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Animal models of male subfertility targeted on LanCL1-regulated spermatogenic redox homeostasis

Abstract

Oxidative stress in spermatozoa is a major contributor to male subfertility, which makes it an informed choice to generate animal models of male subfertility with targeted modifications of the antioxidant systems. However, the critical male germ cell-specific antioxidant mechanisms have not been well defined yet. Here we identify LanCL1 as a major male germ cell-specific antioxidant gene, reduced expression of which is related to human male infertility. Mice deficient in LanCL1 display spermatozoal oxidative damage and impaired male fertility. Histopathological studies reveal that LanCL1-mediated antioxidant response is required for mouse testicular homeostasis, from the initiation of spermatogenesis to the maintenance of viability and functionality of male germ cells. Conversely, a mouse model expressing LanCL1 transgene is protected against high-fat-diet/obesity-induced oxidative damage and subfertility. We further show that germ cell-expressed LanCL1, in response to spermatogenic reactive oxygen species, is regulated by transcription factor specific protein 1 (SP1) during spermatogenesis. This study demonstrates a critical role for the SP1–LanCL1 axis in regulating testicular homeostasis and male fertility mediated by redox balance, and provides evidence that LanCL1 genetically modified mice have attractive applications as animal models of male subfertility.

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Fig. 1: Reduced LanCL1 expression is related to human infertility.
Fig. 2: Correlated expression of LanCL1 with male germ cell maturation.
Fig. 3: LanCL1 deficiency results in poor male fertility.
Fig. 4: Loss of LanCL1 promotes ROS accumulation and proliferation/differentiation of SSCs at juvenile age.
Fig. 5: LanCL1 deficiency causes testicular oxidative stress and affects maturing germ cell survival.
Fig. 6: LanCL1 transgene expression protects mice from HFD-induced oxidative stress and spermatogenic defects.
Fig. 7: Transcription factor Sp1 mediates ROS-induced LanCL1 expression.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31501200, 31871179 and 32071161 to C.H.), Key Research Project from Sichuan Provincial Department of Education, China (16ZA0029 to C.H.), Disciplines and Talents Support Program of Sichuan Agricultural University (2015–2019 to C.H.) and in part by the National Key Technology Support Program of China (2014BAI03B01 to Z.C). We thank P. Zhong for helping with illustration drawing.

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C.H., Z.C. and B.X. designed the experiments and interpreted the data; C.Y. performed most of the staining experiments with the help of H.G.; D.P. did most of the in vitro studies and biochemistry assays with the help of C.L.; Y.C. and M.C. generated the LanCL1 KO and transgenic mice, while X. Cao initiated this project, generated the conditional LanCL1 KO/KI mice and performed studies with human samples; X.H. collected the seminal samples; X. Chen generated the LanCL1 antibody; B.M., W.L. and Q.L. executed the other experiments; C.H. and Z.C. supervised the project; C.H. and B.X. wrote the manuscript.

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Correspondence to Mina Chen, Bo Xiao or Zhengli Chen.

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Huang, C., Yang, C., Pang, D. et al. Animal models of male subfertility targeted on LanCL1-regulated spermatogenic redox homeostasis. Lab Anim 51, 133–145 (2022). https://doi.org/10.1038/s41684-022-00961-w

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