Background: Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, has been shown to exert transgenerational effects on adiposity, metabolism, and reproductive outcomes in rodents, indicating epigenetic inheritance. Recent studies of other environmental insults (stress and high-fat diet) have demonstrated a mechanistic role for spermatozoal microRNAs in the transgenerational transmission of acquired paternal traits.
Objective and hypotheses: To assess the effects of developmental (gestational/lactational) BPA exposure on spermatozoal microRNA expression, with the hypothesis that BPA alters microRNA expression in a dose-dependent manner.
Method: F0 female C57BL/6J mice exposed to vehicle (0.5% ethanol; VEH), low-dose BPA (0.4 mg/kg per day; LD), or high-dose BPA (8 mg/kg per day; HD) via their drinking water were mated with vehicle-exposed males to generate F1 offspring. Offspring were weaned to unadulterated water at 3 weeks of age. At 11 weeks of age, motile spermatozoa were isolated from males (n=10 F1-VEH, n=9 F1-LD, n=8 F1-HD) and pooled in pairs/one trio to determine microRNA expression patterns by deep sequencing.
Results: Median (IQR) post-weaning maternal serum BPA levels were 3.0 (2.621.0) μg/l for VEH, 40.2 (15.873.0) μg/l for LD, and 637.4 (356.74527.5) μg/l for HD. Deep sequencing analyses revealed that three microRNAs were upregulated and seven microRNAs downregulated in F1-LD spermatozoa compared to F1-VEH spermatozoa, including three downregulated microRNAs previously shown to be upregulated by early-life traumatic stress (miR-100-5p, miR-183-5p, and miR-191-5p). However, no microRNAs were differentially expressed between F1-VEH and F1-HD spermatozoa. Significant (P≤0.001) non-monotonic effects of BPA exposure were also observed for serum triglyceride level, inguinal fat-pad mass, and anogenital distance (all lowest in F1-LD mice), as well as liver mass (highest in F1-LD mice).
Conclusion: These findings provide novel evidence that developmental BPA exposure at levels comparable to those observed in humans affects spermatozoal microRNA expression. Further work is required to determine whether this effect contributes to epigenetic intergenerational/transgenerational inheritance.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology