Affiliation:
1. Naval Medical Research Institute (Toxicology Detachment), Wright-Patterson Air Force Base, OH
2. Department of Veterinary Biosciences, Ohio State University, Columbus, OH
Abstract
Triaryl phosphates, including tricresyl phosphate (TCP) and butylated triphenyl phosphates (BTP), are used in the commercial manufacture of plastics, lubricants, and hydraulic fluids. Recent reports implicate these compounds as endocrine and reproductive toxicants that can cause cholesteryl lipidosis in adrenocortical (AC) and ovarian interstitial (OI) cells, suggesting altered metabolism of steroid hormones or cholesterol or of both. We investigated potential mechanisms of BTP and TCP toxicity to determine if there were functional abnormalities of the adrenal cortex or ovary. Groups of intact (nine or 12) and ovariectomized (six) female F344 rats, 10-12 weeks of age, received 0, 0.4 g/kg TCP, or 1.7 g/kg BTP in sesame oil vehicle or 1.7 g/kg neat BTP for 20, 40, or 60 days. All rats administered BTP and TCP developed cholesteryl lipidosis in AC and OI cells; the TCP-treated group was most severely affected. Serum concentrations of androstenedione and corticosterone were unchanged, but estradiol levels were significantly ( P < 0.05) elevated in BTP- and TCP-treated groups (14.5 times and 37.5 times greater than controls, respectively). Vaginal cytology revealed that BTP- but not TCP-treated females had abnormal reproductive cycles that were significantly prolonged in diestrus (3 times greater than control). There were significant elevations in serum total cholesterol (TCP-treated group was 1.3 times greater than controls), low-density lipoprotein (TCP-treated group was 1.8 times greater than controls), alanine transaminase (BTP-treated group was 2 times greater than controls), and albumin (a major serum estradiol-binding protein; BTP-treated group was 4.6 g/dl vs. 3.6 g/dl for controls). Liver weights (134% that of controls) and P-450 enzymes (3 times greater than controls) were significantly increased in BTP-treated rats. Abnormal reproductive cycles, elevated serum albumin, and increased hepatic P-450 concentration suggested fecundity could be affected in female rats exposed to BTP, most likely because of altered liver metabolism. Ovariectomized BTP-treated and control rats had similarly increased uterine weights after challenge with estradiol and estradiol benzoate, indicating that triaryl phosphate-induced esterase inhibition or other xenobiotic-induced block of hormone action in estradiol-responsive tissues was not responsible for the prolonged diestrus in rats with elevated serum estradiol. The pathogenesis of the cholesteryl lipidosis induced by TCP and BTP appeared to be separate from the reproductive effects because the lipidosis was most severe in TCP-treated rats, which had normal reproductive cycles and fertility.
Cited by
24 articles.
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