Impact of Maternal BPA Exposure during Pregnancy on Obesity in Male Offspring: A Mechanistic Mouse Study of Adipose-Derived Exosomal miRNA.

Abstract

Background: The widespread use of bisphenol A (BPA) has led to universal exposure among the population, raising concerns about its health effects. Epidemiological studies have linked environmentally relevant levels of BPA exposure to obesity.

Objectives: We aimed to uncover the complex mechanisms by which oral exposure during pregnancy with BPA affects the offspring.

Methods: We conducted a two-stage mouse study. In stage 1, we gavaged dams with BPA at 0.05, 0.5, and $5\mathrm{mg}/\mathrm{kg}\text{\hspace{0.17em}per\hspace{0.17em}day}$ during pregnancy, and we tracked the offspring's weight and diet to 12 wk of age. In stage 2, exosomes from BPA-exposed dams and offspring were injected into pregnant mice and 3-wk-old males, respectively, and the mice were observed up to 12 wk. We then sequenced exosomal microRNAs (miRNAs) in male offspring whose dams had been exposed to BPA during pregnancy and checked their expression in adipose, liver, and serum samples at weeks 3, 6, 9, and 12. Finally, we explored the functions of exosomes and exosomal miRNAs secreted by adipose-derived mesenchymal stem cells, and we investigated whether the exosomes and miRNAs they secreted could affect glucose uptake, triglyceride synthesis, and the expression of genes related to glucose and lipid metabolism in alpha mouse liver 12 cells.

Results: Gavage of $0.05\mathrm{mg}/\mathrm{kg}\text{\hspace{0.17em}per\hspace{0.17em}day}$ of BPA during pregnancy in dams led to obesity in male offspring mice, and injection of exosomes from male offspring with BPA exposure during pregnancy also induced similar outcomes in the next generation of male pups. Exosomal miRNA sequencing identified differentially expressed miRNAs associated with BPA-induced obesity in male offspring, revealing sustained high expression of miRNAs in adipose tissue and a gradual increase in the liver and serum over time. Further mechanistic studies showed that exosomes derived from BPA-treated adipose-derived stem cells reduced the expression of peroxisome proliferator-activated receptor-gamma and fibroblast growth factor 21, leading to impaired insulin signaling and lipid metabolism in hepatocytes. Overexpression of miR-124-3p in hepatocytes mimicked these effects; in contrast, knockdown of miR-124-3p or inhibition of exosome secretion reversed them.

Discussion: The present study corroborates the regulatory function of adipose-derived exosomal miRNAs in obesity in male offspring mice resulting from BPA exposure during pregnancy. Exosomal miRNA may be a key and novel molecular biomarker in the adverse effects of chemical exposure during pregnancy. https://doi.org/10.1289/EHP14888.