Abstract
Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta.
Highlights
Perturbed gestation affects fetal growth and development, resulting in a predisposition to diseases [1]
We have found that fetal exposure to bisphenol A (BPA) at physiologically relevant doses alters expression and methylation status of imprinted genes in the mouse embryo and placenta, with the latter tissue exhibiting the more significant changes
Dolinoy et al reported that BPA exposure in pregnant viable yellow agouti (Avy) mice resulted in offspring with reduced DNA methylation at 9 CpGs within the intracisternal A particle (IAP) retrotransposon locus and altered Agouti expression [9]
Summary
Perturbed gestation affects fetal growth and development, resulting in a predisposition to diseases [1]. The hypothesis has been supported by a growing number of human diseases associated with unfortunate events during pregnancy including drug exposure [2], chemical exposure [3], prenatal stress [4], and maternal caloric restriction [5]. The available data strongly suggest that the environment significantly impacts fetal development, exact molecular mechanism(s) linking diseases and early life events remain unclear despite significant research. Studies have demonstrated the ability of environmental factors including food constituents [6], prenatal famine [7], and endocrine disruptors [8,9,10] to alter global or gene-specific DNA methylation patterns. Early mammalian development represents a vulnerable window as the genome undergoes dynamic changes of DNA methylation [13] and environmental factors that alter these epigenetic reprogramming events may adversely impact growth and development
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