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Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus

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Abstract

The balance between cytochrome(s) P1-450 and other forms of P-450 in the liver, and probably many nonhepatic tissues as well, appears to be important in the toxicity, carcinogenicity, mutagenicity, and teratogenicity of numerous compounds. Thus, allelic differences in a single gene — the Ah locus —can have profound effects on the susceptibility of mice to drug toxicity and cancer. There is evidence for the Ah locus in the human.

Striking increases in the incidence of stillborns, resorptions, and malformations caused by 3-methylcholanthrene or 7,12-dimethylbenz[a]anthracene were observed in the aromatic hydrocarbon “responsive” C57BL/6N, C3H/HeN, and BALB/cAnN inbred strains, compared with the genetically “nonresponsive” AKR/N. These data suggest that an association exists between the Ah locus and teratogenesis. Although numerous teratogenic differences among inbred mouse strains have been previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance, on the basis of known differences in polycyclic hydrocarbon metabolism regulated by the Ah locus.

Aplastic anemia induced by oral benzo[a]pyrene daily occurs in less than 4 weeks in the nonresponsive Ah d/Ah d individual, whereas his responsive Ah b/Ah b and Ah b/Ah d siblings remain healthy for 6 months while continuously receiving the same daily dose of benzo[a]pyrene. This phenomenon is probably associated with the “first-pass elimination” effect and the relatively high degree of aryl hydrocarbon hydroxylase induction in the bowel, liver, and bone marrow of the Ah b/Ah b or Ah b/Ah d mouse. A latency period of 2–4 weeks is demonstrated between the exposure of Ah d/Ah d mice to oral benzo[a]pyrene and death; morphological changes of toxicity are apparent early during this latency period. We propose that this animal model system might be useful in investigating human genetic differences in susceptibility to drug-induced aplastic anemia.

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Abbreviations

BP:

benzo[a]pyrene

MC:

3-methylcholanthrene

DMBA:

7,12-dimethylbenz[a]anthracene

B6:

the inbred C57BL/6 mouse strain

D2:

the inbred DBA/2 mouse strain

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

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  1. Developmental Pharmacology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 20014, Bethesda, Maryland, USA

    Daniel W. Nebert, Roy C. Levitt, Nancy M. Jensen, George H. Lambert & James S. Felton

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  1. Daniel W. Nebert
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Nebert, D.W., Levitt, R.C., Jensen, N.M. et al. Birth defects and aplastic anemia: differences in polycyclic hydrocarbon toxicity associated with the Ah locus. Arch. Toxicol. 39, 109–132 (1977). https://doi.org/10.1007/BF00343280

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