The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells
Microcystin-LR (MC-LR) is an intracellular toxin with multi-organ toxicity and the testis is one of its important target organs. Although there is increasing research on MC-LR in male reproductive toxicity, the association between DNA damage and autophagy induced by MC-LR in male germ cells are stil...
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2021
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oai:doaj.org-article:2bde358b27514e6ca45bc28180cfbc4c2021-11-06T04:17:19ZThe activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells0147-651310.1016/j.ecoenv.2021.112919https://doaj.org/article/2bde358b27514e6ca45bc28180cfbc4c2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0147651321010319https://doaj.org/toc/0147-6513Microcystin-LR (MC-LR) is an intracellular toxin with multi-organ toxicity and the testis is one of its important target organs. Although there is increasing research on MC-LR in male reproductive toxicity, the association between DNA damage and autophagy induced by MC-LR in male germ cells are still unclear. Therefore, it is important to explore the mechanism of MC-LR-induced DNA damage and the role of the activated ATM/p53 signaling pathway in testicular toxicity. The present study showed that MC-LR exposure significantly reduced gonadal index and induced pathological damage of the testes in mice. In addition, MC-LR increased the oxidative stress-related indicator hydroxyl radical, accompanied by increased levels of DNA damage-related indicators gamma-H2AX, 8-hydroxy-2′-deoxyguanosine, the olive tail moment (OTM) and DNA content of comet tail (TailDNA%) in trailing cells. Moreover, MC-LR activated the ATM/p53 pathway by enhancing the phosphorylation levels of ATM, CHK2 and p53 proteins, and then led to cell autophagy, ultimately triggering disrupted testicular cell arrangement, reduced sperm count and spermatogenic cell shedding. Importantly, after pretreatment with the antioxidant NAC, the expression levels of DNA damage-related indicators and the extent of damage in male germ cells were significantly reduced. Furthermore, pretreatment with the ATM inhibitor KU55933 could reduce the occurrence of autophagy and mitigate testicular toxicity of MC-LR through inhibiting the activation of the ATM/p53 pathway. These results indicate that MC-LR-induced oxidative stress can activate the DNA damage-mediated ATM/p53 signalling pathway to induce autophagy in male germ cells. This study provides a novel insight to further clarify the reproductive toxicity caused by MC-LR and to protect male reproductive health.Zhihui TianHaohao LiuXinghai ChenMichael D. LosiewiczRui WangXingde DuBingqian WangYa MaShiyu ZhangLinjia ShiXing GuoYongshui WangBingyu ZhangShumeng YuanXin ZengHuizhen ZhangElsevierarticleMicrocystin-LRReproductive toxicityDNA damageATMAutophagyOxidative stressEnvironmental pollutionTD172-193.5Environmental sciencesGE1-350ENEcotoxicology and Environmental Safety, Vol 227, Iss , Pp 112919- (2021) |
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DOAJ |
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DOAJ |
| language |
EN |
| topic |
Microcystin-LR Reproductive toxicity DNA damage ATM Autophagy Oxidative stress Environmental pollution TD172-193.5 Environmental sciences GE1-350 |
| spellingShingle |
Microcystin-LR Reproductive toxicity DNA damage ATM Autophagy Oxidative stress Environmental pollution TD172-193.5 Environmental sciences GE1-350 Zhihui Tian Haohao Liu Xinghai Chen Michael D. Losiewicz Rui Wang Xingde Du Bingqian Wang Ya Ma Shiyu Zhang Linjia Shi Xing Guo Yongshui Wang Bingyu Zhang Shumeng Yuan Xin Zeng Huizhen Zhang The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells |
| description |
Microcystin-LR (MC-LR) is an intracellular toxin with multi-organ toxicity and the testis is one of its important target organs. Although there is increasing research on MC-LR in male reproductive toxicity, the association between DNA damage and autophagy induced by MC-LR in male germ cells are still unclear. Therefore, it is important to explore the mechanism of MC-LR-induced DNA damage and the role of the activated ATM/p53 signaling pathway in testicular toxicity. The present study showed that MC-LR exposure significantly reduced gonadal index and induced pathological damage of the testes in mice. In addition, MC-LR increased the oxidative stress-related indicator hydroxyl radical, accompanied by increased levels of DNA damage-related indicators gamma-H2AX, 8-hydroxy-2′-deoxyguanosine, the olive tail moment (OTM) and DNA content of comet tail (TailDNA%) in trailing cells. Moreover, MC-LR activated the ATM/p53 pathway by enhancing the phosphorylation levels of ATM, CHK2 and p53 proteins, and then led to cell autophagy, ultimately triggering disrupted testicular cell arrangement, reduced sperm count and spermatogenic cell shedding. Importantly, after pretreatment with the antioxidant NAC, the expression levels of DNA damage-related indicators and the extent of damage in male germ cells were significantly reduced. Furthermore, pretreatment with the ATM inhibitor KU55933 could reduce the occurrence of autophagy and mitigate testicular toxicity of MC-LR through inhibiting the activation of the ATM/p53 pathway. These results indicate that MC-LR-induced oxidative stress can activate the DNA damage-mediated ATM/p53 signalling pathway to induce autophagy in male germ cells. This study provides a novel insight to further clarify the reproductive toxicity caused by MC-LR and to protect male reproductive health. |
| format |
article |
| author |
Zhihui Tian Haohao Liu Xinghai Chen Michael D. Losiewicz Rui Wang Xingde Du Bingqian Wang Ya Ma Shiyu Zhang Linjia Shi Xing Guo Yongshui Wang Bingyu Zhang Shumeng Yuan Xin Zeng Huizhen Zhang |
| author_facet |
Zhihui Tian Haohao Liu Xinghai Chen Michael D. Losiewicz Rui Wang Xingde Du Bingqian Wang Ya Ma Shiyu Zhang Linjia Shi Xing Guo Yongshui Wang Bingyu Zhang Shumeng Yuan Xin Zeng Huizhen Zhang |
| author_sort |
Zhihui Tian |
| title |
The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells |
| title_short |
The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells |
| title_full |
The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells |
| title_fullStr |
The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells |
| title_full_unstemmed |
The activated ATM/p53 pathway promotes autophagy in response to oxidative stress-mediated DNA damage induced by Microcystin-LR in male germ cells |
| title_sort |
activated atm/p53 pathway promotes autophagy in response to oxidative stress-mediated dna damage induced by microcystin-lr in male germ cells |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/2bde358b27514e6ca45bc28180cfbc4c |
| work_keys_str_mv |
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