Importance of the route of administration for genetic differences in benzo[a]pyrene‐induced in utero toxicity and teratogenicity

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 × (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 ofbenzo[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.

Cytochrome P-450 metabolic activity in embryonic and extraembryonic tissue lineages of mouse embryos.

“…Thus, it appears that the induced SCE frequency in mice in vivo is influenced by genetic differences not only in drug activation but also in drug detoxication or absorption. For example, oral administration of benzo[a]pyrene to nonresponsive pregnant mice leads to greater embryotoxicity in nonresponsive embryos than in responsive embryos, which is the opposite of the results obtained after intraperitoneal administration (7,(31)(32)(33).…”

“…However, there is no detectable activity of the phenobarbital-induced cytochrome P-450 system (not associated with the Ah locus) in 9-day rat embryos (42) or in cultured rat yolk sac cells (43). Furthermore, predominance of quinone formation in mouse embryos treated with benzo[a]pyrene at 4 days of gestation (9) or at 10 days of gestation (33) suggests that detoxication enzymes are relatively inactive at early stages of development. Metabolism of benzo[a]pyrene by cytochrome P-450-mediated oxidation is thus the only system known to be active very early in gestation.…”

Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects

“…In animal experiments, PAHs have been consistently shown to be teratogenic. The embryonic development of fish embryos was disturbed (20), and congenital malformations of various organ systems were induced by benzo(a) pyrene exposure to pregnant mice (21).…”

Molecular evidence of an interaction between prenatal environmental exposures and birth outcomes in a multiethnic population.

“…In addition to being genotoxic and carcinogenic, PAHs such as BaP are endocrine disruptors (Bostrom et al 2002;Bui et al 1986;Davis et al 1993). Prior laboratory and two human studies in Central Europe indicate that transplacental exposure to PAHs at relatively high concentrations (annual average airborne concentrations of 7-17 ng/m 3 BaP in the human studies) is associated with adverse birth outcomes (Barbieri et al 1986;Bui et al 1986;Dejmek et al 2000;Legraverend et al 1984;Perera et al 1998). We recently reported that prenatal PAH exposure estimated by personal air monitoring was associated with reduced birth weight and head circumference among African Americans in the present New York City, New York, cohort (Perera at al.…”