Document Type
Article
Date of Original Version
2017
Department
Biomedical and Pharmaceutical Sciences
Abstract
Background: Exposure to chemicals during critical windows of development may re-program liver for increased risk of nonalcoholic fatty liver disease (NAFLD). Bisphenol A (BPA), a plastics component, has been described to impart adverse effects during gestational and lactational exposure. Our work has pointed to nuclear factor E2-related factor 2 (Nrf2) being a modulator of hepatic lipid accumulation in models of NAFLD.
Objectives: To determine if chemical exposure can prime liver for steatosis via modulation of NRF2 and epigenetic mechanisms.
Methods: Utilizing BPA as a model exposure, pregnant CD-1 mice were administered 25μg/kg/day" role="presentation">25μg/kg/day BPA via osmotic minipumps from gestational day 8 through postnatal day (PND)16. The offspring were weaned on PND21 and exposed to same dose of BPA via their drinking water through PND35. Tissues were collected from pups at week 5 (W5), and their littermates at week 39 (W39).
Results: BPA increased hepatic lipid content concomitant with increased Nrf2 and pro-lipogenic enzyme expression at W5 and W39 in female offspring. BPA exposure increased Nrf2 binding to a putative antioxidant response element consensus sequence in the sterol regulatory-element binding protein-1c (Srebp-1c) promoter. Known Nrf2 activators increased SREBP-1C promoter reporter activity in HepG2 cells. Methylated DNA immunoprecipitation-PCR and pyrosequencing revealed that developmental BPA exposure induced hypomethylation of the Nrf2 and Srebp-1c promoters in livers of W5 mice, which was more prominent in W39 mice than in others.
Conclusion: Exposure to a xenobiotic during early development induced persistent fat accumulation via hypomethylation of lipogenic genes. Moreover, increased Nrf2 recruitment to the Srebp-1c promoter in livers of BPA-exposed mice was observed. Overall, the underlying mechanisms described a broader impact beyond BPA exposure and can be applied to understand other models of NAFLD.
Citation/Publisher Attribution
Shimpi, P. C., More, V. R., Paranjpe, M., Donepudi, A. C., Goodrich, J. M., Dolinoy, D. C., Rubin, B., & Slitt, A. L. (2017). Hepatic Lipid Accumulation and Nrf2 Expression following Perinatal and Peripubertal Exposure to Bisphenol A in a Mouse Model of Nonalcoholic Liver Disease. Environmental Health Perspectives, 125(8), 1-10. doi: 10.1289/EHP664
Available at: https://doi.org/10.1289/EHP664