sakhi AK, Sabaredzovic A, Muckle G, Guichardet K, Slama R, Philippat C. Early-Life Exposure to a Mixture of Phenols and Phthalates in Relation to Child Social Behavior: Applying an Evidence-Based Prioritization to a Cohort with Improved Exposure Assessment. ENVIRONMENTAL HEALTH PERSPECTIVES 2023; 131:87006. [PMID: 37556305 PMCID: PMC10411634 DOI: 10.1289/ehp11798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 05/10/2023] [Accepted: 06/26/2023] [Indexed: 08/11/2023]
Abstract
BACKGROUND Previous studies aiming at relating exposure to phenols and phthalates with child social behavior characterized exposure using one or a few spot urine samples, resulting in substantial exposure misclassification. Moreover, early infancy exposure was rarely studied. OBJECTIVES We aimed to examine the associations of phthalates and phenols with child social behavior in a cohort with improved exposure assessment and to a priori identify the chemicals supported by a higher weight of evidence. METHODS Among 406 mother-child pairs from the French Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES) cohort, 25 phenols/phthalate metabolites were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (∼ 21 samples/trimester) and at 2 months and 1-year of age (∼ 7 samples/period). Social behavior was parent-reported at 3 years of age of the child using the Social Responsiveness Scale (SRS). A structured literature review of the animal and human evidence was performed to prioritize the measured phthalates/phenols based on their likelihood to affect social behavior. Both adjusted linear regression and Bayesian Weighted Quantile Sum (BWQS) regression models were fitted. False discovery rate (FDR) correction was applied only to nonprioritized chemicals. RESULTS Prioritized compounds included bisphenol A, bisphenol S, triclosan (TCS), diethyl-hexyl phthalate (Σ DEHP ), mono-ethyl phthalate (MEP), mono-n -butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). With the exception of bisphenols, which showed a mixed pattern of positive and negative associations in pregnant mothers and neonates, few prenatal associations were observed. Most associations were observed with prioritized chemicals measured in 1-y-old infants: Each doubling in urinary TCS (β = 0.78 ; 95% CI: 0.00, 1.55) and MEP (β = 0.92 ; 95% CI: - 0.11 , 1.96) concentrations were associated with worse total SRS scores, whereas MnBP and Σ DEHP were associated with worse Social Awareness (β = 0.25 ; 95% CI: 0.01, 0.50) and Social Communication (β = 0.43 ; 95% CI: - 0.02 , 0.89) scores, respectively. BWQS also suggested worse total SRS [Beta 1 = 1.38 ; 95% credible interval (CrI): - 0.18 , 2.97], Social Awareness (Beta 1 = 0.37 ; 95% CrI: 0.06, 0.70), and Social Communication (Beta 1 = 0.91 ; 95% CrI: 0.31, 1.53) scores per quartile increase in the mixture of prioritized compounds assessed in 1-y-old infants. The few associations observed with nonprioritized chemicals did not remain after FDR correction, with the exception of benzophenone-3 exposure in 1-y-old infants, which was suggestively associated with worse Social Communication scores (corrected p = 0.07 ). DISCUSSION The literature search allowed us to adapt our statistical analysis according to the weight of evidence and create a corpus of experimental and epidemiological knowledge to better interpret our findings. Early infancy appears to be a sensitive exposure window that should be further investigated. https://doi.org/10.1289/EHP11798.
