Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, 151 36, Södertälje, Sweden.
Karolinska Institutet, Department of Clinical Neuroscience, Centre for Molecular Medicine (CMM), 171 64, Solna, Sweden.
Sci Rep. 2018 Jul 27;8(1):11315. doi: 10.1038/s41598-018-29732-9.
Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, low APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and low APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.
双酚 A (BPA) 暴露与神经发育障碍以及对参与大脑功能的基因的表观遗传调控（如 DNA 甲基化）有关。高剂量的 BPA 已被证明会改变参与基因 Grin2b 的表达和调控。然而，动物和人类中是否存在这种变化以及剂量相关尚未得到解决。我们研究了低剂量发育性 BPA 暴露是否会影响成年大鼠大脑中 Grin2b 的 DNA 甲基化和表达。此外，我们评估了产前 BPA 暴露与 7 岁儿童 Grin2b 甲基化之间的关联。我们发现，雌性大鼠的 Grin2b mRNA 表达增加，而雄性大鼠的 Grin2b 表达没有变化。在人类中，产前 BPA 暴露与女孩的 Grin2b 甲基化水平升高有关。此外，低 APGAR 评分（神经发育疾病风险增加的预测因子）与女孩的 Grin2b 甲基化水平升高有关。因此，我们可以将发育性 BPA 暴露和低 APGAR 评分与 Grin2b 的表观遗传调控变化联系起来，Grin2b 是一个对神经元功能很重要的基因，其变化具有性别二态性。DNA 甲基化变化的确切位置和方向的差异可能反映了物种、分析组织、暴露水平和/或时间的差异。
