Molecular Mechanisms Involved in the Regulation of Agouti-related Peptide and Neuropeptide Y by Endocrine Disrupting Chemical Bisphenol A in Hypothalamic Neurons

Bisphenol A (BPA), a ubiquitous endocrine disrupting chemical found in plastics and receipts, is a disruptor of reproductive function and is a known ‘obesogen’ as it is linked to increased body mass index in humans and leads to weight gain in animal models. The hypothalamus houses orexigenic NPY/AgRP neurons, which integrate peripheral hormones and nutritional signals, to increase food intake and decrease energy expenditure. NPY neurons are also afferent regulators of the hypothalamic-pituitary gonadal axis, and thus reproductive function. This thesis investigated whether the NPY/AgRP neurons, and particularly Npy and Agrp expression, are altered by BPA. We hypothesized that BPA increases Npy and Agrp gene expression in hypothalamic neurons and that this effect is mediated through nuclear receptor activation, induction of cellular stress and subsequent transcription factor activation or circadian dysregulation. We demonstrated that BPA increased Agrp mRNA expression in mHypoA-59 and mHypoE-41 cells. Inhibition of AMPK and knock-down of transcription factor ATF3 prevented the BPA-mediated increase in Agrp expression in the mHypoA-59 cells. ATF3 was also required for BPA-mediated increase in Npy in the mHypoE-41 cells. We also described subpopulation-specific changes in Npy expression in response to BPA. While BPA induced Npy expression in mHypoA-59, -2/12 and mHypoE-41, -42 neurons, Npy expression was downregulated in mHypoE-46 and -44 neurons. Inhibition of AMPK with compound C or oxidative stress with antioxidants and vitamin B6 prevented the BPA-mediated induction in Npy in the mHypoA-59 cells, whereas antagonism of ERß or GPER prevented the decrease in Npy mRNA in the mHypoE-46 cells. Finally, we showed that circadian gene dysregulation occurred with BPA exposure and using hypothalamic cell lines lacking BMAL1, demonstrated that the BPA-mediated induction of Npy, but not Agrp, required BMAL1. Accordingly, treatment with BPA increased BMAL1 binding to the Npy promoter. These findings illustrate distinct mechanisms responsible for the BPA-mediated changes in appetite-increasing Npy and Agrp gene expression, suggesting that NPY/AgRP neurons are susceptible to the endocrine disrupting effects of BPA. Furthermore, we describe potential targetable pathways to combat the obesogenic or reproductive dysfunction-inducing effects of BPA at the hypothalamic level.

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