Bisphenol A AltersBmal1,Per2, andRev-ErbamRNA and Requires Bmal1 to Increase Neuropeptide Y Expression in Hypothalamic Neurons

Dec 1, 2018Endocrinology

Bisphenol A changes daily rhythm genes and needs one gene (Bmal1) to raise appetite-related signals in brain cells controlling hunger

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Abstract

BPA significantly alters mRNA expression of circadian clock genes in hypothalamic neurons.

BPA affects the expression of circadian clock genes Bmal1, Per2, and Rev-Erbα in hypothalamic cell lines.
In wild type hypothalamic cells, BPA increases mRNA expression of neuropeptides Npy, Agrp, and Pomc.
The increase in Npy expression triggered by BPA is abolished in cells lacking BMAL1.
BPA enhances BMAL1 binding to the Npy promoter, which may lead to increased transcription of Npy.
Dysregulation of the circadian molecular clock by BPA is linked to changes in neuropeptide expression.

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Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, is considered an obesogen. However, its role in the hypothalamic control of energy balance remains largely unexplored. Because disruption of the circadian clock is tightly associated with metabolic consequences, we explored how BPA affects the components of the molecular circadian clock in the feeding-related neurons of the hypothalamus. In immortalized POMC and NPY/AgRP-expressing hypothalamic cell lines and primary culture, we describe how BPA significantly alters mRNA expression of circadian clock genes Bmal1,Per2, and Rev-Erbα. Furthermore, we use newly generated Bmal1-knockout (KO) hypothalamic cell lines to link the BPA-induced neuropeptide dysregulation to the molecular clock. Specifically, BPA increased Npy, Agrp, and Pomc mRNA expression in wild type hypothalamic cells, whereas the increase in Npy, but not Agrp or Pomc, was abolished in cell lines lacking BMAL1. In line with this increase, BPA led to increased BMAL1 binding to the Npy promotor, potentially increasing Npy transcription. In conclusion, we show that BPA-mediated dysregulation of the circadian molecular clock is linked to the deleterious effects of BPA on neuropeptide expression. Furthermore, we describe hypothalamic Bmal1-KO cell lines to study the role of BMAL1 in hypothalamic responses to metabolic, hormonal, and environmental factors.

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Bisphenol A AltersBmal1,Per2, andRev-ErbamRNA and Requires Bmal1 to Increase Neuropeptide Y Expression in Hypothalamic Neurons

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