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Affiliation(s)
- Vicente Mustieles
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France
| | - Matthieu Rolland
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France
| | - Isabelle Pin
- Pediatric Department, Grenoble Alpes University Hospital, La Tronche, France
| | | | | | | | - Gina Muckle
- Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, Canada
| | - Karine Guichardet
- Pediatric Department, Grenoble Alpes University Hospital, La Tronche, France
| | - Rémy Slama
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France
| | - Claire Philippat
- University Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Team of Environmental Epidemiology Applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France
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14
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Xiong C, Xu L, Dong X, Cao Z, Wang Y, Chen K, Guo M, Xu S, Li Y, Xia W, Zhou A. Trimester-specific associations of maternal exposure to bisphenols with neonatal thyroid stimulating hormone levels: A birth cohort study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 880:163354. [PMID: 37023811 DOI: 10.1016/j.scitotenv.2023.163354] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/09/2023] [Accepted: 04/03/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Growing evidence suggests that exposure to bisphenol A (BPA) during pregnancy could interfere with neonatal thyroid function. Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as the substitutes of BPA. However, little is known about the effects of maternal exposure to BPS and BPF on neonatal thyroid function. The current study was aimed to investigate the trimester-specific associations of maternal exposure to BPA, BPS, and BPF with neonatal thyroid stimulating hormone (TSH) levels. METHODS Between November 2013 and March 2015, a total of 904 mother-newborn pairs were recruited from the Wuhan Healthy Baby Cohort Study, providing maternal urine samples in the first, second, and third trimesters for bisphenol exposure assessment, and neonatal heel prick blood samples for TSH measurement. Multiple informant model and quantile g-computation were used to evaluate the trimester-specific associations of bisphenols individually and mixture with TSH, respectively. RESULTS Each doubling concentration increase of maternal urinary BPA in the first trimester was significantly related to a 3.64 % (95% CI: 0.84 %, 6.51 %) increment in neonatal TSH. Each doubling concentration increase of BPS in the first, second and third trimesters were associated with 5.81 % (95 % CI: 2.27 %, 9.46 %), 5.70 % (95 % CI: 1.99 %, 9.55 %), 4.36 % (95 % CI: 0.75 %, 8.11 %) higher neonatal blood TSH, respectively. No significant association between trimester-specific BPF concentration and TSH was observed. The relationships between exposures to BPA/BPS and neonatal TSH were more evident in female infants. Quantile g-computation indicated that maternal co-exposure to bisphenols in the first trimester was significantly associated with neonatal TSH levels in a non-linear fashion. CONCLUSION Maternal exposure to BPA and BPS were positively associated with neonatal TSH levels. The results indicated the endocrine disrupting effect of prenatal exposure to BPS and BPA, which should be of particular concern.
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Affiliation(s)
- Chao Xiong
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Luli Xu
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaohan Dong
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhongqiang Cao
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuji Wang
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kai Chen
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Menglan Guo
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shunqing Xu
- Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; School of Life Science, Hainan University, Haikou, Hainan, China
| | - Yuanyuan Li
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Xia
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, State Key Laboratory of Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Aifen Zhou
- Wuhan Children's Hospital, Wuhan Maternal and Child Healthcare Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
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15
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Irvine N, England-Mason G, Field CJ, Letourneau N, Bell RC, Giesbrecht GF, Kinniburgh DW, MacDonald AM, Martin JW, Dewey D. Associations between maternal folate status and choline intake during pregnancy and neurodevelopment at 3-4 years of age in the Alberta Pregnancy Outcomes and Nutrition (APrON) study. J Dev Orig Health Dis 2023; 14:402-414. [PMID: 36939090 PMCID: PMC10202845 DOI: 10.1017/s2040174423000041] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2023]
Abstract
Folate and choline are methyl donor nutrients that may play a role in fetal brain development. Animal studies have reported that prenatal folate and choline supplementation are associated with better cognitive outcomes in offspring and that these nutrients may interact and affect brain development. Human studies that have investigated associations between maternal prenatal folate or choline levels and neurodevelopmental outcomes have reported contradictory findings and no human studies have examined the potential interactive effect of folate and choline on children's neurodevelopment. During the second trimester of pregnancy, maternal red blood cell folate was measured from blood samples and choline intake was estimated using a 24-h dietary recall in 309 women in the APrON cohort. At 3-5 years of age, their children's neurodevelopment was assessed using the Wechsler Preschool and Primary Scales of Intelligence - Fourth EditionCND, NEPSY-II language and memory subtests, four behavioral executive function tasks, and the Movement Assessment Battery for Children - Second Edition. Adjusted regressions revealed no associations between maternal folate and choline levels during pregnancy and most of the child outcomes. On the Dimensional Change Card Sort, an executive function task, there was an interaction effect; at high levels of choline intake (i.e., 1 SD above the mean; 223.03 mg/day), higher maternal folate status was associated with decreased odds of receiving a passing score (β = -0.44; 95%CI -0.81, -0.06). In conclusion, maternal folate status and choline intake during the second trimester of pregnancy were not associated with children's intelligence, language, memory, or motor outcomes at 3-4 years of age; however, their interaction may have an influence children's executive functions.
