Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development
Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development
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DOI：
10.1073/pnas.0703739104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Jirtle, Randy L.
中科院分区：
文献类型：
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作者：
Dolinoy, Dana C.;Huang, Dale;Jirtle, Randy L.
成人疾病源自胎儿的假说认为，早期发育暴露涉及表观遗传修饰，例如 DNA 甲基化，从而影响成人疾病的易感性。在子宫内或新生儿中接触双酚 A (BPA)（一种用于制造聚碳酸酯塑料的高产量化学品）会导致体重增加、乳腺癌和前列腺癌增加以及生殖功能改变。这项研究表明，母体接触这种内分泌活性化合物，通过降低 Agouti 基因上游 A 颗粒逆转录转座子中的 CpG（胞嘧啶鸟嘌呤二核苷酸）甲基化，使可存活的黄色刺豚鼠 (A(vy)) 小鼠后代的毛色分布向黄色转变。另一个亚稳态位点 CDK5 激活剂结合蛋白 (Cabp(IAP)) 的 CpG 甲基化也有所减少。 Avy 基因座的 DNA 甲基化在三个胚层的组织中相似，这提供了早期干细胞发育过程中的表观遗传模式对 BPA 暴露敏感的证据。此外，母亲膳食补充剂（叶酸等甲基供体或植物雌激素染料木黄酮）可以抵消 BPA 的 DNA 低甲基化作用。因此，我们提出了令人信服的证据，表明早期发育接触 BPA 可以通过稳定改变表观基因组来改变后代表型，这种效应可以通过母体膳食补充剂来抵消。
The hypothesis of fetal origins of adult disease posits that early developmental exposures involve epigenetic modifications, such as DNA methylation, that influence adult disease susceptibility. In utero or neonatal exposure to bisphenol A (BPA), a high-production-volume chemical used in the manufacture of polycarbonate plastic, is associated with higher body weight, increased breast and prostate cancer, and altered reproductive function. This study shows that maternal exposure to this endocrine-active compound shifted the coat color distribution of viable yellow agouti (A(vy)) mouse offspring toward yellow by decreasing CpG (cytosineguanine dinucleotide) methylation in an intracisternal A particle retrotransposon upstream of the Agouti gene. CpG methylation also was decreased at another metastable locus, the CDK5 activator-binding protein (Cabp(IAP)). DNA methylation at the Avy locus was similar in tissues from the three germ layers, providing evidence that epigenetic patterning during early stem cell development is sensitive to BPA exposure. Moreover, maternal dietary supplementation, with either methyl donors like folic acid or the phytoestrogen genistein, negated the DNA hypomethylating effect of BPA. Thus, we present compelling evidence that early developmental exposure to BPA can change offspring phenotype by stably altering the epigenome, an effect that can be counteracted by maternal dietary supplements.