Molecular Pharmacology, Vol 11, 850-865, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Relationship between "Aromatic Hydrocarbon Responsiveness" and the Survival Times in Mice Treated with Various Drugs and Environmental Compounds

¹ Section on Developmental Pharmacology, Neonatal and Pediatric Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 200l4

Differences in toxicity caused by various environmental pollutants or drugs were studied in several inbred strains of mice and in siblings of the (C57BL/6N) (DBA/2N)F₁ x DBA/2N backcross, in which the phenotypes aromatic hydrocarbon "responsiveness" or "nonresponsiveness" had been determined. This trait of "responsiveness"—which refers to the capacity for induction of cytochrome P₁450 and numerous monooxygenase activities by certain aromatic hydrocarbons—has been previously shown to segregate almost exclusively as a single gene among offspring of the (C57BL/6N) (DBA/2N)F₁ x DBA/2N backcross. "Responsiveness" is associated with shortened survival times following large (500 mg kg^-1 day^-1) doses of intraperitoneal benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, -naphthoflavone, or polychlorinated biphenyls; the cause of death in these experiments is not yet certain. "Nonresponsiveness" is associated with shortened survival times following smaller (120 mg kg^-1 day^-1) oral doses of benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, or lindane, yet is associated with a longer survival time following small daily doses of oral polychlorinated biphenyls. All nonresponsive mice ingesting benzo[a]pyrene daily die within 4 weeks, whereas the survival of responsive mice ingesting benzo[a]pyrene daily is not significantly different from that of control mice; the apparent cause of early death in these experiments is toxic depression of the bone marrow, the pancytopenia leading to death due to hemorrhage or overwhelming infection. When given an intraperitoneal dose of lindane that is lethal to normal mice within 12 hr, 3-methylcholanthrene-treated responsive mice are protected and therefore do not die during this time period. A dose of bromobenzene sufficient to cause considerable necrosis in the liver of a pregnant mouse does not transplacentally cause any detectable necrosis in fetal liver. Genetic differences in aromatic hydrocarbon responsiveness between C57BL/6N and DBA/2N mice are not associated with toxicity caused by large intraperitoneal daily doses of bromobenzene, zoxazolamine, diphenylhydantoin, dichlorodiphenyltrichloroethane (p,p'-DDT), hexachlorobenzene, butylated hydroxytoluene , chlorpromazine, tetracycline hydrochloride, carbamazepine, or diphenylbarbituric acid, and are not associated with differences in survival time following bromobenzene or p,p'-DDT in the diet. These data suggest that the life span of animals exposed to certain environmental compounds can be markedly influenced by a single gene or a very small number of genes, and that the same genetic trait can be either beneficial on detrimental to the animal, depending on whether detoxification on metabolic potentiation occurs.

Note:
ACKNOWLEDGMENTS We greatly appreciate the frequent help of Drs. Alan and Ruth Rabson and Laurence Corash (National Cancer Institute) and Dr. Unnur P. Thorgeirsson (Department of Pathology, George Washington University Medical School) in the histological evaluation of numerous tissue sections. The valuable technical assistance of Mr. Rodney L. Bright and Ms. Nancy A. Jensen is also appreciated. We also thank Drs. Alan H. Conney and Alvito P. Alvares for valuable discussions of this work.

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