Abstract
Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) associated with non-alcoholic fatty liver disease (NAFLD). The effects of gestational BPA exposure on hepatic lipid accumulation in offspring are not fully understood. Here, we investigate the sex-dependent effects of gestational BPA exposure on hepatic lipid and glucose metabolism in the offspring of mice to reveal the mechanisms underlying gestational BPA exposure-associated NAFLD. Pregnant mice were administered gavage with or without 1 μg kg−1 day−1 BPA at embryonic day 7.5 (E7.5)–E16.5. Hepatic glucose and lipid metabolism were evaluated in these models. Both male and female offspring mice exhibited hepatic fatty liver after BPA treatment. Lipid accumulation and dysfunction of glucose metabolism were observed in male offspring. We revealed abnormal expression of lipid regulators in the liver and that inhibition of peroxisome proliferator-activated receptor γ (PPARγ) repressed hepatic lipid accumulation induced by gestational BPA exposure. We also found a sex-dependent decrease of hepatocyte nuclear factor 1b (HNF1b) expression in male offspring. The transcriptional repression of PPARγ by HNF1b was confirmed in L02 cells. Downregulation of HNF1b, upregulation of PPARγ, and subsequent upregulation of hepatic lipid accumulation were essential for NAFLD development in male offspring gestationally exposed to BPA as well as BPA-exposed adult male mice. Dysregulation of the HNF1b/PPARγ pathway may be involved in gestational BPA exposure-induced NAFLD in male offspring. These data provide new insights into the mechanism of gestational BPA exposure-associated sex-dependent glucose and lipid metabolic dysfunction.Graphical abstractSchematic of the mechanism of gestational BPA exposure-induced glucose and lipid metabolic dysfunction.
Highlights
The incidence of nonalcoholic fatty liver disease (NAFLD) has sharply increased since the 1990s
We revealed abnormal expression of lipid regulators in the liver and that inhibition of peroxisome proliferatoractivated receptor γ (PPARγ) repressed hepatic lipid accumulation induced by gestational Bisphenol A (BPA) exposure
The BPA-induced increase of mRNA and protein expression levels of PPARγ was significantly inhibited by the upregulation of hepatocyte nuclear factor 1b (HNF1b) (Fig. 8h–l). These results demonstrated that HNF1b functioned as a transcriptional repressor of PPARγ expression and that the dysregulation of HNF1b and PPARγ played a role in the BPA-induced increase of hepatic lipid accumulation and glucose metabolic dysfunction
Summary
The incidence of nonalcoholic fatty liver disease (NAFLD) has sharply increased since the 1990s. It is estimated that one billion people worldwide suffer from NAFLD with numbers expected to continuously increase (Loomba and Sanyal 2013). The causes of epidemic NAFLD currently remain unclear. Clinical, and epidemiological studies have shown that contaminants in food may negatively affect endocrine and metabolic functions, thereby promoting NAFLD and other related metabolic diseases (Marmugi et al 2012). Prior to the increase of the incidence of NAFLD, synthetic chemicals being used in food has increased exponentially. These synthetic chemicals include BPA (IUPAC ID: 4,4′-(propane-2,2-diyl) diphenol) (Baillie-Hamilton 2002). BPA has become one of the most convenient and extensively used plasticizers in the manufacturing of polycarbonate plastics and epoxies
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