Abstract
Hexavalent chromium [Cr(VI)], an environmental toxicant, causes severe male reproductive abnormalities. However, the actual mechanisms of toxicity are not clearly understood and have not been studied in detail. The present in vitro study aimed to investigate the mechanism of reproductive toxicity of Cr(VI) in male somatic cells (mouse TM3 Leydig cells and TM4 Sertoli cells) and spermatogonial stem cells (SSCs) because damage to or dysfunction of these cells can directly affect spermatogenesis, resulting in male infertility. Cr(VI) by inducing oxidative stress was cytotoxic to both male somatic cells and SSCs in a dose-dependent manner, and induced mitochondria-dependent apoptosis. Although the mechanism of Cr(VI)-induced cytotoxicity was similar in both somatic cells, the differences in sensitivity of TM3 and TM4 cells to Cr(VI) could be attributed, at least in part, to cell-specific regulation of P-AKT1, P-ERK1/2, and P-P53 proteins. Cr(VI) affected the differentiation and self-renewal mechanisms of SSCs, disrupted steroidogenesis in TM3 cells, while in TM4 cells, the expression of tight junction signaling and cell receptor molecules was affected as well as the secretory functions were impaired. In conclusion, our results show that Cr(VI) is cytotoxic and impairs the physiological functions of male somatic cells and SSCs.
Highlights
Cr(VI) have an increased risk of poor semen quality and sperm abnormalities that lead to infertility or cause developmental problems in children[15]
In the spermatogonial stem cells (SSCs), treatment with 12.5 μ M Cr(VI) increased the percentage of annexin-V-positive and TUNEL-positive cells compared to that in the control, indicative of apoptosis (Fig. 2). These results show that Cr(VI) caused apoptosis in all the cells and the relative IC50 results suggest that SSCs are more sensitive to Cr(VI) than the somatic cells
To the best of our knowledge, this study is the first to report that the dose-dependent cytotoxic effects of Cr(VI) exposure in both male somatic cells and SSCs are mediated through apoptosis
Summary
Cr(VI) have an increased risk of poor semen quality and sperm abnormalities that lead to infertility or cause developmental problems in children[15]. We investigated the mechanism underlying the toxic effects of Cr(VI) in male somatic and spermatogonial stem cells (SSCs). Sertoli cells are located in the convoluted seminiferous tubules and are responsible for supporting/promoting the development of germ cells. The objectives of the present in vitro study were to: (i) determine the cytotoxic effects of Cr(VI) on mouse TM3 cells (a well-known mouse Leydig cell line), mouse TM4 cells (a well-known mouse Sertoli cell line), and mouse SSCs; (ii) evaluate the effects of Cr(VI) on oxidative stress; (iii) assess the effects of Cr(VI) on apoptotic signaling mechanisms; (iv) understand the role of Cr(VI) in cell proliferation/ self-renewal mechanisms of SSCs; and (v) explore the effects of Cr(VI) on the physiological functions of TM3 and TM4 cells
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