The Murine Ah locus: In utero toxicity and teratogenesis associated with genetic differences in benzo[a]pyrene metabolism

Abstract

Benzo[a]pyrene, at dose between 50 and 300 mg per kg body weight given at Day 7 or 10 of gestation, causes in utero toxicity and teratogenicity more so in genetically "responsive" C57BL/6 than in "nonresponsive" AKR inbred mice. With the use of AKR X (C57BL/6) (AKR)F1 and (C57BL/6) (AKR)F1 X AKR backcrosses, it was shown that allelic differences at the Ah locus in the fetus can be correlated with dysmorphogenesis. If the mother is nonresponsive (Ahd/Ahd), the Ahb/Ahd genotype in the fetus is associated with more stillborns and resorptions, decreased fetal weight, increased congenital anomalies, and enhanced P1-450-mediated covalent binding of BP metabolites to fetal protein and DNA, when compared with the Ahd/Ahd genotype in the fetus from the same uterus. If the mother is responsive (Ahb/Ahd), however, none of these parameters can be distinguished between Ahb/Ahd and Ahd/Ahd individuals in the same uterus, presumably because enhanced BP metabolism in maternal tissues and placenta cancels out these differences between individual fetuses. Of particular interest in our study is the fact that the mother and the father both must be of a particular genotype before differences in teratogenesis among fetuses (due to their genotype) will be expressed. These data might provide an example in attempting to explain clinically why only one child is affected with an apparent "drug-induced syndrome" although the mother has taken the same dose of the particular drug during each of numerous pregnancies.

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).…”

Development of an In Vitro System Detecting Pro-embryotoxin

“…Thus, we have tried to establish a cytotoxicity detecting system combined with a pre-incubation step to detect a broad class of embryo toxic chemicals. It is well known that metabolically activated forms of benzo[a]pyrene induce teratogenesis (12). The cytotoxicity of benzo[a]pyrene was, however, not observed at a concentration less than 100 m M in embryo fibroblasts.…”

Relationship between ambient air pollution and DNA damage in Polish mothers and newborns.

“…Experimental bioassays have shown a number of PAHs to be transplacental carcinogens and developmental toxicants (6)(7)(8)(9)(10)(11). PAH-DNA adducts represent the net effect of exposure, absorption, activation, detoxification, and repair and thus are a better measure of the individual biologically effective dose of PAHs than estimates of external exposure (12,13).…”