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Affiliation(s)
- Nathalie Irvine
- Bachelor of Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Gillian England-Mason
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
| | - Catherine J Field
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Nicole Letourneau
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Faculty of Nursing, University of Calgary, Calgary, Alberta, Canada
- Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Rhonda C Bell
- Department of Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Gerald F Giesbrecht
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Psychology, University of Calgary, Calgary, Alberta, Canada
| | - David W Kinniburgh
- Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Amy M MacDonald
- Alberta Centre for Toxicology, University of Calgary, Calgary, Alberta, Canada
| | - Jonathan W Martin
- Science for Life Laboratory, Department of Environmental Sciences, Stockholm University, Stockholm, Sweden
| | - Deborah Dewey
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Owerko Centre, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
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16
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Tehrani JM, Kennedy E, Tung PW, Burt A, Hermetz K, Punshon T, Jackson BP, Hao K, Chen J, Karagas MR, Koestler DC, Lester B, Marsit CJ. Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth. Pediatr Res 2023; 93:1410-1418. [PMID: 35906307 PMCID: PMC9884320 DOI: 10.1038/s41390-022-02201-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 06/22/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND Prenatal cadmium (Cd) exposure has been implicated in both placental toxicity and adverse neurobehavioral outcomes. Placental microRNAs (miRNAs) may function to developmentally program adverse pregnancy and newborn health outcomes in response to gestational Cd exposure. METHODS In a subset of the Rhode Island Child Health Study (RICHS, n = 115) and the New Hampshire Birth Cohort Study (NHBCS, = 281), we used small RNA sequencing and trace metal analysis to identify Cd-associated expression of placental miRNAs using negative binomial generalized linear models. We predicted mRNAs targeted by Cd-associated miRNAs and relate them to neurobehavioral outcomes at birth through the integration of transcriptomic data and summary scores from the NICU Network Neurobehavioral Scale (NNNS). RESULTS Placental Cd concentrations are significantly associated with the expression level of five placental miRNAs in NHBCS, with similar effect sizes in RICHS. These miRNA target genes overrepresented in nervous system development, and their expression is correlated with NNNS metrics suggestive of atypical neurobehavioral outcomes at birth. CONCLUSIONS Gestational Cd exposure is associated with the expression of placental miRNAs. Predicted targets of these miRNAs are involved in nervous system development and may also regulate placental physiology, allowing their dysregulation to modify developmental programming of early life health outcomes. IMPACT This research aims to address the poor understanding of the molecular mechanisms governing adverse pregnancy and newborn health outcomes in response to Gestational cadmium (Cd) exposure. Our results outline a robust relationship between Cd-associated placental microRNA expression and NICU Network Neurobehavioral Scales (NNNS) at birth indicative of atypical neurobehavior. This study utilized healthy mother-infant cohorts to describe the role of Cd-associated dysregulation of placental microRNAs as a potential mechanism by which adverse neurobehavioral outcomes are developmentally programmed.
