Arsenic induces dysfunctional autophagy via dual regulation of mTOR pathway and Beclin1-Vps34/PI3K complex in MLTC-1 cells.

Chen Liang, Zhiyuan Feng, Ram Kumar Manthari, Chong Wang, Yongli Han, Weixiang Fu, Jundong Wang, Jianhai Zhang

Journal of hazardous materials 2020 Jun 05

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Arsenic poisoning and induced potential lesion is a global concern. However, the exact mechanisms underlying its toxicity especially in male reproductive system still remain unclear. Hence, this study aimed to explore the roles of mTOR and Beclin1-Vps34/PI3K complex during As-induced-toxicity using Rapamycin (mTOR inhibitor), Beclin1 siRNA and 3-methyladenine (3-MA, Vps34/PI3K inhibitor) in testicular stromal cells. For this, mouse testis Leydig Tumor Cell lines (MLTC-1) were challenged with As2O3 (0, 3, 6 and 9 μM) exposure for 24 hs. Lyso-Tracker Red and Monodansylcadaverine (MDC) staining results depicted a significant accumulation of autophagosomes in MLTC-1 cells exposed to arsenic. Meanwhile, arsenic treatment up-regulated autophagic markers including LC3, Atg7, Beclin1 and Vps34 expressions, mTOR downstream autophagy related genes and the Beclin1-Vps34/PI3K complex associated members. Furthermore, silencing of Beclin1, and inhibition of Vps34/PI3K and mTOR altered the arsenic-induced autophagosomes formation. However, p62, the substrate protein of autophagy, was also up-regulated by arsenic administration independent on Beclin1-Vps34/PI3K complex. Altogether, our results revealed that arsenic exposure induced autophagosomes formation via regulation of the Beclin1-Vps34/PI3K complex and mTOR pathway; the blockage of autophagosomes degradation maybe due to impaired function of lysosomes. Thus, this study provides a novel mechanistic approach with respect to As-induced male reproductive toxicity. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Chen Liang, Zhiyuan Feng, Ram Kumar Manthari, Chong Wang, Yongli Han, Weixiang Fu, Jundong Wang, Jianhai Zhang. Arsenic induces dysfunctional autophagy via dual regulation of mTOR pathway and Beclin1-Vps34/PI3K complex in MLTC-1 cells. Journal of hazardous materials. 2020 Jun 05;391:122227