Effects of Mono(2-Ethylhexyl) Phthalate, a Testicular Toxicant, on Follicle-Stimulating Hormone Binding to Membranes from Cultured Rat Sertoli Cells1

Abstract

The widely used plasticizer di(2-ethylhexyl) phthalate (DEHP) is a male reproductive toxicant. Its toxicity has been shown to be due primarily to the action of its metabolite mono(2-ethylhexyl) phthalate (MEHP) on Sertoli cells. We have previously shown that at least one of the sites of action of MEHP on the Sertoli cell is the cAMP second messenger system. MEHP inhibits the ability of FSH but not isoproterenol, forskolin, or cholera toxin to stimulate cAMP accumulation in cultured Sertoli cells in a dose- and time-dependent manner. To further characterize this effect of MHP, we prepared a light membrane fraction from control and MEHP-treated Sertoli cells cultured from 18-day-old Fischer 344 rats and measured FSH binding in a radioligand receptor assay using 125I-labeled human FSH (125I-hFSH). MEHP inhibited FSH binding when preincubated with Sertoli cells in culture but not when added simultaneously with 125I-hFSH to the purified membrane preparation. Attenuation of FSH binding was evident after a 3-h preincubation with 100 microM MEHP (18%) and was maximal after 15-24 h of preincubation (70-90%). Preincubation of Sertoli cells for 24 h with 100 microM DEHP had no effect on FSH binding. Half-maximal inhibition occurred at approximately 0.1 microM MEHP. Scatchard analysis indicated a four-fold decrease in FSH affinity with no change in receptor concentration. Exposure of Sertoli cells to MEHP amplified the attenuating effect of guanosine triphosphate (GTP) on FSH binding, suggesting that the action of MEHP may be at the level of the GTP-binding protein that couples the FSH receptor to the adenylate cyclase catalytic subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Mono-butyl phthalate-induced mouse testis injury is associated with oxidative stress and down-regulated expression of <i>Sox9</i> and <i>Dazl </i>

“…The results obtained from the present study are similar with previous research. Some authors (Lloyd and Foster, 1988;Grasso et al, 1993) have suggested that the Sertoli cells is the primary target of the phthalate esters in adult rat testes. It was reported that exposure to MBP destroyed tight junctional structure in Sertoli cell (Schettler, 2006).…”

Mechanisms of phthalate ester toxicity in the female reproductive system.

“…Sufficient estradiol production during the preovulatory stage is critical for stimulating the ovulatory surge of LH. Aromatase is rapidly shut down after the LH surge, both by increased degradation of (Grasso et al 1993). MEHP also activates PPARs, possibly by release of fatty acids, endogenous activators of PPAR.…”

Long-term effects of intrauterine exposure to mono-n-butyl phthalate on the reproductive function of postnatal rats

“…Several authors [18,19] have suggested that the primary target of the phthalate esters is the Sertoli cells in adult rat testes. Phthalate monoesters reduced the ability of folliclestimulating hormone to stimulate cyclic adenosine monophosphate accumulation in Sertoli cells in adult rats [18,19].…”