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Affiliation(s)
- Jesse M Tehrani
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Elizabeth Kennedy
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Pei Wen Tung
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Amber Burt
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Karen Hermetz
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Tracy Punshon
- Department of Biological Sciences, Dartmouth College, Hanover, NH, USA
| | - Brian P Jackson
- Department of Earth Sciences, Dartmouth College, Hanover, NH, USA
| | - Ke Hao
- Department of Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jia Chen
- Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Margaret R Karagas
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA
| | - Devin C Koestler
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, KS, USA
| | - Barry Lester
- Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI, USA
- The Brown Center of the Study of Children at Risk, Brown University, Providence, RI, USA
| | - Carmen J Marsit
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
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17
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Wang X, Wang Y, Xu T, Fan Y, Ding Y, Qian J. A novel compound heterozygous mutation of the CLCN7 gene is associated with autosomal recessive osteopetrosis. Front Pediatr 2023; 11:978879. [PMID: 37168803 PMCID: PMC10165073 DOI: 10.3389/fped.2023.978879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 03/28/2023] [Indexed: 05/13/2023] Open
Abstract
Osteopetrosis is a genetic condition of the skeleton characterized by increased bone density caused by osteoclast formation and function defects. Osteopetrosis is inherited in the form of autosomal dominant and autosomal recessive manner. We report autosomal recessive osteopetrosis (ARO; OMIM 611490) in a Chinese case with a history of scarce leukocytosis, vision and hearing loss, frequent seizures, and severe intellectual and motor disability. Whole-exome sequencing (WES) followed by Sanger sequencing revealed novel compound heterozygous mutations in the chloride channel 7 (CLCN7) gene [c.982-1G > C and c.1208G > A (p. Arg403Gln)] in the affected individual, and subsequent familial segregation showed that each parent had transmitted a mutation. Our results confirmed that mutations in the CLCN7 gene caused ARO in a Chinese family. Additionally, our study expanded the clinical and allelic spectrum of the CLCN7 gene and enhanced the applications of WES technology in determining the etiology of prenatal diagnoses in fetuses with ultrasound anomalies.
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Affiliation(s)
- Xia Wang
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yingcan Wang
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Ting Xu
- Department of Pediatric Endocrinology/Genetics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yanjie Fan
- Department of Pediatric Endocrinology/Genetics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yifeng Ding
- Department of Neurology, Children's Hospital of Fudan University & National Children Medical Center, Shanghai, China
| | - Jihong Qian
- Department of Neonatology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
- Correspondence: Jihong Qian
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18
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Zheng J, Reynolds JE, Long M, Ostertag C, Pollock T, Hamilton M, Dunn JF, Liu J, Martin J, Grohs M, Landman B, Huo Y, Dewey D, Kurrasch D, Lebel C. The effects of prenatal bisphenol A exposure on brain volume of children and young mice. ENVIRONMENTAL RESEARCH 2022; 214:114040. [PMID: 35952745 PMCID: PMC11959573 DOI: 10.1016/j.envres.2022.114040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 06/15/2023]
Abstract
Bisphenol A (BPA) is a synthetic chemical used for the manufacturing of plastics, epoxy resin, and many personal care products. This ubiquitous endocrine disruptor is detectable in the urine of over 80% of North Americans. Although adverse neurodevelopmental outcomes have been observed in children with high gestational exposure to BPA, the effects of prenatal BPA on brain structure remain unclear. Here, using magnetic resonance imaging (MRI), we studied the associations of maternal BPA exposure with children's brain structure, as well as the impact of comparable BPA levels in a mouse model. Our human data showed that most maternal BPA exposure effects on brain volumes were small, with the largest effects observed in the opercular region of the inferior frontal gyrus (ρ = -0.2754), superior occipital gyrus (ρ = -0.2556), and postcentral gyrus (ρ = 0.2384). In mice, gestational exposure to an equivalent level of BPA (2.25 μg BPA/kg bw/day) induced structural alterations in brain regions including the superior olivary complex (SOC) and bed nucleus of stria terminalis (BNST) with larger effect sizes (1.07≤ Cohens d ≤ 1.53). Human (n = 87) and rodent (n = 8 each group) sample sizes, while small, are considered adequate to perform the primary endpoint analysis. Combined, these human and mouse data suggest that gestational exposure to low levels of BPA may have some impacts on the developing brain at the resolution of MRI.
