Reproductive and developmental effects on rats after prenatal, postnatal, or pre- and postnatal exposure to the hypotensive agent losulazine.
Losulazine was administered orally to 21 bred Sprague-Dawley rats per group at 0, 4, and 8 mg/kg/day by three dosing schedules: gestation day 15 until term (prenatal section); postnatal days 1 to 21 (postnatal section); and gestation day 15 until postnatal day 21 (pre- and postnatal section). Dams were allowed to deliver and the number of live and dead pups recorded. Each pup was sexed and weighed on days 0, 4, and 21. Also, pinna detachment and eye opening were monitored. Randomly selected offspring were allowed to mature and then cohabited for assessment of reproductive performance. Dam body weight gain during dosing was reduced in the high dose group of the pre- and postnatal section. Treated dams in the postnatal and pre- and postnatal sections had litters with reduced body weight, delayed development, and decreased survival. In the F1 mating portion of the postnatal and pre- and postnatal sections, F1 offspring from losulazine-treated dams had reduced body weights over the entire study. A dose-related decrease was found for both the percentage of F1 males that bred and the conception rate of bred F1 females. All F1 females entered estrus at least once, and those that conceived delivered normal litters. Neither microscopic examination of F1 male reproductive organs nor analyses of serum prolactin, luteinizing hormone (LH), and testosterone levels indicated the cause of impaired fertility. Thus, although prenatal exposure only did not result in adverse effects, postnatal exposure to losulazine via lactation affected offspring growth, development, and reproductive capacity.
Poppe
S M
SM
Reproductive and Developmental Toxicology, Upjohn Company, Kalamazoo, Michigan 49001.
Marks
T A
TA
Mesfin
G M
GM
Soule
D L
DL
Shaw
C I
CI
Morris
D F
DF
Black
D L
DL
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D005260:Female; D006728:Hormones / Q000097:blood; D008098:Litter Size; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011919:Rats, Inbred Strains
D006728:Hormones; D010879:Piperazines; C036654:losulazine hydrochloride