Antiandrogenic effects of dibutyl phthalate and its metabolite, monobutyl phthalate, in rats.
Developmental toxicity following administration of dibutyl phthalate (DBP) and its major metabolite, monobutyl phthalate (MBuP), by gavage was determined in Wistar rats. DBP on days 0-8 of pregnancy induced an increase in the incidence of preimplantation loss at 1250 mg/kg and higher and postimplantation loss at 750 mg/kg and higher. MBuP on days 0-8 of pregnancy produced an increase in the incidence of pre- and postimplantation loss at 1000 mg/kg. DBP on days 7-15 of pregnancy caused an increase in the incidence of fetuses with malformations at 750 mg/kg. MBuP on days 7-15 of pregnancy produced an increased incidence of fetuses with malformations at 500 mg/kg and higher. DBP on days 15-17 of pregnancy resulted in a decrease in the anogenital distance (AGD) of male fetuses and increase in the incidence of fetuses with undescended testes at 500 mg/kg and higher. MBuP on days 15-17 of pregnancy caused a decreased male AGD and increased incidence of fetuses with undescended testes at 250 mg/kg and higher. No effect of DBP and MBuP on the AGD was found in female offspring. The spectrum of fetal malformations, dependence of gestational days of treatment on the manifestation of teratogenicity, and alterations in development of the male reproductive system observed after administration of DBP were in good agreement with those observed after administration of MBuP. These findings suggest that MBuP may be responsible for the induction of developmental toxic effects of DBP. The doses that produced a decrease in the AGD and undescended testes in male offspring were lower than those producing maternal toxicity, fetal malformations after administration during major organogenesis, and embryonic loss. The male reproductive system may be more susceptible than other organ systems to DBP and MBuP toxicity after maternal exposure.
Ema
Makoto
M
Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, Tokyo 158-8501, Japan. ema@nihs.go.jp
D000726:Androgen Antagonists / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D003993:Dibutyl Phthalate / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D010795:Phthalic Acids / Q000494:pharmacology* / Q000633:toxicity; D011247:Pregnancy / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D000726:Androgen Antagonists; D010795:Phthalic Acids; D003993:Dibutyl Phthalate; C028577:monobutyl phthalate