title: Dose-response effects of diphenylhydantoin on pregnant dams and embryo-fetal development in rats.
abstract: Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose-response relationship of DPH. This study investigated the dose-response effects of DPH on pregnant dams and embryo-fetal development as well as the relationship between maternal and developmental toxicity. DPH was orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment-related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of DPH for pregnant dams and embryo-fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.
authors.affiliation: College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Lee
authors.forename: Hyung-Seon
authors.initials: HS
authors.lastname: Baek
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Lim
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.forename: Dong-Ho
authors.initials: DH
authors.lastname: Shin
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Seung-Chun
authors.initials: SC
authors.lastname: Park
authors.forename: Jong-Choon
authors.initials: JC
authors.lastname: Kim
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D002585:Cesarean Section; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000196:embryology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D014781:Viscera / Q000187:drug effects
chemical_list: D010672:Phenytoin