Hepatic Lipid Accumulation and Nrf2 Expression following Perinatal and Peripubertal Exposure to Bisphenol A in a Mouse Model of Nonalcoholic Liver Disease

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 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. https://doi.org/10.1289/EHP664

Developmental programming: Sex‐specific programming of growth upon prenatal bisphenol A exposure

“…While studies addressing causal relationships between prenatal exposure to BPA on postnatal programming of human liver are not feasible, animal studies show that developmental exposure to BPA induces alterations in hepatic gene expression and diseases such as hepatic steatosis, liver tumors and metabolic syndrome (DeBenedictis, Guan, & Yang, ; Moustafa & Ahmed, ; Wei et al, ); e.g., prenatal BPA from embryonic day 7.5 to 18.5 in mice affects liver maturation in a sex‐specific fashion with effects seen only in females (DeBenedictis et al, ). Another study also found exposure to BPA 25 μg/kg/day from GD8 through postnatal day 16, increased hepatic lipid content in 5‐ and 39‐week‐old females, but not male mice (Shimpi et al, ). Other animal studies exploring the impact of BPA on liver focused on either of the sexes; e.g., a study focusing on male offspring noted that, at exposure to 50 mg/kg/day BPA from GD0 to the end of lactation at postnatal day 21, results showed abnormalities of liver function and hepatic damage in male rats (Xia et al, ).…”

Comparison of Hepatic NRF2 and Aryl Hydrocarbon Receptor Binding in 2,3,7,8-Tetrachlorodibenzo-p-dioxin–Treated Mice Demonstrates NRF2-Independent PKM2 Induction

“…Indeed, the presence of DREs and AhR binding upstream of Nrf2 implicates the AhR in antioxidant defense regulation mediated by Nrf2 (Miao et al, 2005), whereas NRF2 regulates AhR expression (Shin et al, 2007). NRF2 also regulates lipid homeostasis (Huang et al, 2010;Chambel et al, 2015;Shimpi et al, 2017) and has been associated with NAFLD development induced by high-fat diets, developmental exposure to bisphenol A, and TCDD (Lu et al, 2011;Meakin et al, 2014;Shimpi et al, 2017). For example, TCDDtreated Nrf2-null (Nrf2 2/2 ) mice exhibit increased weight loss and NAFLD pathologies, including more pronounced lipid accumulation and inflammation, as well as oxidative stress marker induction (Lu et al, 2011).…”

“…For example, TCDDtreated Nrf2-null (Nrf2 2/2 ) mice exhibit increased weight loss and NAFLD pathologies, including more pronounced lipid accumulation and inflammation, as well as oxidative stress marker induction (Lu et al, 2011). In addition, NRF2 activation increases nuclear receptor small heterodimer partner (Nr0b2), which regulates lipogenic genes (Huang et al, 2010), and regulates sterol regulatory-element binding protein-1c expression (Shimpi et al, 2017).…”

Endocrine disruption of gene expression and microRNA profiles in hippocampus and hypothalamus of California mice: Association of gene expression changes with behavioural outcomes

“…This finding, however, does not exlclude the possibility that the non‐metabolised fat may be accumulating in organs, particularly the liver. Other studies have reported that BPA exposure can increase hepatic lipid content, otherwise considered as hepatic lipidosis, in mice, zebrafish and humans 85‐88 …”