Deciphering mechanisms of cisplatin-induced male infertility

Project Overview:

In 1972, the introduction of cis-diamminedichloroplatinum (II) (cDDP, cisplatin) for the treatment of testicular germ cell tumors dramatically increased the overall cure rate and patient survivorship. Unfortunately, since testicular cancers occur most commonly in young men ~15-34 years of age, the prolonged, sometimes permanent, infertility that often results from cDDP treatment is a devastating side effect for these young men. We (Seaman et al., 2003 Apoptosis 8 (1):101-108), and others have shown that testicular germ cells are extremely sensitive to undergo apoptosis after cDDP exposure. The germ cell subtypes reported to undergo cDDP-induced cell death in rodent models include undifferentiated and differentiated spermatogonia as well as spermatocytes; with subtype sensitivity closely dependent on both the dose and developmental age of the animal. We developed a cDDP multi-cycle dosing paradigm in mice that closely mimics that used in the clinic and showed that this treatment results in the prolonged disruption in spermatogenesis in these mice (Sawhney et al., 2005 Journal of Andrology 26:136-145) and that the undifferentiated spermatogonia were increasingly affected by multiple cycles of cDDP treatment (Harman et al., 2014 Toxicology Letters 227:99-112). Although spermatogonial stem cells (SSCs) are regarded to be mostly insensitive to DNA-damaging agents like cDDP due to their quiescent nature, it has recently been shown in the lab of Shosei Yoshida (2014, Cell Stem Cell 14:658-672) that the progeny of SSCs, the undifferentiated spermatogonia, can dedifferentiate into SSCs and serve as a mechanism for maintaining the functional stem cell pool throughout the life of the animal. Therefore, the prolonged loss of spermatogonia that we have observed in mice using the cDDP multi-cycle dosing paradigm in mice may negatively affect the size of the testicular SSC pool, reducing male fertility. ThisĀ  research project is specifically targeted to test if cDDP is preferentially taken up in specific germ cell subtypes via their enhanced expression of the high affinity membrane copper transporter 1 (CTR1; SLC31A1) and accounts for their distinctive sensitivity to elimination after cDDP exposure. This hypothesis is based upon the growing body of evidence in the literature indicating that CTR1 is the major influx transporter for cDDP. As well as our preliminary observations showing a robust expression of this protein in the testis and that the testis of Ctr1+/- mice show a limited loss of germ cells after 2 treatment cycles of cDDP. Although our hypothesis predicts that germ cell CTR1 underlies the sensitivity of these cells to cDDP-induced apoptosis, the evaluation of CTR1 in other cells of the seminiferous epithelium (e.g., Sertoli cells) is also closely considered as CTR1-mediated cDDP influx in other testicular cells could also contribute to the pathogenic mechanism responsible for the sustained loss of germ cells after a repeated multi-cycle treatment of cDDP by disrupting the maintenance of the microenvironment necessary for germ cell development.

It is anticipated that this research will impact the field by offering a mechanistic foundation to explain the distinct sensitivity of testicular germ cells to cDDP-induced elimination thus providing insights for the development of translational research into innovative clinical strategies that will continue to allow for the efficient elimination of tumor cells by cDDP while sparing the long-term fertility of men.

Relevant Publications:

Harman, J and Richburg, JH (2014). Cisplatin-induced alterations in the functional stem cell pool and niche in C57BL/6J mice following a clinically relevant multi-cycle exposure. Toxicology Letters Apr 2;227(2):99-112.

Sawhney, P, Giammona, CJ, Meistrich, ML and Richburg, JH (2005). Cisplatin-induced long-term failure of spermatogenesis in adult C57/Bl/6J mice. Journal of Andrology 26:136-145.

Seaman FC, Sawhney, P, Giammona, CJ and Richburg, JH (2003). Cisplatin-induced pulse of germ cell apoptosis precedes long-term elevated apoptotic rates in C57/B6 mouse testis. Apoptosis 8 (1):101-108.

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