Microcystin-LR induces ovarian injury and apoptosis in mice via activating apoptosis signal-regulating kinase 1-mediated P38/JNK pathway

• Published in: Ecotoxicology and environmental safety Vol. 213; p. 112066
• Main Authors: Du, Xingde, Liu, Haohao, Liu, Xiaohui, Chen, Xinghai, Yuan, Le, Ma, Ya, Huang, Hui, Wang, Yueqin, Wang, Rui, Zhang, Shiyu, Tian, Zhihui, Shi, Linjia, Zhang, Huizhen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.04.2021; Elsevier
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins; Apoptosis signal-regulating kinase 1; Female; Male; MAP Kinase Kinase Kinase 5 - metabolism; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Marine Toxins - toxicity; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Microcystin-LR; Microcystins - toxicity; Ovarian injury; Ovary; Reproductive toxicity; Ovarian injury; Apoptosis signal-regulating kinase 1; Reproductive toxicity; Microcystin-LR; Apoptosis
• ISSN: 0147-6513; 1090-2414
• DOI: 10.1016/j.ecoenv.2021.112066

As an emerging pollutant in the aquatic environment, microcystin-LR (MC-LR) can enter the body through multiple pathways, and then induce apoptosis and gonadal damage, affecting reproductive function. Previous studies focused on male reproductive toxicity induced by MC-LR neglecting its effects on females. The apoptotic signal-regulated kinase 1 (ASK1) is an upstream protein of P38/JNK pathway, closely associated with apoptosis and organ damage. However, the role of ASK1 in MC-LR-induced reproductive toxicity is unclear. Therefore, this study investigated the role of ASK1 in mouse ovarian injury and apoptosis induced by MC-LR. After MC-LR exposure, ASK1 expression in mouse ovarian granulosa cells was increased at the protein and mRNA levels, and decreased following pretreatment by antioxidant N-acetylcysteine, suggesting that MC-LR-induced oxidative stress has a regulatory role in ASK1 expression. Inhibition of ASK1 expression with siASK1 and NQDI-1 could effectively alleviate MC-LR-induced mitochondrial membrane potential damage and apoptosis in ovarian granulosa cells, as well as pathological damage, apoptosis and the decreased gonadal index in ovaries of C57BL/6 mice. Moreover, the P38/JNK pathway and downstream apoptosis-related proteins (P-P38, P-JNK, P-P53, Fas) and genes (MKK4, MKK3, Ddit3, Mef2c) were activated in vivo and vitro, but their activation was restrained after ASK1 inhibition. Data presented herein suggest that the ASK1-mediated P38/JNK pathway is involved in ovarian injury and apoptosis induced by MC-LR in mice. It is confirmed that ASK1 has an important role in MC-LR-induced ovarian injury, which provides new insights for preventing MCs-induced reproductive toxicity in females. [Display omitted] •MC-LR upregulates ASK1 expression via oxidative stress in mouse ovarian cells.•Inhibition of ASK1 alleviates MC-LR-induced ovarian injury and apoptosis in mice.•ASK1-mediated P38/JNK pathway is involved in MC-LR-induced ovarian injury and apoptosis.•ASK1 activates the P38/JNK pathway via MKK3/4 after ovarian cells exposed to MC-LR.