Targeting testis-specific proteins to inhibit spermatogenesis: lesson from endocrine disrupting chemicals

Abstract

Introduction Exposure to endocrine disrupting chemicals (EDCs) has recently been linked to declining fertility in men in both developed and developing countries. Since many EDCs possess intrinsic estrogenic or androgenic activities, thus, the gonad is one of the major targets of EDCs. Areas covered For the past 2 decades, studies found in the literature regarding the disruptive effects of these EDCs on reproductive function in human males and also rodents were mostly focused on oxidative stress-induced germ cell apoptosis, disruption of steroidogenesis, abnormal sperm production and disruption of spermatogenesis in particular cell adhesion function and the blood–testis-barrier (BTB) function. Herein, we highlight recent findings in the field illustrating testis-specific proteins are also targets of EDCs. Expert opinion This information should be helpful in developing better therapeutic approach to manage ECD-induced reproductive toxicity. This information is also helpful to identify potential targets for male contraceptive development.

Histological and Transcriptomic Changes in Male Zebrafish Testes Due to Early Life Exposure to Low Level 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

“…23 Delayed spermiation has been associated with toxicant exposure and hormone disruption, but spermiation is a highly complex process and the mechanism(s) involved in delayed spermiation remain unknown and are likely varied. 23 Interestingly, oxidative stress can lead to junction and communication disruption between Sertoli cells and spermatids, 12 and TCDD is known to induce oxidative stress in testis. 24 If our delayed spermiation hypothesis is confirmed by future studies, to our knowledge, it would be the first finding of delayed spermiation due to TCDD, as well as the first in fish due to toxicant exposure.…”

“…This is not surprising because changes to the localized hormonal environment of Sertoli cells, which includes both testosterone and estrogen, can alter cell adhesion within germinal epithelium, notably between Sertoli cells and spermatids. 12 Testicular pathology in TCDD-treated Twenty-three genes were selected from the microarray data based on the criteria of the largest fold changes, most significant changes (lowest p value), classic TCDD-responsive genes, or genes involved in testicular development and spermatogenesis. These were validated with qPCR.…”

“…27 In fact, this may lend support to our retained spermatid hypothesis because spermiation is particularly sensitive to hormonal fluctuations. 12 In contrast, TCDD could cause direct damage to the germinal epithelium if the blood-testis barrier was compromised as a consequence of juvenile exposure. However, then we would expect that spermatogonia would decrease, or at least remain stable.…”

“…Understanding the mechanism of toxin-induced reproductive disease is important because infertility, and particularly malemediated infertility, is increasingly prevalent in people around the world, 12 and associated with population-level consequences in wild fish. 1 Research that uncovers critical pathways and biomarkers of effect can inform novel therapies, future research needs, and prevention and conservation strategies.…”

Toxicants target cell junctions in the testis: Insights from the indazole-carboxylic acid model

“…These signaling molecules alter the phosphorylation states of proteins at the Sertoli-Sertoli cell and/or Sertoli-germ cell interface, which in turn disrupts protein localization (often, but not always, resulting in the re-localization of proteins from the cell membrane into the cytosol via endocytic vesicle-mediated protein trafficking), damages cell junctions and the blood-testis barrier, and results in germ cell loss from the seminiferous epithelium. 2,[33][34][35] Furthermore, a disruption of kinase and/or phosphatase activity by environmental toxicants, such as cadmium, bisphenol A, phthalates, and other androgen disruptors can affect androgen action, including the transcriptional regulation of androgen-related genes necessary for the maintenance of spermatogenesis. 34,[36][37][38][39][40] Because the disruption of cell junctions in the testis 2,4,6,33 and other organs 13,41 by environmental toxicants has been the subject of several reviews, we will use this short review to describe the main features of the different types of junctions in the testis as summarized in Table 1, and discuss recent findings on adjudin, a potential male contraceptive that affects the testis similar to that of various toxicants.…”