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Affiliation(s)
- Jing Zheng
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Jess E Reynolds
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Madison Long
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Curtis Ostertag
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Tyler Pollock
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Max Hamilton
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Jeff F Dunn
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Jiaying Liu
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Jonathan Martin
- Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, SE-106 91, Sweden
| | - Melody Grohs
- Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Bennett Landman
- Department of Electrical Engineering & Computer Science, Vanderbilt University, Nashville, TN, USA
| | - Yuankai Huo
- Department of Electrical Engineering & Computer Science, Vanderbilt University, Nashville, TN, USA
| | - Deborah Dewey
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Deborah Kurrasch
- Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Catherine Lebel
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
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19
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Bragg M, Chavarro JE, Hamra GB, Hart JE, Tabb LP, Weisskopf MG, Volk HE, Lyall K. Prenatal Diet as a Modifier of Environmental Risk Factors for Autism and Related Neurodevelopmental Outcomes. Curr Environ Health Rep 2022; 9:324-338. [PMID: 35305256 DOI: 10.1007/s40572-022-00347-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Environmental chemicals and toxins have been associated with increased risk of impaired neurodevelopment and specific conditions like autism spectrum disorder (ASD). Prenatal diet is an individually modifiable factor that may alter associations with such environmental factors. The purpose of this review is to summarize studies examining prenatal dietary factors as potential modifiers of the relationship between environmental exposures and ASD or related neurodevelopmental outcomes. RECENT FINDINGS Twelve studies were identified; five examined ASD diagnosis or ASD-related traits as the outcome (age at assessment range: 2-5 years) while the remainder addressed associations with neurodevelopmental scores (age at assessment range: 6 months to 6 years). Most studies focused on folic acid, prenatal vitamins, or omega-3 fatty acids as potentially beneficial effect modifiers. Environmental risk factors examined included air pollutants, endocrine disrupting chemicals, pesticides, and heavy metals. Most studies took place in North America. In 10/12 studies, the prenatal dietary factor under study was identified as a significant modifier, generally attenuating the association between the environmental exposure and ASD or neurodevelopment. Prenatal diet may be a promising target to mitigate adverse effects of environmental exposures on neurodevelopmental outcomes. Further research focused on joint effects is needed that encompasses a broader variety of dietary factors, guided by our understanding of mechanisms linking environmental exposures with neurodevelopment. Future studies should also aim to include diverse populations, utilize advanced methods to optimize detection of novel joint effects, incorporate consideration of timing, and consider both synergistic and antagonistic potential of diet.
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Affiliation(s)
- Megan Bragg
- AJ Drexel Autism Institute, Drexel University, 3020 Market St., Philadelphia, PA, 19104, USA
| | - Jorge E Chavarro
- Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - Ghassan B Hamra
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Jaime E Hart
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Loni Philip Tabb
- Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, 3020 Market St., Philadelphia, PA, 19104, USA
| | - Marc G Weisskopf
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Heather E Volk
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Kristen Lyall
- AJ Drexel Autism Institute, Drexel University, 3020 Market St., Philadelphia, PA, 19104, USA. .,Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, 3020 Market St., Philadelphia, PA, 19104, USA.
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20
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Letourneau N, Aghajafari F, Bell RC, Deane AJ, Dewey D, Field C, Giesbrecht G, Kaplan B, Leung B, Ntanda H. The Alberta Pregnancy Outcomes and Nutrition (APrON) longitudinal study: cohort profile and key findings from the first three years. BMJ Open 2022; 12:e047503. [PMID: 35131812 PMCID: PMC8823238 DOI: 10.1136/bmjopen-2020-047503] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
PURPOSE The objectives of the ongoing Canadian longitudinal cohort called the Alberta Pregnancy Outcomes and Nutrition (APrON) study are to: (1) determine the relationship between maternal nutrient intake and status before, during, after pregnancy, and (a) maternal mental health, (b) pregnancy and birth outcomes, and (c) infant/child neurodevelopment and behavior; (2) identify maternal mental health and nutrient predictors of child behaviour; and (3) establish a DNA biobank to explore genomic predictors of children's neurodevelopment and behavior. The purpose of this paper is to describe the participants, measures, and key findings on maternal and paternal mental health, maternal nutrition, and child outcomes to when children are 3 years of age. PARTICIPANTS Participants included mothers and their children (n=2189) and mothers' partners (usually fathers; n=1325) from whom data were collected during the period from pregnancy to when children were 3 years of age, in Alberta, Canada. More than 88% of families have been retained to take part in completed data collection at 8 years of age. FINDINGS TO DATE Data comprise: questionnaires completed by pregnant women/mothers and their partners on mothers', fathers' and children's health; dietary interviews; clinical assessments; linkage to hospital obstetrical records; and biological samples such as DNA. Key findings on mental health, nutrition and child outcomes are presented. APrON women who consumed more selenium and omega-3 were less likely to develop symptoms of perinatal depression. Higher prenatal consumption of choline rich foods such as eggs and milk were recommended as was vitamin D supplementation for both mothers and children to meet guidelines. Couples in which both mothers and fathers were affected by perinatal depression reported lower incomes and higher maternal prenatal depressive symptoms and lower support from fathers postnatally and their children presented with the most behavioural problems. Maternal experiences of early adversity predicted increased likelihood of perinatal depression and anxiety and children's behavioural problems. FUTURE PLANS The APrON cohort offers a unique opportunity to advance understanding of the developmental origins of health and disease. There is a planned follow-up to collect data at 12 years of age.
