Reproductive effects of tris(4-chlorophenyl)methanol in the rat

Tris(4-chlorophenyl)methanol (TCPM) is a global contaminant of unknown origin that is structurally related to the endocrine modulating pesticides 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and Dicofol. Therefore, the potential reproductive toxic effects of TCPM were investigated in sexually mature male Sprague Dawley rats (n = 20) treated with 1.0, 10.0 or 100 ppm of TCPM mixed in the diet for 28 days. The calculated TCPM intake was 0.0, 0.1, 1.2 and 12.4 mg/kg/day, respectively. Serum concentrations of follicle stimulating hormone (FSH) in terminal blood samples were significantly (P < 0.02) elevated in the highest dose group compared to the controls. In contrast, dietary exposure to TCPM had no effect on circulating levels of luteinizing hormone (LH), testosterone (T) and the T/LH ratio. Incubation of MCF-7 cells with increasing concentrations of TCPM failed to either induce proliferation or to block the proliferative effect induced by estradiol indicating that TCPM is neither estrogenic or anti-estrogenic. Relative binding affinity studies using androgen receptors from the prostate revealed that TCPM has a binding affinity comparable to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the principle metabolite of DDT. In addition, the calculated Ki (0.62 microM) for TCPM is lower than the reported Ki's for the antiandrogenic pesticides p,p'-DDE and vinclozolin. Although TCPM binds with the androgen receptor in vitro, the absence of both an effect on serum T levels and morphological changes in the testis suggests that the mechanism of action for elevated FSH levels seen in vivo may not involve an antiandrogenic effect of TCPM at the dose level used in this study. The no adverse effect level for reproductive effects of TCPM is 10 ppm which is equivalent to a calculated intake of 1.2 mg/kg/day.