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Effect of 3-Methylcholanthrene on Atherosclerosis in Two Congenic Strains of Mice with Different Susceptibilities to Methylcholanthrene-induced Tumors¹

Bruce Lyon Memorial Research Laboratory, Children's Hospital Medical Center, Oakland, California 94609

Inbred mouse strains AKXL-38 and AKXL-38a are congenic strains that differ at the Ah locus, a gene which affects the inducibility of the cytochrome P-450 enzymes. The Ah-responsive strain, AKXL-38a, is more susceptible to 3-methylcholanthrene-induced tumors than the Ah-nonresponsive strain, AKXL-38. We previously reported that 3-methylcholanthrene (MC) increased the number and the size of atherosclerotic lesions in a dose-dependent fashion. We now demonstrate that the effect of MC is greater in Ah-responsive mice than in Ah-nonresponsive mice indicating that Ah-responsive mice not only are more susceptible to MC-induced cancer but also are more susceptible to MC-enhanced atherosclerosis.

Mice that received atherogenic diet for 14 weeks but no MC had 1.3–1.4 lesions/mouse regardless of genetic type. When mice were treated with MC, the number of lesions increased to 2.1 ± 0.1 (SE) in Ah-nonresponsive mice, 2.6 ± 0.2 in Ah-responsive mice, and 2.3 ± 0.2 in the F₁ hybrid. The total area involved in lesions was 9.3–12.6 µm² in untreated animals. When mice were treated with MC, the total lesion area increased to 23.5 ± 5.2 µm² in Ah-nonresponsive mice, to 43.9 ± 6.6 µm² in Ah-responsive mice, and to 36.2 ± 4.8 µm² in F₁ hybrids. Thus MC increased the lesion area in both strains of mice, but the increase was significantly greater in Ah-responsive than in Ah-nonresponsive animals. High density lipoprotein levels were not significantly affected by MC treatment or Ah genotype.

In order to determine whether the increased susceptibility to MC-induced atherosclerosis segregated with the Ah gene, AKXL-38 and AKXL-38a mice were mated and the F₁ progeny were backcrossed to the Ah-nonresponsive parent. Backcross progeny were tested for Ah genotype by zoxazolamine sleeping time. Measurements of lesions showed that increased susceptibility to MC-enhanced atherosclerosis segregated with the Ah locus.

¹ This work was supported by USPHS Grants HL-28943 and HL-32087 from the National Heart, Lung and Blood Institute.

² To whom requests for reprints should be addressed, at Children's Hospital Medical Center, 747 Fifty-second Street, Oakland, CA 94609.

Received 11/ 4/85. Revised 2/24/86. Accepted 3/21/86.

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