Effects of oral exposure to bisphenol A on gene expression and global genomic DNA methylation in the prostate, female mammary gland, and uterus of NCTR Sprague-Dawley rats

Abstract

Bisphenol A (BPA), an industrial chemical used in the manufacture of polycarbonate and epoxy resins, binds to the nuclear estrogen receptor with an affinity 4–5 orders of magnitude lower than that of estradiol. We reported previously that “high BPA” (100,000 and 300,000 μg/kg body weight (bw)/day), but not “low BPA” [2.5–2700 μg/kg bw/day], induced clear adverse effects in NCTR Sprague-Dawley rats gavaged daily from gestation day 6 through postnatal day 90. The “high BPA” effects partially overlapped those of ethinyl estradiol (EE2, 0.5 and 5.0 μg/kg bw/day). To evaluate further the potential of “low BPA” to induce biological effects, here we assessed the global genomic DNA methylation and gene expression in the prostate and female mammary glands, tissues identified previously as potential targets of BPA, and uterus, a sensitive estrogen-responsive tissue. Both doses of EE2 modulated gene expression, including of known estrogen-responsive genes, and PND 4 global gene expression data showed a partial overlap of the “high BPA” effects with those of EE2. The “low BPA” doses modulated the expression of several genes; however, the absence of a dose response reduces the likelihood that these changes were causally linked to the treatment. These results are consistent with the toxicity outcomes.

Evidence for bisphenol A-induced female infertility: a review (2007–2016)

“…These factors are important for endometrial proliferation and receptivity. In contrast, in utero high dose BPA exposure did not affect expression levels of coding complement component 3 ( C3 ), Pgr , calbindin D9K ( S100g ), and Vegfa in the adult offspring of rats (71); hence, it is unclear whether they are primary targets for BPA-induced uterine toxicity.…”

Global gene expression and morphological alterations in the mammary gland after gestational exposure to bisphenol A, genistein and indole-3-carbinol in female Sprague-Dawley offspring

“…Furthermore, in SD rats Moral et al (2008) also reported a significant increase in TDs and TEBs in BPA250-treated group when compared to control or control and BPA25 at PND 21 or PND 100, respectively. Depending on the experimental design, windows of exposure, dose range and rodent strain used BPA can induce either a dose-response or a U-response/nonmonotonic dose response curve (Vandenberg, 2014;Camacho et al, 2015). In the present study, the intrauterine exposure to an environmentally low dose of BPA (25 μg/kg bw/day) rather than to a high dose (250 μg/kg bw/day) had an effective deleterious effect on the development of the mammary gland structures, cell proliferation in TEBs and global gene expression at PND 21.…”

“…A few rodent studies have investigated the modulation of the gene expression signatures in the mammary gland from female offspring after maternal exposure to BPA, including the two doses and window of exposure evaluated in the present study (Moral et al, 2008;Wadia et al, 2013, Dhimolea et al, 2014Camacho et al, 2015). Moral et al (2008) reported that both doses of BPA (25 and 250 μg/kg bw/day) changed the gene expression signature in the mammary gland; BPA25 had the highest effect on the number of gene modulated at 50 days, whereas BPA250 had the highest influence on gene expression 100 days after maternal BPA administration.…”

“…The results of this study showed that fetal exposure to BPA induces large scale epigenetic changes in the rat mammary gland, with the majority of epigenetic changes occurring at PND21, while transcriptional analysis revealed that the majority of gene expression differences between BPA-treated and control animals were observed at PND50. Camacho et al (2015) reported that several genes were found to be modulated in the mammary gland from female SD offspring at PND4 whose dams were exposed dose range (2.5-300,000 μg/kg bw/day) from GD6 until parturition. The findings of this study using microarray analysis in female mammary gland showed alterations in several genes in the "low BPA" dose, but the lack of a dose-response reduces the likelihood that these effects were causally linked to the treatment.…”

NIEHS/FDA CLARITY-BPA research program update

“…In that study, there were clear adverse effects of BPA treatment at the two highest doses of 100,000 and 300,000 μg BPA/kg bw/day, some of which were also seen in the EE 2 groups. Statistically significant changes at the gene expression level of siblings were detected in the “low BPA” dose range [ 25 ]. The biological meaning of these changes is unclear.…”