Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin

Abstract

Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 micrograms/kg body wt; maintenance dose: 5 micrograms/kg body wt, once weekly) and TCDD-75 (initial dose: 75 micrograms/kg body wt; maintenance dose: 15 micrograms/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25 = 5.1%, controls = 2.6%), and incompletely ossified ossa zygomatica (TCDD-25 = 1.8%, controls = 0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25 = 1.3%, controls = 0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls = 0.6%). There was no difference in postnatal mortality (TCDD-25 = 1.3%, controls = 1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn.

Inhibition of CYP450scc expression in dioxin-exposed rat Leydig cells

“…The molar concentrations for 0·2 and 2 ng/ml used in this study are equivalent to 0·62 and 6·2 nM respectively. The concentrations of TCDD used are comparable or even lower than other reports that had demonstrated the inhibitory effect of TCDD on Leydig cell function or testosterone production in animal models (Rune et al 1991b, Chahoud et al 1992, Johnson et al 1992, Mably et al 1992, Peterson et al 1993, Wilker et al 1995, Latchoumycandane et al 2002a. In addition, it is comparable to others' cell-culture systems where nanomolar levels of TCDD exposure were needed to cause noticeable effects on signaling molecules (Shibazaki et al 2004, Vogel et al 2004).…”

“…Those studies demonstrated that TCDD altered the process of testicular steroidogenesis and caused a reduction of Leydig cell volume and number (Johnson et al 1992, Wilker et al 1995. Detrimental effects on Sertoli and germ cells of rat testes, such as reduction of the intercellular contact of neighboring cells, disruption of germ cell development, decrease of spermatogenesis, depletion of antioxidant enzymes and increase in the levels of lipid peroxidation were observed (Rune et al 1991a, Chahoud et al 1992, Mably et al 1992, Peterson et al 1993, Latchoumycandane et al 2002a. It is generally believed that the adverse effects exerted by TCDD on male reproductive functions are manifold and pleiotropic.…”

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

“…21,22 This key difference may be dose dependent because the rodent studies used considerably higher TCDD doses (0.5-50 lg/mL vs. 50 pg/ mL) and more active routes of exposure (subcutaneous or intraperitoneal injection vs. immersion). Our results may be consistent with delayed spermiation (spermatid retention), in which spermatids are phagocytosed by Sertoli cells rather than released into the lumen of the seminiferous tubules to become spermatozoa.…”

“…Altered germinal epithelium was observed after TCDD exposure in rodent studies. 21,25,26 According to these rodent studies, TCDD's adverse effect on germinal epithelium is dose dependent and concurrent with hypospermatogenesis. 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.…”

Proteome Analysis of the Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Murine Testicular Leydig and Sertoli Cells.

“…Its effect on the male reproductive system has been widely discussed, and many such effects are reported in rodents exposed to TCDD: reduced testis and sex accessory gland weight, impaired spermatogenesis, decreased ejaculation, and decreased plasma androgen concentrations. [7][8][9] Since maternal TCDD exposure in rodents could similarly affect the perinatal androgenic status in male offspring in utero and during lactation, 8,[10][11][12][13] the effects on future generations are worrisome. The probability of developing any one of these disorders varies greatly with dose, length of exposure, and, most importantly, the species exposed, 1) making it difficult to determine the TCDD threshold for toxicity.…”