REPRODUCTIVE TOXICOLOGY: Environmental exposures, fetal testis development and function: phthalates and beyond

Abstract

Fetal development of the mammalian testis relies on a series of interrelated cellular processes: commitment of somatic progenitor cells to Sertoli and Leydig cell fate, migration of endothelial cells and Sertoli cells, differentiation of germ cells, deposition of basement membrane, and establishment of cell-cell contacts, including Sertoli-Sertoli and Sertoli-germ cell contacts. These processes are orchestrated by intracellular, endocrine, and paracrine signaling processes. Because of this complexity, testis development can be disrupted by a variety of environmental toxicants. Toxicity of phthalic acid esters (phthalates) to the fetal testis has been the subject of extensive research for two decades, and phthalates have become an archetypal fetal testis toxicant. Phthalates disrupt the seminiferous cord formation and maturation, Sertoli cell function, biosynthesis of testosterone in Leydig cells, and impair germ cell survival and development, producing characteristic multinucleated germ cells. However, the mechanisms responsible for these effects are not fully understood. This review describes current knowledge of the adverse effects of phthalates on the fetal testis and their associated windows of sensitivity, and compares and contrasts the mechanisms by which toxicants of current interest, bisphenol A and its replacements, analgesics, and perfluorinated alkyl substances, alter testicular developmental processes. Working towards a better understanding of the molecular mechanisms responsible for phthalate toxicity will be critical for understanding the long-term impacts of environmental chemicals and pharmaceuticals on human reproductive health.

Interaction between mono-(2-ethylhexyl) phthalate and retinoic acid alters Sertoli cell development during fetal mouse testis cord morphogenesis

“…6 ). This observation is consistent with prior studies on mice and in human fetal testis xenotransplants, in which phthalates induced MNGs or caused seminiferous cord malformation through androgen-independent mechanisms ( Spade et al, 2014 , Heger et al, 2012 , Lambrot et al, 2009 , Mitchell et al, 2012 ), Several recent reviews, including our own, have proposed mechanisms or adverse outcome pathways to describe the events that are involved in phthalate toxicity ( Howdeshell et al, 2015 , Conley et al, 2018 , Clewell et al, 2020 , Arzuaga et al, 2020 , Gray et al, 2020 , Li and Spade, 2021 ). We believe that the data generated by the present study, when analyzed in the context of previous papers that investigated phthalate toxicity in mouse, rat, and human fetal testis, strongly suggest that phthalates have either a single mechanistic target upstream of developmental and function of both Sertoli and Leydig cells, or a primary target in the Sertoli cell that adversely affects Leydig cell function in the rat in a manner that is not reproduced in the mouse.…”

“…A commonly reported effect of phthalates on the fetal testis is induction of MNGs. In utero phthalate exposure has consistently induced MNGs in rats and mice, and this has been replicated in human fetal testis xenotransplant studies ( Li and Spade, 2021 ). In testis culture experiments, MEHP has been reported to induce MNGs in cultured GD 15 and GD 18 mouse testes, as well as cultured GD 20 and PND 3 rat testes ( Boisvert et al, 2016 , Lehraiki et al, 2009 ).…”

Impact of endocrine disrupting chemicals and pharmaceuticals on Sertoli cell development and functions

“…Additionally, this review seeks to underscore the consequences of exposing fetal and/or perinatal Sertoli cells to endocrine disrupting chemicals (EDCs) as well as to drugs reported to target Sertoli cells. Chemicals are characterized as EDCs based on their ability to perturb hormonal homeostasis, by either disrupting the production of hormones by endocrine tissues, their metabolism, or their functions by altering hormone receptors on target tissues ( 2 – 4 ). While the term “endocrine disruptor”, often referred to as EDC, was coined in the 1990s by Theo Colborn and colleagues, its definition has evolved over the last decades and varies between scientific societies, regulatory and governmental agencies worldwide ( 5 ).…”

Impact of Fetal Exposure to Endocrine Disrupting Chemical Mixtures on FOXA3 Gene and Protein Expression in Adult Rat Testes

“…DEHP is an anti-androgenic compound that decreases Leydig cell production of testosterone in males [ 21 ]. It has also been shown to decrease Sertoli cell function and anogenital distance, an androgen-dependent process, in male rodents and humans [ 22 ].…”