Jr. Latendresse et al., TOXIC EFFECTS OF BUTYLATED TRIPHENYL PHOSPHATE-BASED HYDRAULIC FLUID AND TRICRESYL PHOSPHATE IN FEMALE F344 RATS, Veterinary pathology, 32(4), 1995, pp. 394-402
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.