Cuscuta chinensis flavonoids down-regulate the DNA methylation of the H19/Igf2 imprinted control region and estrogen receptor alpha promoter of the testis in bisphenol A exposed mouse offspring

Abstract

Exposure to the emerging contaminant bisphenol A (BPA) is ubiquitous and associated with reproductive disorders. The BPA effect as an endocrine disruptor is widely known but other mechanisms underlying developmental disease, such as epigenetic modifications, still remain unclear. The objective of this study was to investigate whether Cuscuta chinensis flavonoids (CCFs) can be used as a dietary supplement to reverse BPA-induced epigenetic disorders, by analyzing the molecular processes related to BPA impairment of testicular development. BPA and different concentrations of CCFs were administered to the dams at gestation day (GD) 0.5–17.5. The testis and serum of male mice were collected at postnatal day (PND) 21 and PND 56 for the detection of related indicators. Our results showed that compared with the BPA group, CCFs could significantly increase the serum contents of testosterone (T), estradiol (E₂) in males at PND 21 and PND 56, as well as the contents and transcription levels of DNA methyltransferase 3A (Dnmt3A), Dnmt3B in males at PND 21 and that of estrogen receptor alpha (ERα) at PND 56. The expressions of Dnmt1 and ERα at PND 21 and ERβ at both PND 21 and PND 56 in males were significantly decreased with the administration of different concentrations of CCFs (P < 0.01 or P < 0.05). CCFs also significantly inhibited the BPA-induced hypermethylated status of the ERα promoter and H19/Igf2 imprinting control region (ICR) in the testis at PND 56. These results indicated that CCFs could decrease the methylation levels of ERα and H19/Igf2 genes by inhibiting the expression of DNA methyltransferases (DNMTs), thereby decreasing the levels of reproductive hormones and receptors in adult males, and ultimately alleviating the negative effect of BPA on testicular development in male mice.