Dissecting the Phthalate-Induced Sertoli Cell Injury: The Fragile Balance of Proteases and Their Inhibitors1

Abstract

Spermatogenesis is a dynamic, finely hormonally regulated, and strictly spatially organized process by which spermatogonia divide, develop, and differentiate into spermatozoa. Spermatogenesis relies on two apparently opposite processes: the maintenance of the integrity of the seminiferous epithelium and the movement of germ cells from its base to its apex. Maintenance of the architectural integrity that is fundamental for spermatogenesis is ensured by three checkpoints: the seminiferous tubule basement membrane; the inter-Sertoli cell blood-testis barrier (BTB), sometimes more accurately referred to as the blood-seminiferous tubule barrier; and ectoplasmic specializations (ES) between Sertoli and differentiating germ cells. The BTB divides the seminiferous epithelium into two compartments: the basal compartment, which forms the niche for spermatogonial proliferation and renewal and the initiation of meiosis, and the adlumenal compartment, where meiosis is completed and spermiogenesis occurs. The migration of germ cells across the BTB as well as their release in the lumen relies on disassembly and reassembly of junctional components. Progress has been made on understanding the nature of proteases and their inhibitors involved in these processes and the regulations that finely tune this homeostasis [1][2][3][4][5]. With respect to proteases expressed in the testis, the matrix metalloproteinase (MMP) 2/MMP14/tissue inhibitor of metalloproteinase (TIMP) 2 system has emerged as crucial in apical ES dynamics [3,4,6]. The MMP2/TIMP2 homeostasis is fragile and was previously reported to be sensitive to phthalate [7]. In the current issue of Biology of Reproduction, Yao et al.[8] explore the transcriptional mechanism of Timp2 downregulation that follows phthalate exposure.

Man is not a big rat: concerns with traditional human risk assessment of phthalates based on their anti-androgenic effects observed in the rat foetus

“…It is not clear whether phthalate-induced disturbances in gonocyte development result from a direct effect on this cell type or whether they are mediated by Sertoli cells. Indeed, Sertoli cell proliferation and/or gene expression are altered by phthalates both in rat and human foetuses [103, 132, 133]. In conclusion, as gonocytes and Sertoli cells are common targets of phthalates in different species, including humans, efforts should be made to define a set of genes the expression of which is changed by phthalates both in rat and human testes in order to establish new endpoints for human risk assessment.…”

NC1 domain of collagen α3(IV) derived from the basement membrane regulates Sertoli cell blood-testis barrier dynamics

“…These findings thus support the notion that there is a local autocrine-based regulatory axis in the seminiferous epithelium, known as the “apical ES-BTB-hemidesmosome” axis, that regulates and/or coordinates cellular events across the epithelium during the epithelial cycle 41 , 42 . The presence of this local functional axis was also supported by studies using a Sertoli cell injury model, based on the use of phthalates, which showed that a disruption of the apical ES involving cleavage of laminin-γ3 chains during spermatid loss also led to a BTB disruption 43 - 45 …”

Phthalate esters affect maturation and function of primate testis tissue ectopically grafted in mice

“…Sertoli cells are considered to be one of the primary targets of phthalates, particularly in exposure during the postnatal period. Effects on Sertoli cells include vacuolization, lost integrity of vimentin filaments and alterations of tight junctions, resulting in germ cell sloughing and germ cell loss (reviewed by (Mazaud-Guittot, 2011). We did not observe abnormalities in the general histological attributes of seminiferous epithelium (i.e.…”