Prenatal programming of hepatic monoamine oxidase by 5,5-diphenylhydantoin.
ABSTRACT During ontogeny, rat liver monoamine oxidase gradually increased in activity in both sexes until the pubertal period when female activity rose 1.5- to 2.0-fold higher than male activity. Oral administration of 5,5-diphenylhydantoin (10 mg/kg body wt) to pregnant rats on days 7,9, 12, 14and 16 of gestation had no effect on the monoamine oxidase activity of immature male or female offspring. The enzyme activity in adult male offspring, from females prenatally treated with diphenylhydantoin, was elevated to a level similar to that of adult females. Subcutaneous injection of diphenylhydantoin (10 mg/kg body wt) for 5 days prior to death failed to induce changes in monoamine oxidase activity in either pre- or postpubertal males or females. Thus, prenatal administration of diphenylhydantoin can program changes in adult male monoamine oxidase activity. The serum levels of testosterone in the male offspring of prenatally treated females, on days 5 and 63 postpartum, were the same as those of their respective controls, demonstrating that the changes caused by diphenylhydantoin are not due to diminished levels of testosterone.
SourceAvailable from: aacrjournals.orgCancer Research 07/1983; 43(6):2576-83. · 9.28 Impact Factor
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ABSTRACT: C57BL/6N (Ahb/Ahb) mice have a high-affinity Ah receptor in tissues, whereas AKR/J and DBA/2N (Ahd/Ahd) mice have a poor-affinity Ah receptor. The cytochrome P1-450 induction response (enhanced benzo[a]pyrene metabolism) occurs much more readily in Ahb/Ahb and Ahb/Ahd than in Ahd/Ahd mice, at any given dose of the inducer benzo[a]pyrene. Embryos from the AKR/J X (C57BL/6N)(AKR/J)F1 and the reciprocal backcross were studied during benzo[a]pyrene feeding of the pregnant females. Oral benzo[a]pyrene (120 mg/kg/day) given to pregnant Ahd/Ahd mice between gestational day 2 and 10 produces more intrauterine toxicity and malformations in Ahd/Ahd than Ahb/Ahd embryos. This striking allelic difference is not seen in pregnant Ahb/Ahd mice receiving oral benzo[a]pyrene. Pharmacokinetics studies with [3H]benzo[a]pyrene in the diet and high-performance liquid chromatographic analysis of benzo[a]pyrene metabolism in vitro by the maternal intestine, liver, and ovary and the embryos of control and oral benzo[a]pyrene-treated pregnant females are consistent with "first-pass elimination" kinetics and differences in benzo[a]pyrene metabolism by the embryos and/or placentas versus maternal tissues. In the pregnant Ahd/Ahd mouse receiving oral benzo[a]pyrene, little induction of benzo[a]pyrene metabolism occurs in her intestine and liver; this leads to much larger amounts of benzo[a]pyrene reaching her embryos, and genetic differences in toxicity and teratogenesis are manifest. In the pregnant Ahb/Ahd mouse receiving oral benzo[a]pyrene, benzo[a]pyrene metabolism is greatly enhanced in her intestine and liver; this leads to less benzo[a]pyrene reaching her embryos, much less intrauterine toxicity and malformations, and no genetic differences are manifest. More toxic metabolites (especially benzo[a]pyrene 1,6- and 3,6-quinones) are shown to occur in Ahd/Ahd embryos than in Ahb/Ahd embryos. In additional studies, no prenatal or neonatal "imprinting" effect in C57BL/6N mice by 2,3,7,8-tetrachlorodibenzo-p-dioxin or Aroclor 1254 on benzo[a]pyrene metabolism later in life was detectable. These genetic differences in intrauterine toxicity and teratogenicity induced by oral benzo[a]pyrene are just opposite those induced by intraperitoneal benzo[a]pyrene [Shum et al., '79; Hoshino et al., '81). The data in the present report emphasize the importance of the route of administration when the teratogen induces its own metabolism.Teratology 02/1984; 29(1):35-47. DOI:10.1002/tera.1420290106
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ABSTRACT: The long-term behavioral outcome subsequent to prenatal exposure to phenytoin was examined in an animal model for the Fetal Hydantoin Syndrome. Behavioral outcome was determined by two different techniques—the residential maze, which provided a 24-hour measure of horizontal movement frequency in a group of animals, and time-lapse photography, which allowed quantification of frequency, duration, distribution, and sequencing of 15 motor acts performed by individual rats. Phenytoin induced significant, sex-related changes in motor behavior. Ten-week-old females exposed in utero to phenytoin displayed hypoactivity comprised of a longer duration, greater frequency, and more random distribution of grooming behaviors. Prenatally exposed males at that age displayed an opposite effect of hyperactivity consisting of a longer duration and greater frequency of exploratory behaviors. It appears that prenatal exposure to phenytoin may affect normal maturational changes in motor behavior so that immature activity levels are maintained in the adult animal.Teratology 04/1983; 27(2):149 - 157. DOI:10.1002/tera.1420270203