Friday, May 16, 2025
5/16/2025
Understanding mechanisms of liver carcinogenesis following developmental BPA exposure - PROJECT SUMMARY Exposure to the endocrine disrupting compound bisphenol A (BPA) is strongly correlated with risk for metabolic syndrome (MetS) but mechanistic evidence is limited. MetS is defined by the co-occurrence of several correlated cardiovascular disease risk factors, including insulin resistance and high blood triglycerides. MetS is a predictor of type II diabetes, fatty liver disease, cardiovascular disease, and hepatocellular carcinoma (HCC); therefore, preventing MetS reduces the burden of multiple diseases. Both MetS and BPA exposure are widespread problems in the U.S. The national prevalence of MetS is 41% and rising; ~92% of the U.S. population are chronically exposed to BPA. Thus, identifying a causal relationship between exposure and disease development is crucial to improve prevention and treatment of MetS. The etiology of MetS is unknown, but current evidence supports lipid accumulation followed by tissue-specific insulin resistance as initiating events. In liver, lipid accumulation is promoted by persistent Nrf2 signaling and is prevented by estrogen receptor 1 (ESR1) signaling. When cellular reactive oxygen species (ROS) is high, Nrf2 activates the transcription of antioxidant defense enzymes and the sterol regulatory element-binding proteins (SREBPs), including SREBPF1, which encodes SREBP-1c, which, in turn, triggers de novo lipogenesis. Persistent Srebp-1c upregulation leads to harmful hepatic lipid deposition and downstream hepatic insulin resistance. BPA promotes ROS; therefore, we hypothesize that BPA promotes MetS by increasing ROS and subsequently upregulating Srebp-1c. In contrast, ESR1 signaling suppresses Srebp-1c expression and protects against hepatic lipid deposition and insulin resistance, particularly in females. BPA is a weak ESR1 agonist that binds the receptor when endogenous estrogen is low (e.g., in pre-pubertal females), but is incapable of eliciting transcription of ESR1 target genes. We hypothesize that developmental BPA reverses this estrogenic protection. Therefore, our central hypothesis is that developmental BPA exposure causes hepatic lipid deposition and insulin resistance by triggering persistent, ROS-mediated Nrf2 signaling and by disrupting protective ESR1 signaling. In Aim 1, we will test the causal role of cellular ROS in liver metabolic dysfunction by exposing to BPA mice that are genetically susceptible to ROS-dependent metabolic syndrome (which should exacerbate metabolic dysfunction) and by co-exposing mice to BPA and an antioxidant (which should rescue metabolic dysfunction). In Aim 2, we will test the causal role of ESR1 signaling in liver metabolic dysfunction by experimentally increasing signaling (by co-exposing mice to BPA and an ESR1 agonist) and decreasing signaling (by co-exposing mice to BPA and an ESR1 antagonist). The results of these studies will clarify mechanisms by which this ubiquitous environmental pollutant explains the substantial and increasing metabolic disease burden in the U.S.
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