Nucleoside reverse transcriptase inhibitor-induced rat oocyte dysfunction and low fertility mediated by autophagy
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Li Tang1,2,*, Shengfu Yang3,*, Huawei Wang1,4,*, Hai Gu2, Xueshan Xia5, Yue Feng5, Zexing Yang1, Shuhua Zhao1, Cunmei Su1, Zhenfang Su1 and Kunhua Wang4
1Department of Reproduction and Genetics, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan Province, China
2Department of Reproductive Medicine, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan Province, China
3Department of Pharmacy, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan Province, China
4Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan Province, China
5Department of Life Science, Kunming University of Science and Technology, Kunming, 650093, Yunnan Province, China
*These authors contributed equally to this work
Kunhua Wang, email: [email protected]
Keywords: low fertility; NRTIs; mitochondrial toxicity, autophagy
Received: October 26, 2017 Accepted: December 01, 2017 Published: December 13, 2017
Low fertility is one of the most common side effects caused by nucleoside reverse transcriptase inhibitors (NRTIs), whereas the molecular mechanism underlying this process were largely unclear. This study was conducted to investigate whether autophagy plays a role in NRTIs-induced oocyte dysfunction and low fertility in female rat. Both in vivo and in vitro experiments were conducted. For the in vivo experiment, female adult Sprague-Dawley rats were subjected to zidovudine (AZT) and lamivudine (3TC) intragastric treatment for 3, 6, 9, and 12 weeks; a control was also set. Oocytes were collected for maturation evaluation, in vitro fertilization and mitochondrial function assays, and apoptosis and autophagy analysis. For the in vitro experiment, oocytes were collected and assigned to the control, 3-methyladenine (3-MA, an effective autophagy inhibitor), AZT, AZT+3-MA, 3TC, and 3TC+3-MA groups. The oocytes were cultured with the abovementioned drugs for 24, 48, and 72 h and then, subjected to the same assays as in the in vivo study. The results showed a significant time-dependent decrease in oocyte maturation-related maker levels, oocyte cleavage rate, blastocyst formation rate, mitochondrial DNA copy number and adenosine triphosphate level, and apoptosis, and a significant increase in the reactive oxygen species levels (all P-values < 0.05), in both the in vivo and the in vitro experiments. These changes, except for the changes in the oocyte maturation-related markers, were partially attenuated by 3-MA. In conclusion, we demonstrated that NRTIs can cause rat oocyte dysfunction and low fertility, and this damage was, at least partially, mediated by autophagy.
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