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Affiliation(s)
- Nicole Letourneau
- Faculty of Nursing, University of Calgary, Calgary, Alberta, Canada
- Cumming School of Medicine (Departments of Paediatrics, Psychiatry & Community Health Sciences), University of Calgary, Calgary, Alberta, Canada
| | - Fariba Aghajafari
- Cumming School of Medicine (Family Medicine & Community Health Sciences), University of Calgary, Calgary, Alberta, Canada
| | - Rhonda C Bell
- Faculty of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Andrea J Deane
- Cumming School of Medicine (Pediatrics), University of Calgary, Calgary, Alberta, Canada
| | - Deborah Dewey
- Cumming School of Medicine (Pediatrics), University of Calgary, Calgary, Alberta, Canada
| | - Catherine Field
- Faculty of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Gerald Giesbrecht
- Cumming School of Medicine (Pediatrics & Community Health Sciences), University of Calgary, Calgary, Alberta, Canada
| | - Bonnie Kaplan
- Cumming School of Medicine (Pediatrics & Community Health Sciences), University of Calgary, Calgary, Alberta, Canada
| | - Brenda Leung
- Health Science - Public Health Program, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Henry Ntanda
- Cumming School of Medicine (Pediatrics), University of Calgary, Calgary, Alberta, Canada
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21
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Hudson KM, Shiver E, Yu J, Mehta S, Jima DD, Kane MA, Patisaul HB, Cowley M. Transcriptomic, proteomic, and metabolomic analyses identify candidate pathways linking maternal cadmium exposure to altered neurodevelopment and behavior. Sci Rep 2021; 11:16302. [PMID: 34381081 PMCID: PMC8357970 DOI: 10.1038/s41598-021-95630-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 07/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cadmium (Cd) is a ubiquitous toxic heavy metal of major public concern. Despite inefficient placental transfer, maternal Cd exposure impairs fetal growth and development. Increasing evidence from animal models and humans suggests maternal Cd exposure negatively impacts neurodevelopment; however, the underlying molecular mechanisms are unclear. To address this, we utilized multiple -omics approaches in a mouse model of maternal Cd exposure to identify pathways altered in the developing brain. Offspring maternally exposed to Cd presented with enlarged brains proportional to body weights at birth and altered behavior at adulthood. RNA-seq in newborn brains identified exposure-associated increases in Hox gene and myelin marker expression and suggested perturbed retinoic acid (RA) signaling. Proteomic analysis showed altered levels of proteins involved in cellular energy pathways, hypoxic response, and RA signaling. Consistent with transcriptomic and proteomic analyses, we identified increased levels of retinoids in maternally-exposed newborn brains. Metabolomic analyses identified metabolites with significantly altered abundance, supportive of changes to cellular energy pathways and hypoxia. Finally, maternal Cd exposure reduced mitochondrial DNA levels in newborn brains. The identification of multiple pathways perturbed in the developing brain provides a basis for future studies determining the mechanistic links between maternal Cd exposure and altered neurodevelopment and behavior.
