Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans

Alavian-Ghavanini, Ali; Lin, Ping; Lind, P. Monica; Rimfors, Sabina Risén; Lejonklou, Margareta Halin; Dunder, Linda; Tang, Mandy; Lindh, Christian; Bornehag, Carl‐Gustaf; Rüegg, Joëlle

doi:10.1038/s41598-018-29732-9

Cited by 49 publications

(31 citation statements)

References 69 publications

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“…Similarly, interference with GABAergic and glutamatergic signalling and neurone differentiation has also been shown in several different capacities, especially in the amygdala. Linked functional outcomes vary but include behavioural perturbations and a shift in the age at pubertal onset …”

Section: Clarity‐bpa: Brain and Behaviourmentioning

confidence: 99%

Achieving CLARITY on bisphenol A, brain and behaviour

Patisaul

2019

J Neuroendocrinology

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There is perhaps no endocrine disrupting chemical more controversial than bisphenol A (BPA). Comprising a high‐volume production chemical used in a variety of applications, BPA has been linked to a litany of adverse health‐related outcomes, including effects on brain sexual differentiation and behaviour. Risk assessors preferentially rely on classical guideline‐compliant toxicity studies over studies published by academic scientists, and have generally downplayed concerns about the potential risks that BPA poses to human health. It has been argued, however, that, because traditional toxicity studies rarely contain neural endpoints, and only a paucity of endocrine‐sensitive endpoints, they are incapable of fully evaluating harm. To address current controversies on the safety of BPA, the United States National Institute of Environmental Health Sciences, the National Toxicology Program (NTP), and the US Food and Drug Administration established the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY‐BPA). CLARITY‐BPA performed a classical regulatory‐style toxicology study (Core study) in conjunction with multiple behavioural, molecular and cellular studies conducted by academic laboratories (grantee studies) using a collaboratively devised experimental framework and the same animals and tissues. This review summarises the results from the grantee studies that focused on brain and behaviour. Evidence of altered neuroendocrine development, including age‐ and sex‐specific expression of oestrogen receptor (ER)α and ERβ, and the abrogation of brain and behavioural sexual dimorphisms, supports the conclusion that developmental BPA exposure, even at doses below what regulatory agencies regard as “safe” for humans, contribute to brain and behavioural change. The consistency and the reproducibility of the effects across CLARITY‐BPA and prior studies using the same animal strain and almost identical experimental conditions are compelling. Combined analysis of all of the data from the CLARITY‐BPA project is underway at the NTP and a final report expected in late 2019.

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Section: Clarity‐bpa: Brain and Behaviourmentioning

confidence: 99%

Achieving CLARITY on bisphenol A, brain and behaviour

Patisaul

2019

J Neuroendocrinology

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“…The activation of GnRH neurons in the POA by glutamate is necessary for reproductive function, and administration of a specific antagonist of the NMDAR2b subunit alter GnRH and downstream luteinizing hormone (LH) release in rats [ 75 ]. Limited work also suggests that EDCs may change Grin2b expression [ 63 , 76 ]. Our finding provides further support that glutamatergic neurotransmission may be altered by prenatal EDC exposure.…”

Section: Discussionmentioning

confidence: 99%

EDCs Reorganize Brain-Behavior Phenotypic Relationships in Rats

Scudder

Young

Thompson

et al. 2021

Journal of the Endocrine Society

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All species, including humans, are exposed to endocrine-disrupting chemicals (EDCs). Previous experiments have shown behavioral deficits caused by EDCs that have implications for social competence and sexual selection. The neuromolecular mechanisms for these behavioral changes induced by EDCs have not been thoroughly explored. Here, we tested the hypothesis that EDCs administered to rats during a critical period of embryonic brain development would lead to disruption of normal social preference behavior, and that this involves a network of underlying gene pathways in brain regions that regulate these behaviors. Rats were exposed prenatally to human-relevant concentrations of EDCs [polychlorinated biphenyls (PCB), vinclozolin (VIN)], or vehicle. In adulthood, a sociosexual preference test was administered. We profiled gene expression of in preoptic area (POA), medial amygdala (MeA), and ventromedial nucleus (VMN). Prenatal PCBs impaired sociosexual preference in both sexes, and VIN disrupted this behavior in males. Each brain region had unique sets of genes altered in a sex- and EDC-specific manner. Effects of EDCs on individual traits were typically small, but robust; EDC exposure changed the relationships between gene expression and behavior, a pattern we refer to as dis-integration and reconstitution. These findings underscore the effects that developmental exposure to EDCs can have on adult social behavior, highlight sex-specific and individual variation in responses, and provide a foundation for further work on the disruption of genes and behavior after prenatal exposure to EDCs.

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“…[ 51 ], a priori selected GRIN2B , a gene involved in neural function, and assessed associations between prenatal BPA exposure and DNA methylation at this gene in buccal DNA of 7-year old children. While GRIN2B was not associated with prenatal BPA in this study, GRIN2B and two genes associated with BPA in the present study, SLC2A1 and HIF1A , are related to one another via overlapping biological pathways [ 51 , 81 , 82 ]. Miura et al [ 49 ] utilized a Japanese cohort for whom they measured BPA concentrations in cord blood and evaluated cross-sectional epigenome-wide associations with cord blood DNA methylation.…”

Section: Discussionmentioning

confidence: 99%

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood

McCabe

Padmanabhan

Jones

et al. 2020

Environmental Epigenetics

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Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring’s risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes (N = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.

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Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans

Cited by 49 publications

References 69 publications

Achieving CLARITY on bisphenol A, brain and behaviour

Achieving CLARITY on bisphenol A, brain and behaviour

EDCs Reorganize Brain-Behavior Phenotypic Relationships in Rats

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood

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