Table 1.
Effects of toxicants on Sertoli cell functions in rodents and humans*
| Species | Toxicant | Studies in vitro | Studies in vivo |
|---|---|---|---|
| Mouse Sertoli cells |
Mono (2- ethyhexyl) phthalate (MEHP) |
Oral gavage at 700 mg/kg/day for 3 consecutive days led to an increase TUNEL-positive cells, inducing germ cell degeneration [157] |
|
| Rat Sertoli cells |
2,5- Hexanedione (HD) |
0.08-1% HD in drinking water led to a dose-dependent increase in retaining spermatids in stages IX- XII tubules [144]; 40-211 mmol HD/kg b.w. induced Sertoli cell injury typified by cell vacuolation; also germ cell necrosis and exfoliation [158] |
|
| Bisphenol-A (BPA) |
Induced Sertoli cell apoptosis, up-regulation of Pten and Akt expression; reduced phopho-Akt and procaspase-3 expression [159]; BPA at 10 and 50 μM induced an increase in GSH level in Sertoli cells [18]; BPA at 200 μM perturbed Sertoli cell TJ- barrier function [25] |
BPA at 0.4 mg/kg b.w. impaired male fertility; neonatal rats exposed to BPA down-regulated Cx43 but up-regulated N-cadherin and ZO-1 expression [160]; BPA at 10-50 mg/kg b.w. induced small but insignificant increase in germ cell loss from seminiferous tubules in adult rats; BPA disrupted the BTB function in 20-day-old rats [25] |
|
| 1-dichloro-2,2 bis(p- chlorophenyl) ethylene (p,p’- DDE) |
Treatment of Sertoli cells with p’p- DDE (30 μM) for 24 hr induced cell apoptosis; up-regulation of Fasl mRNA and protein level; activation of caspase-3 and -8, as well as NF-κB [161, 162] |
||
| ß-Benzene | ß-Benzene (30 μM) induced Sertoli cell apoptosis via an increase in ROS [163] |
||
| 1,3- Dinitrobenzene (1,3-DNB) |
Rats treated with 1,3-DNB led to changes in the expression of genes that regulated apoptosis, cell junction integrity, and signaling pathways [164]; a single dose of 1,3-DNB at 25 mg/kg b.w. for 24 hr led to an increase in pachytene spermatocyte apoptosis, expression of Bax, Bcl-2, Bcl-xL, and Bcl-xs were up-regulated.[165]; daily administration of 1,3-DNB at 6 mg/kg b.w. led to reduced testis weight, loss of pachytene spermatocytes and Sertoli cell vacuolization in seminiferous tubules, and a reduced inhibin B expression [166] |
||
| Di-(2- ethylhexyl) phthalate (DEHP) |
Prepubertal rats treated with DEHP at 1 gm/kg b.w. by oral gavage reduction the expression of Cx43 and ZO-1, delaying the onset of spermatogenesis [167] |
||
| Cadmium | Treatment of Sertoli cells with CdCl2 (0.1-5 μM) perturbed the TJ-permeability barrier [11, 43] |
Treatment of adult rats with CdCl2
(30 μmol/kg b.w.; ~5 mg/kg b.w.) by i.p. induced irreversible disruption of the BTB, apoptosis and necrosis of testicular tissue [49, 50, 168]; adult rats treated with CdCl2 at 3 mg/kg b.w. by i.p. induced TGF-ß3 production that led to BTB disruption and p38 MAPK activation, which could be blocked by p38 specific inhibitor [22, 23]; CdCl2 also activated JNK to induce a2-macroglobulin to protect testes from unwanted proteolysis [51] |
|
| Di-n- pentylphthalate (DPP) |
Oral treatment of adult rats with DPP at 2200 mg/kg b.w. for 12 hr induced germ cell apoptosis in tubules in particular among differentiating spermatogonia and spermatocytes [169, 170] |
||
| 1,2-Dibromo-3- chloropropane (DBCP) |
Rats received DBCP once a week via s.c. for 3 weeks at 20 mg/kg b.w. led to reduced testis weight and infertility [171]; and an increase in serum gonadotropin level and intratesticular testosterone concentration [172] |
||
| Human Sertoli cells |
BPA | Human Sertoli cell treated with BPA at 20 or 200 μM for 2 days led to a decrease in the expression of ZO-1, N-cadherin, and ß-catenin; BPA also induced mis-localization of adhesion proteins at the cell-cell interface mediated via truncated and retracton of actin microfilaments from the Sertoli cell cortical zone; these changes in F-actin organization was mediated by an alteration in the localization of Eps8 and Arp3 [76] |
|
| CdCl2 | Treatment of human Sertoli cells with CdCl2 at 0.5-5 μM for 2 days induced re-distribution of ZO-1, N- cadherin, and ß-catenin with actin microfilaments re-localized by moving from the cell cortical zone to cell cytosol [76] |
||
| 1,2-Dibromo-3- chloropropane (DBCP) |
Severe impairment of spermatogenesis was found in 18 of 23 workers after exposure to DBCP [173] |
*
This Table is not intended to be exhaustive, only selected references are included to illustrate the effects of toxicants on rodent and human Sertoli cell function. Abbreviations used: Akt, murine thymoma viral oncogene homolog 1, also known as protein kinase B (PKB); Arp3, actin-related protein 3; Bax, Bcl2-associated X protein, also known as Bcl-2-like protein 4; Bcl, B-cell lymphoma; Bcl-xL, B-cell lymphoma-extra large; Bcl-xs, Bcl2-like 1; b.w., body weight; Cx43, connexin 43; Eps8, epidermal growth factor receptor pathway substrate 8; Fasl, Fas ligand, also known as apoptosis antigen 1; GSH, glutathione; i.p., intraperitoneal injection; JNK, c-Jun N-terminal protein kinase; NF-κB, nuclear factor kappa-light chain enhancer of activated B cells; p38 MAPK; p38 mitogen activated protein kinase; Pten, phosphatase and tensin homolog; ROS, reactive oxygen species; sc, subcutaneous injection; TJ, tight junction; ZO-1, zonula occludens 1.