Time course of testicular degeneration in rats induced by a synthetic retinoid (Ro 23-2895) and evidence for induction of hypovitaminosis A in the testes.
Eight-week-old male Sprague--Dawley rats were dosed by gavage with 90 mg/kg of Ro 23-2895, (all-E)-9-[2-(nonyloxy)phenyl]-2,4,6,8 nonatetraenoic acid, dissolved in Tween 80. Treated animals (n = 3--4) were sacrificed after 3, 7, 11 and 21 days of dosing. Control rats (n = 3) received an equal volume of Tween 80 and were sacrificed after 3 or 21 days. Cross sections of formalin fixed testes were embedded in glycolmethacrylate, sectioned at 3 microns, and stained with periodic acid-Schiff and hematoxylin. No morphologic alterations were observed in the control rats or in treated rats after 3 days. After 7 days of treatment, there were occasional tubules in which there was a delayed release of mature sperm and occasionally the retained sperm were being resorbed. The frequency and severity of these morphologic changes was increased after 11 days of treatment, and round spermatids were occasionally observed with marginated chromatin in their nuclei. After 21 days of treatment, there was a significant reduction in testicular weight accompanied by marked degenerative changes and in some cases almost a complete desquamation of the germinal epithelium. Multinucleated giant cells and germ cells with marginated chromatin in their nuclei were commonly observed and there was moderate to severe oligospermia in the tubules. Sertoli cell nuclei were swollen and showed lucent, vesiculated nucleoplasm. In a parallel 21-day study, treated rats (n = 10) showed an 80% reduction in plasma retinol and a 56% decrease in testicular retinol compared to vehicle-treated rats (n = 10). A 53% decrease in plasma testosterone levels was also observed in treated rats. The testicular lesions produced by treatment with Ro 23-2895 were similar to vitamin A deficiency, which supports the hypothesis that high doses of synthetic retinoids may cause testicular degeneration through interference of normal retinol homeostasis.
Bosakowski
T
T
Department of Toxicology and Pathology, Roche Research Center, Nutley, NJ 07110.
Levin
A A
AA
Durham
S K
SK
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000187:drug effects* / Q000473:pathology; D013739:Testosterone / Q000097:blood; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000633:toxicity; D014801:Vitamin A / Q000097:blood; D014802:Vitamin A Deficiency / Q000139:chemically induced*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C061341:Ro 23-2895; D014801:Vitamin A; D013739:Testosterone; D014212:Tretinoin