The Effect of Bisphenol Α and Bisphenol S on Feeding-Related Hypothalamic Npy and Agrp Neurons

Presentation Number: SAT 251
Date of Presentation: April 1st, 2017

Neruja Loganathan*1, Emma McIlwraith2 and Denise D Belsham3
1Univeristy of Toronto, Toronto, ON, CANADA, 2University of Toronto, Toronto, ON, CANADA, 3University of Toronto, Toronto, ON, Canada

Abstract

Bisphenol A (BPA), a environmentally ubiquitous endocrine disrupting chemical (EDC), has been linked to the increasing prevalence of obesity, and has been revealed to induce adipogenesis, lipogenesis and pancreatic dysfunction in experimental models. However, the effect of BPA and its chemically-similar alternative, bisphenol S (BPS), on the hypothalamic control of energy balance is currently unknown. BPA and BPS are both postulated to be estrogen mimics. In the hypothalamus, 17-β estradiol (E2) decreases feeding and increases energy expenditure by downregulating NPY and AgRP expression. We hypothesized that BPA and BPS either interfere with the actions of E2 or have their own effects on hypothalamic neurons, thereby dysregulating NPY and/or AgRP transcription. Using immortalized murine hypothalamic cell lines (mHypoE-46, mHypoE-41, mHypoA-2/12 and mHypoA-59), representing populations of male, female, embryonic- and adult-derived cells, we studied changes in NPY and AgRP gene expression after BPA or BPS treatment by quantitative real-time PCR. In contrast to E2 treatment, exposure to BPA increased AgRP gene expression in all cell lines (50 and 100 uM), and NPY expression in the female-derived cell lines (100 uM) at 4 h. Furthermore, exposure to 100 uM BPA for 16 h upregulated NPY and AgRP expression approximately 16-fold and 2-fold, respectively, in the female, mHypoA-59 cells. Similarly, 100 uM BPS increased AgRP expression at 4 hours in male and female-derived cells, whereas NPY increased in only the female-derived lines. Thus, male-derived and female-derived cell lines differed in their responses. As BPA and BPS are putative estrogen mimics, we investigated their effect on the expression of estrogen receptors. BPA and BPS decreased the mRNA levels of GPR30 and the ERβ/ERα mRNA ratio, suggesting the action of these EDCs may be linked to these receptors. We have also found that BPA upregulated mRNA levels of ER stress markers, CHOP, Bax/Bcl2, and GRP78, and neuroinflammatory markers, TNFα and IL6, as well as the transcription factors, ERRγ and PPARγ over 24 h, pointing to alternative pathways through which BPA may upregulate NPY and AgRP gene expression. In conclusion, whereas E2 decreases NPY expression, BPA and BPS increase NPY and AgRP expression, illustrating a potential mechanism behind EDC-induced dysregulation of feeding, and ultimately obesity, a primary risk factor for diabetes and cardiovascular disease. Future studies will focus on the specific mechanisms utilized by BPA and BPS to induce NPY and AgRP transcription by analyzing the 5’ regulatory regions of the NPY and AgRP genes. We will also determine whether the induction of NPY and AgRP expression can be blocked by anti-inflammatory compounds. These studies provide a potential mechanism by which BPA and BPS may act as ‘obesogens’ at the hypothalamic level by increasing orexigenic neuropeptide expression.

 

Nothing to Disclose: NL, EM, DDB