Effects of in utero exposure to the organophosphate insecticide fenitrothion on androgen-dependent reproductive development in the Crl:CD(SD)BR rat.
Fenitrothion [0,0-dimethyl-O-(4-nitro-m-tolyl) phosphorothioate] is an organophosphate insecticide that has been shown to have antiandrogenic activity using in vitro and in vivo screening assays. Studies were performed to evaluate the ability of fenitrothion to disrupt androgen-dependent sexual differentiation in the male rat. Pregnant Crl:CD(SD)BR rats were administered fenitrothion by gavage at 0, 5, 10, 15, 20, or 25 mg/kg/day ( n = 6-11/group) from gestation day (GD) 12 to 21. Maternal toxicity was observed in the dams treated with 20 and 25 mg fenitrothion/kg/day based on muscle tremors and decreases in body weight gain from GD 12 to 21. Fetal death was increased in the 20 and 25 mg/kg/day exposure groups, as evidenced by a decrease in the proportion of pups born alive. Androgen-mediated development of the reproductive tract was altered in male offspring exposed in utero to maternally toxic levels of fenitrothion (25 mg/kg/day), as evidenced by reduction in anogenital distance on postnatal day (PND) 1 and retention of areolae on PND 13. However, these effects were only transient, and there were no indications of abnormal phenotypes or development of androgen-dependent tissues on PND 100. At the dose levels evaluated in this study, fenitrothion was only weakly antiandrogenic in vivo compared with other androgen receptor antagonists such as flutamide, linuron, and vinclozolin. Based on observed fetotoxicity at 20 mg/kg/day, the lowest observed adverse effect level (LOAEL) for developmental effects can be lowered from 25 to 20 mg/kg/day.
Turner
Katie J
KJ
CIIT Centers for Health Research, P.O. Box 12137, Research Triangle Park, North Carolina 27709, USA. kturner@ciit.org
Barlow
Norman J
NJ
Struve
Melanie F
MF
Wallace
Duncan G
DG
Gaido
Kevin W
KW
Dorman
David C
DC
Foster
Paul M D
PM
D000014:Abnormalities, Drug-Induced; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000728:Androgens / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D005260:Female; D005278:Fenitrothion / Q000008:administration & dosage / Q000633:toxicity*; D005313:Fetal Death / Q000139:chemically induced; D005837:Genitalia, Male / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012741:Sexual Maturation / Q000187:drug effects* / Q000502:physiology
D000726:Androgen Antagonists; D000728:Androgens; D007306:Insecticides; D005278:Fenitrothion