Time course of the tri-o-cresyl phosphate-induced testicular lesion in F-344 rats: Enzymatic, hormonal, and sperm parameter studies.
The testicular toxicity of tri-o-cresyl-phosphate (78308) (TOCP) was studied in rats. Male Fischer-344-rats were administered 0 or 150mg/kg TOCP daily by gavage for 3, 7, 10, 14, or 21 days. A separate group of animals was maintained for 98 days after dosing to observe the effects of recovery. The animals were observed for signs of neurotoxicity. They were killed 24 hours after the last dose and the testes were removed and weighed. Brain acetylcholinesterase (AChE) and testicular nonspecific esterase (NSE), neurotoxic-esterase (NTE), and beta-glucuronidase (BGD) were determined. Blood samples were obtained and assayed for serum luteinizing-hormone (LH), follicle-stimulating-hormone (FSH), and testosterone. Interstitial fluid testosterone content was also measured. Cauda epididymal sperm samples were obtained and motility and sperm density were measured. Testicular sections as well as sections from the spleen, liver, kidney, pancreas, pituitary and adrenal glands, and small intestine were examined for histopathological changes. Signs of acute cholinergic toxicity (lacrimation and diarrhea) were seen in 30 percent of the animals during the first 5 days. No signs of delayed neurotoxicity were seen. TOCP decreased sperm motility and density after 10 days. Relative testes weights were significantly decreased only in animals dosed for 21 days. Brain AChE and testicular NSE and NTE were decreased. BGD was not affected. TOCP did not decrease serum LH, FSH, or testosterone, or interstitial testosterone. A complete absence of germinal cells was seen in all treated animals. The tubules appeared to have decreased diameters, and the epididymides did not contain any sperm. These changes did not reverse during the recovery period. No histopathological changes were seen in other organs. The authors conclude that TOCP acts directly on the testes in rats and at the tested dose produces irreversible testicular lesions.