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Toxicol Sci. 2018 Oct 1;165(2):431-446. doi: 10.1093/toxsci/kfy172.

m6A Demethylase FTO Regulates Dopaminergic Neurotransmission Deficits Caused by Arsenite.

Author information

1
Department of Occupational and Environmental Health, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People's Republic of China.
2
Institute of Life Sciences, Chongqing Medical University, Chongqing, People's Republic of China.
3
Post-doctoral Research Stations of Nursing Science, School of Nursing, Chongqing Medical University, Chongqing, People's Republic of China.
4
Chongqing Key Laboratory of Neurology, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
5
Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
6
Center of Experimental Teaching for Public Health.
7
Laboratory of Tissue and Cell Biology, Experimental Teaching and Management Center, Chongqing Medical University, Chongqing, People's Republic of China.

Abstract

Arsenite exposure is known to increase the risk of neurological disorders via alteration of dopamine content, but the detailed molecular mechanisms remain largely unknown. In this study, using both dopaminergic neurons of the PC-12 cell line and C57BL/6J mice as in vitro and in vivo models, our results demonstrated that 6 months of arsenite exposure via drinking water caused significant learning and memory impairment, anxiety-like behavior and alterations in conditioned avoidance and escape responses in male adult mice. We also were the first to reveal that the reduction in dopamine content induced by arsenite mainly resulted from deficits in dopaminergic neurotransmission in the synaptic cleft. The reversible N6- methyladenosine (m6A) modification is a novel epigenetic marker with broad roles in fundamental biological processes. We further evaluated the effect of arsenite on the m6A modification and tested if regulation of the m6A modification by demethylase fat mass and obesity-associated (FTO) could affect dopaminergic neurotransmission. Our data demonstrated for the first time that arsenite remarkably increased m6A modification, and FTO possessed the ability to alleviate the deficits in dopaminergic neurotransmission in response to arsenite exposure. Our findings not only provide valuable insight into the molecular neurotoxic pathogenesis of arsenite exposure, but are also the first evidence that regulation of FTO may be considered as a novel strategy for the prevention of arsenite-associated neurological disorders.

PMID:
29982692
DOI:
10.1093/toxsci/kfy172

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