TOXIC EFFECTS OF BUTYLATED TRIPHENYL PHOSPHATE-BASED HYDRAULIC FLUID AND TRICRESYL PHOSPHATE IN FEMALE F344 RATS

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 t hese 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 chole sterol or of both. We investigated potential mechanisms of BTP and TCP toxicity to determine if there were functional abnormalities of the a drenal cortex or ovary. Groups of intact (nine or 12) and ovariectomiz ed (six) female F344 rats, 10-12 weeks of age, received 0, 0.4 g/kg TC P, 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 cholestery l lipidosis in AC and OI cells; the TCP-treated group was most severel y affected. Serum concentrations of androstenedione and corticosterone were unchanged, but estradiol levels were significantly (P less than or equal to 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 reproducti ve cycles that were significantly prolonged in diestrus (3 times great er than control). There were significant elevations in serum total cho lesterol (TCP-treated group was 1.3 times greater than controls), low- density lipoprotein (TCP-treated group was 1.8 times greater than cont rols), alanine transaminase (BTP-treated group was 2 times greater tha n 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 contro ls) were significantly increased in BTP-treated rats. Abnormal reprodu ctive cycles, elevated serum albumin, and increased hepatic P-450 conc entration suggested fecundity could be affected in female rats exposed to BTP, most likely because of altered liver metabolism. Ovariectomiz ed BTP-treated and control rats had similarly increased uterine weight s after challenge with estradiol and estradiol benzoate, indicating th at triaryl phosphate-induced esterase inhibition or other xenobiotic-i nduced block of hormone action in estradiol-responsive tissues was not responsible for the prolonged diestrus in rats with elevated serum es tradiol. 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 re productive cycles and fertility.