Triaryl
phosphates including
tricresyl phosphate (TCP) and butylated
triphenyl phosphate (BTP) are
organophosphates used in the commercial manufacture of plastics,
lubricants, and hydraulic fluids. Rat steroidogenic tissues such as adrenocortical (AC), ovarian interstitial (OI), and Leydig cells use an intracellular pathway to store
cholesterol (substrate for biosynthesis of
steroid hormones) as
cholesteryl ester (CE). This pathway and the pathway for uptake of serum
cholesterol are less used in Leydig cells of the adult male rat, resulting in a lower CE pool. BTP and TCP caused cholesteryl
lipidosis in
steroid hormone-synthesizing AC and OI, but not Leydig cells in the adult rat. The objectives of this study were to determine if the administration of triaryl
phosphate fluids caused a defect in the
cholesterol storage pathway of AC and OI cells and to determine the mechanism of action. Female rats received daily oral doses of 0 or 0.4 g/kg TCP in
sesame oil vehicle or 1.7 g/kg neat BTP for 40 days. Adrenal glands from both treatment groups and ovaries from TCP-treated rats were heavier than controls. Microscopic and biochemical studies revealed cholesteryl
lipidosis composed of CE in the adrenal glands and ovaries in BTP- and TCP-treated rats with the latter group affected most severely. The activity of neutral CE
hydrolase (nCEH), an
enzyme that converts CE to
cholesterol in the uptake and storage pathways, also was inhibited most in the TCP-treated group (97% inhibition compared to that of control). The activity of
acyl coenzyme A:
cholesterol acyl
transferase, an
enzyme that esterifies
cholesterol to make CE, was depressed 27% compared to that of control adrenal glands of the TCP group, resulting in elevated intracellular
cholesterol levels in AC cells. An inhibition of nCEH in the storage and uptake pathways by triaryl
phosphates most likely resulted in the striking accumulation of CE in cytoplasmic lipid droplets of AC and OI cells in F344 rats.