Abstract
Exposure to environmental estrogens (xenoestrogens) may play a causal role in the increased breast cancer incidence which has been observed in Europe and the US over the last 50 years. The xenoestrogen bisphenol A (BPA) leaches from plastic food/beverage containers and dental materials. Fetal exposure to BPA induces preneoplastic and neoplastic lesions in the adult rat mammary gland. Previous results suggest that BPA acts through the estrogen receptors which are detected exclusively in the mesenchyme during the exposure period by directly altering gene expression, leading to alterations of the reciprocal interactions between mesenchyme and epithelium. This initiates a long sequence of altered morphogenetic events leading to neoplastic transformation. Additionally, BPA induces epigenetic changes in some tissues. To explore this mechanism in the mammary gland, Wistar-Furth rats were exposed subcutaneously via osmotic pumps to vehicle or 250 µg BPA/kg BW/day, a dose that induced ductal carcinomas in situ. Females exposed from gestational day 9 to postnatal day (PND) 1 were sacrificed at PND4, PND21 and at first estrus after PND50. Genomic DNA (gDNA) was isolated from the mammary tissue and immuno-precipitated using anti-5-methylcytosine antibodies. Detection and quantification of gDNA methylation status using the Nimblegen ChIP array revealed 7412 differentially methylated gDNA segments (out of 58207 segments), with the majority of changes occurring at PND21. Transcriptomal analysis revealed that the majority of gene expression differences between BPA- and vehicle-treated animals were observed later (PND50). BPA exposure resulted in higher levels of pro-activation histone H3K4 trimethylation at the transcriptional initiation site of the alpha-lactalbumin gene at PND4, concomitantly enhancing mRNA expression of this gene. These results show that fetal BPA exposure triggers changes in the postnatal and adult mammary gland epigenome and alters gene expression patterns. These events may contribute to the development of pre-neoplastic and neoplastic lesions that manifest during adulthood.
Highlights
The link between the fetal exposure to environmental perturbations and the diseases manifested in adulthood is generally referred to as ‘‘developmental origins of adult disease’’ [1,2]
Unconjugated bisphenol A (BPA) was undetectable in dams exposed to 25 mg BPA/kg body weight (BW)/day but was detected in all dams exposed to 250 mg BPA/kg BW/day (1.6860.74 ng/ ml)
Animals used in the epigenome and transcriptome studies were exposed to 250 mg BPA/kg BW/day, which unlike the lower dose induced hyperplasias and ductal carcinomas in situ (DCIS)
Summary
The link between the fetal exposure to environmental perturbations and the diseases manifested in adulthood is generally referred to as ‘‘developmental origins of adult disease’’ [1,2]. Epidemiological data showed that high doses of pharmacological agents as well as increased prenatal levels of endogenous estrogens, such as those existing in twin pregnancies, may increase the susceptibility to breast cancer in adulthood [3,4]. These facts provide the bases for the hypothesis that prenatal exposure to environmental estrogens induce malformations of the male genital tract, obesity, infertility [5] and the increased incidences of uterine leiomyoma, and testicular, prostatic and breast cancers observed in European and US populations over the last 50 years [6,7,8,9]. BPA has been reported to be present in plasma of men, women, fetuses and children as well as in the placenta [15,16]
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