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Affiliation(s)
- Kathleen M Hudson
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
| | - Emily Shiver
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
| | - Jianshi Yu
- School of Pharmacy Mass Spectrometry Center, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, 21201, USA
| | - Sanya Mehta
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
| | - Dereje D Jima
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, 27695, USA
| | - Maureen A Kane
- School of Pharmacy Mass Spectrometry Center, Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD, 21201, USA
| | - Heather B Patisaul
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA
| | - Michael Cowley
- Department of Biological Sciences, North Carolina State University, Raleigh, NC, 27695, USA.
- Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA.
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22
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Zhou Z, Yu D, Chen G, Li P, Wang L, Yang J, Rao J, Lin D, Fan D, Wang H, Gou X, Guo X, Suo D, Huang F, Liu Z. Fasting Plasma Glucose Mediates the Prospective Effect of Maternal Metal Level on Birth Outcomes: A Retrospective and Longitudinal Population-Based Cohort Study. Front Endocrinol (Lausanne) 2021; 12:763693. [PMID: 34867806 PMCID: PMC8635137 DOI: 10.3389/fendo.2021.763693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/22/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Previously, we found that the presence of maternal serum metals before the 24th week of gestation prospectively increased fasting plasma glucose (FPG) at 24-28 weeks. We further explored the prospective association between levels of metals and neonatal outcomes and assessed the mediating effects of FPG on these relationships. METHODS A total of 7,644 pregnant women were included in a retrospective cohort study, and the relationships between metals [manganese (Mn), copper (Cu), lead (Pb), zinc (Zn), and magnesium (Mg)] and birth outcomes were explored. Quantile and linear regressions were performed to detect the shifts and associations between metals and neonatal size distribution focused on the 10th, 50th, and 90th percentiles. Mediation analysis was performed to assess the mediating effect of FPG on metals and birth outcomes. RESULTS After adjustment, a 50% increase in Mn and Zn levels was related to a 0.136-cm (95% CI: 0.067-0.205) and 0.120-cm (95% CI: 0.046-0.193) increase in head circumference, respectively. Based on head circumference distribution, the magnitude of the association with Mn was smaller at the upper tail, while the magnitude of correlation with Zn was greater at the upper tail. A 50% increase in Mn and Zn levels was related to a 0.135-cm (95% CI: 0.058-0.212) and 0.095-cm (95% CI: 0.013-0.178) increase in chest circumference, respectively. The magnitude of the association with Mn increased with increasing chest circumference, while the magnitude of correlation with Zn decreased with increasing chest circumference. FPG explained 10.00% and 17.65% of the associations of Mn with head and chest circumference. A positive indirect effect of Zn associated with head circumference (0.004, 95% CI: 0.002-0.006) and chest circumference (0.005, 95% CI: 0.003-0.008) through FPG was also observed, and the estimated proportion of the mediating effect was 13.79% and 26.32%, respectively. CONCLUSION Maternal serum Mn and Zn levels before the 24th week of gestation may prospectively increase the circumference of the neonatal head and chest. FPG at 24-28 weeks had positive mediating effects on these relationships. Further research is needed to identify a balance between maternal blood glucose and birth size.
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Affiliation(s)
- Zixing Zhou
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Dandan Yu
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Gengdong Chen
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Pengsheng Li
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Lijuan Wang
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Jie Yang
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Jiaming Rao
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Dongxin Lin
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Dazhi Fan
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Haiyan Wang
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Xiaoyan Gou
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Xiaoling Guo
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
| | - Dongmei Suo
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- *Correspondence: Zhengping Liu, ; Fang Huang, ; Dongmei Suo,
| | - Fang Huang
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- *Correspondence: Zhengping Liu, ; Fang Huang, ; Dongmei Suo,
| | - Zhengping Liu
- Foshan Fetal Medicine Research Institute, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- Department of Obstetrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan, China
- *Correspondence: Zhengping Liu, ; Fang Huang, ; Dongmei Suo,
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