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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 NRE2 and epigenetic mechanisms.

METHODS: Utilizing BPA as a model exposure, pregnant CD -1 mice were administered 25 tg/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 (W.5), 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 -lc (Srebp-lc) promoter. Known Nrf2 activators increased SREBP-IC promoter reporter activity in HepCi2 cells. Methylated DNA immunoprecipitation-PCR and pyrosequencing revealed that developmental BPA exposure induced hypomethylation of the 16f2 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-lc 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.