Endocrine disruptors, gene deregulation and male germ cell tumors

Abstract

Endocrine disruptors (EDs) belong to a large group of compounds, usually present as environmental pollutants, which can alter the homeostasis of living organisms by modifying hormonal balance and changing the normal patterns of gene regulation during development and cell differentiation. Hence, the development of male gonads and their functionality may be affected by exposure to specific EDs or their mixtures. The molecular mechanisms of action of these reprotoxicants leading to pathologies of the reproductive system such as testicular cancer, are complex and not well characterized. It is likely, however, that these compounds alter the interaction between the mechanisms of gene regulation and functional gene networks in windows of risk, mainly during embryonic development. Moreover, such changes could be transmitted through generations by epigenetic mechanisms. There are examples of the action of EDs on the expression of mRNAs, small non-coding RNAs and epigenetic marks in the developing testis associated with cellular and molecular alterations found in germ cell tumors. In the present review, we will discuss various aspects of genetic, transcriptomic and epigenetic changes related to testicular development, exposure to EDs and the occurrence of germ cell tumors.

Environmental endocrine disruptors: Effects on the human male reproductive system

“…This interpretation is supported by findings that human TGCTs show similar gene expression profiles and DNA methylation patterns to PGCs and embryonic stem cells [32]. In fact, the only mouse model to develop experimentally-induced TC, the 129/SvJ strain, have tumors arising from PGC populations [138].…”

“…In particular, microRNAs (miR) are involved in proper differentiation of primordial germ cells (PGCs) and have been shown to be dysregulated in testicular germ cell tumors [32]. Alterations in miR expression have been observed in mouse Sertoli cells that were exposed to nonyl-phenol [33].…”

“…Alterations in miR expression have been observed in mouse Sertoli cells that were exposed to nonyl-phenol [33]. Other EDCs, such as BPA and DDT have also been linked to altered miR expression in estrogen-responsive human breast cancer MCF-7 cells and in placental cell lines, respectively [32]. …”

“…TGCTs consist of a diverse group of neoplasms, based on the different anatomical locations within the testis where they appear. Histopathologically, they have been classified into two main categories - seminomas, which have features similar to those of PGCs and non-seminomas, which include mixed germ cell tumors (the most common), embryonal carcinomas, teratomas, choriocarcinomas and yolk sac tumors [32, 136]. The incidence of TC has increased worldwide over the last 40 years, with an incidence peak in young adults [136, 137].…”

Gonadal development and germ cell tumors in mouse and humans

“…In humans, exposure to high levels of maternal estrogens during pregnancy as well as cryptorchidism are strongly associated with the risk to develop TGCT [84,91]. Moreover, environmental exposure to endocrine disruptors during fetal and/or postnatal life has lead to the hypothesis that PGCs and gonocytes or SSCs might be the preferential targets of neoplastic transformation found in TGCTs [92][93][94].…”