Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development

Abstract

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 A vy 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.

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…Methylation differences reported in this study are small as compared to those reported at the A vy locus in BPA-exposed animals 40 and in human liver cancer pathology, 41 but are similar to effect sizes reported at other epigenetic loci in A vy mice exposed to BPA. 24,42 Further, several comparisons yielded p-values between 0.05 and 0.1, indicating that several additional data points may have reached our chosen threshold for statistical significant (P<0.05) given a larger sample size and therefore greater power to detect small effect sizes.…”

Prospects for Epigenetic Epidemiology

“…Such exposure also decreases methylation of the cancer-causing oncogene c-fos (121) and the estrogen-responsive gene lactoferrin in mice (122). In animals, in utero or neonatal exposure to bisphenol A is associated with higher body mass, altered reproductive function, increasing cancer risk, and specific DNA methylation changes (123)(124)(125).…”

Time to Think Outside the (Genetic) Box

“…Indeed, folate (and diet in general) may be just the tip of an iceberg of epigenetic modulators. Exposure to environmental chemicals can affect DNA methylation in pregnant mice (20), and in vitro fertilization was associated with incomplete epigenetic reprogramming at some loci in children (21), raising the fear that each of these events may lead to constitutional defects such as that reported by Wong et al in this issue of the journal.…”