Bisphenol A Induces Agrp Gene Expression in Hypothalamic Neurons through a Mechanism Involving ATF3

Background: Bisphenol A (BPA) is a ubiquitous endocrine disrupting chemical and obesogen. Although limited evidence exists of the effects of BPA on hypothalamic agouti-related peptide (AgRP) levels, the mechanisms underlying these effects remain unknown. Given that AgRP is a potent orexigenic neuropeptide, determining the mechanism by which BPA increases AgRP is critical to preventing the progression to metabolic disease. Methods: Using quantitative reverse transcriptase polymerase chain reaction, we investigated the response of Agrp-expressing mouse hypothalamic cell lines to BPA treatment. The percentage of total BPA entering hypothalamic cells in culture was quantified using an enzyme-linked immunosorbent assay. In order to identify the mechanism underlying BPA-mediated changes in Agrp, siRNA knockdown of transcription factors, FOXO1, CHOP, ATF3, ATF4, ATF6, and small-molecule inhibitors of endoplasmic reticulum stress, JNK or MEK/ERK were used. Results: BPA increased mRNA levels of Agrp in six hypothalamic cell lines (mHypoA-59, mHypoE-41, mHypoA-2/12, mHypoE-46, mHypoE-44, and mHypoE-42). Interestingly, only 18% of the total BPA in the culture medium entered the cells after 24 h, suggesting that the exposure concentration is much lower than the treatment concentration. BPA increased pre-Agrp mRNA levels, indicating increased Agrp transcription. Knockdown of the transcription factor ATF3 prevented BPA-mediated increase in Agrp, pre-Agrp, and in part Npy mRNA levels. However, chemical chaperone, sodium phenylbutyrate, JNK inhibitor, SP600125, or the MEK/ERK inhibitor PD0352901 did not block BPA-induced Agrp upregulation. Conclusion: Overall, these results indicate that hypothalamic Agrp is susceptible to dysregulation by BPA and implicate ATF3 as a common mediator of the orexigenic effects of BPA in hypothalamic neurons.

Automated summary

The study found that BPA increased mRNA levels of Agrp in hypothalamic cell lines, and ATF3 may be a common mediator of the orexigenic effects of BPA in hypothalamic neurons.