Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, interferes with reproduction and is also considered an obesogen. The neuropeptide Y (NPY) neurons of the hypothalamus control both food intake and reproduction and have emerged as potential targets of BPA. These functionally diverse subpopulations of NPY neurons are differentially regulated by peripheral signals, such as estrogen and leptin. Whether BPA also differentially alters Npy expression in subpopulations of NPY neurons, contributing to BPA-induced endocrine dysfunction is unclear. We investigated the response of six immortalized hypothalamic NPY-expressing cell lines to BPA treatment. BPA upregulated Npy mRNA expression in four cell lines (m... More
Bisphenol A (BPA), a ubiquitous endocrine-disrupting chemical, interferes with reproduction and is also considered an obesogen. The neuropeptide Y (NPY) neurons of the hypothalamus control both food intake and reproduction and have emerged as potential targets of BPA. These functionally diverse subpopulations of NPY neurons are differentially regulated by peripheral signals, such as estrogen and leptin. Whether BPA also differentially alters Npy expression in subpopulations of NPY neurons, contributing to BPA-induced endocrine dysfunction is unclear. We investigated the response of six immortalized hypothalamic NPY-expressing cell lines to BPA treatment. BPA upregulated Npy mRNA expression in four cell lines (mHypoA-59, mHypoE-41, mHypoA-2/12, mHypoE-42), and downregulated Npy in two lines (mHypoE-46, mHypoE-44). This differential expression of Npy occurred concurrently with differential expression of estrogen receptor mRNA levels. Inhibition of GPR30 or ERβ prevented the BPA-mediated decrease in Npy, wherease inhibition of energy sensor 5' adenosine monophosphate-activated protein kinase (AMPK) with compound C prevented BPA-induced increase in Npy. BPA also altered neuroinflammatory and oxidative stress markers in both mHypoA-59 and mHypoE-46 cell lines despite the differential regulation of Npy. Remarkably, treatment with BPA in an antioxidant-rich media, neurobasal A (NBA), or with ROS scavenger tauroursodeoxycholic acid (TUDCA) mitigated the BPA-induced increase and decrease in Npy. Furthermore, two anti-oxidant species from NBA, N-acetylcysteine and vitamin B6, diminished the induction of Npy in the mHypoA-59 cells, demonstrating these supplements can counteract BPA-induced dysregulation in certain subpopulations. Overall, these results illustrate the differential regulation of Npy by BPA in neuronal subpopulations, and point to oxidative stress as a pathway that can be targeted to block BPA-induced Npy dysregulation in hypothalamic neurons.
