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Testicular Stem Cell Dysfunction Due to Environmental Insults Could Be Responsible for Deteriorating Reproductive Health of Men

  • Reproductive Biology: Perspective, Opinions and Commentaries
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Abstract

Reproductive health of men has declined over time including reduced semen quality specifically sperm count, increased incidence of infertility, and testicular cancers. Our recent findings suggest that these disease states possibly arise as a result of disruption of testicular stem cells biology by perinatal insults including exposure to endocrine disrupting chemicals. Testicular stem cells include relatively quiescent, very small embryonic-like stem cells (VSELs), and actively dividing spermatogonial stem cells (SSCs). Both VSELs and SSCs express estrogen receptors and are directly vulnerable to endocrine disruption. Exposing mice pups to estradiol (20 μg/pup/day on days 5–7) or diethylstilbestrol (2 μg/pup/day on days 1–5) affected spermatogenesis during adult life with reduced numbers of tubules in stage VIII, tetraploid cells and sperm. These mice were infertile and majority of diethylstilbestrol treated mice revealed testicular cancer-like changes. An increase in VSEL numbers, observed by both flow cytometry and qRT-PCR, was associated with marked reduction of c-KIT positive spermatogonial cells. VSELs undergo epigenetic changes due to endocrine disruption that results in blocked differentiation (impaired spermatogenesis) leading to reduced sperm count and infertility, and their excessive self-renewal initiates cancer-like changes in adult life. Thus, testicular dysgenesis syndrome (TDS) has a stem cell rather than a genetic basis.

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Acknowledgments

Sincere thanks to ICMR and ICMR-NIRRH for their trust in our research efforts focused on VSELs and for providing financial support.

Funding

Core support by Indian Council of Medical Research, Government of India, New Delhi.

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Authors and Affiliations

  1. Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India

    Deepa Bhartiya & Ankita Kaushik

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  1. Deepa Bhartiya
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  2. Ankita Kaushik
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DB wrote this article with help of AK. Both read and approved the final version.

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Correspondence to Deepa Bhartiya.

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The authors declare that they have no conflict of interest.

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The study was approved by NIRRH Institute Animal Ethics Committee.

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NIRRH approved publication of this article (OTH/932/07-2020).

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Salient Highlights

• Adult mammalian testes harbors pluripotent, relatively quiescent VSELs along with tissue specific “progenitors,” the SSCs similar to VSELs and OSCs in the ovaries

• VSELs/SSCs express receptors for FSH and estrogens and thus both FSH and estrogens act directly on the stem cells. Results call for a paradigm shift in our current understanding of FSH action, which is not limited to only the Sertoli cells. Presence of ER α and β make these stem cells directly vulnerable to endocrine disrupting chemicals.

• Exposure to E2 or DES during neonatal life affects epigenetic status of the stem cells that supports their excessive self-renewal but blocks their differentiation (spermatogenesis). The niche (Sertoli cells) for the stem cells is also affected.

• C-KIT negative, primitive stem/progenitor cells fail to convert into c-KIT positive spermatogonia due to disruption of NP95 expression. As a result, meiosis and further spermiogenesis is blocked and results in reduced sperm count and infertility.

• Testicular cancer-like changes are initiated with an increase in OCT-4A positive VSELs after neonatal exposure to DES. Thus, it is the endogenous VSELs that initiate testicular cancers rather than the concept of presence of a pre-CIS.

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Bhartiya, D., Kaushik, A. Testicular Stem Cell Dysfunction Due to Environmental Insults Could Be Responsible for Deteriorating Reproductive Health of Men. Reprod. Sci. 28, 649–658 (2021). https://doi.org/10.1007/s43032-020-00411-3

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