Reversible effects of triamcinolone and lack of effects with aspirin or L-656,224 on external genitalia of male Sprague-Dawley rats exposed in utero.
Inhibitors of the arachidonic acid cascade were given to pregnant rats during the critical period for morphogenesis of the external genitalia. Groups treated subcutaneously (s.c.) with 0.1 or 0.25 mg/kg/day of triamcinolone acetonide (TA) on gestational days (GD) 14-19 had male fetuses on GD 20 with moderate decreases in absolute anogenital distance (AGD), but gross and histological examinations revealed no alterations to the genital tubercle (i.e., no hypospadias). The s.c. coadministration of arachidonic acid at 100 mg/kg/day had minimal to no effect on AGD in the TA-exposed groups. No effect on AGD was observed in male fetuses from groups administered aspirin orally at 150 mg/kg/day, and only a 6% decrease was observed in the 300-mg/kg/day group. Neither TA nor aspirin adversely affected AGD of female fetuses. In another study, TA was administered on GD 11-19 at dose levels of 0.05 and 0.1 mg/kg/day, and dams were allowed to deliver. High-dose male offspring examined on postcoitum day (PCD) 23, had moderate decreases in AGD. In both studies with TA, there were also significant decreases in offspring weights. The contribution of the decreased weight to the decrease in absolute AGD was examined by a variety of methods (ratio of AGD to cube root of weight or biparietal distance, comparison to weight-matched controls, and covariance analysis). We conclude that TA caused a specific decrease in AGD on GD 20 that was largely reversed by PCD 23. When examined as adults (8 weeks old), the external genitalia of TA-exposed offspring were normal. Thus, the TA-induced decreases in AGD on GD 20 did not predict irreversible malformation. TA also caused other effects, which included a somewhat flattened genital tubercle and apparently thinned and glossy skin between the tubercle and the anus in both sexes on GD 20 and PCD 23, but not as adults. In addition, there were high pup mortality and high incidences of micrognathia and omphalocele (in the 0.25-mg/kg/day group only). Aspirin at 75 or 150 mg/kg/day and a specific lipoxygenase inhibitor (L-656,224) at 1,000 or 2,000 mg/kg/day were also administered from GD 14 to 19, and no offspring effects were observed. Thus, of the three agents that potentially inhibit the arachidonic acid cascade, only triamcinolone produced moderate effects on rat external genitalia that were largely reversible.(ABSTRACT TRUNCATED AT 400 WORDS)
Wise
L D
LD
Merck Sharp & Dohme Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania 19486.
Vetter
C M
CM
Anderson
C A
CA
Antonello
J M
JM
Clark
R L
RL
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors*; D001241:Aspirin / Q000633:toxicity*; D001572:Benzofurans / Q000633:toxicity*; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D005837:Genitalia, Male / Q000002:abnormalities*; D005865:Gestational Age; D007021:Hypospadias / Q000139:chemically induced; D008297:Male; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014221:Triamcinolone / Q000633:toxicity*; D014886:Weaning
D001572:Benzofurans; C055868:L 656224; D014221:Triamcinolone; D016718:Arachidonic Acid; D001241:Aspirin