Susceptibility to the biological effects of polyaromatic hydrocarbons is influenced by genes of the major histocompatibility complex

Abstract

Polyaromatic hydrocarbons are ubiquitous environmental chemicals that are important mutagens and carcinogens. The purpose of this study was to determine whether genes within the major histocompatibility complex (MHC) influence their biological activities. Cell-mediated immunity to dimethylbenz(a)anthracene (DMBA) was investigated in congenic strains of mice. On three different backgrounds, H-2(k) and H-2(a) haplotype mice developed significantly greater contact-hypersensitivity responses to DMBA than H-2(b), H-2(d), and H-2(s) mice. In B10.A(R1) mice, which are Kk and Id, a vigorous contact-hypersensitivity response was present, indicating that the response was governed by class I, rather than class II, MHC genes. C3H/HeN (H-2(k)) and C3H.SW (H-2(s)) strains were also compared for the development of skin tumors and the persistence of DMBA-DNA adducts. When subjected to a DMBA initiation, phorbol 12-tetradecanoate 13-acetate (TPA)-promotion skin-tumorigenesis protocol, C3H/HeN mice, (which develop cell-mediated immunity to DMBA) were found to have significantly fewer tumors than C3H.SW mice (a strain that failed to develop a cell-mediated immune response to DMBA). DMBA-DNA adducts were removed more rapidly in C3H/HeN than in C3H.SW mice. The results indicate that genes within the MHC play an important role in several of the biological activities of carcinogenic polyaromatic hydrocarbons. The observations are consistent with the hypothesis that cell-mediated immunity to chemical carcinogens serves to protect individuals by removing mutant cells before they can evolve into clinically apparent neoplasms.

Figure 1

DMBA contact-hypersensitivity response in C3H and A-strain mice. Panels of mice that were sensitized to 100 μl of DMBA and were ear-challenged with 20 μl of DMBA served as positive controls. Panels of mice that were only ear-challenged with 20 μl of DMBA served as negative controls. Positive controls are the solid bars; negative controls are the shaded bars.

Figure 2

DMBA contact hypersensitivity response in AKR, C57BL/6, and AKRxC57BL/6 F₁ hybrid mice. Panels of mice that were sensitized to 100 μl ofDMBA and were ear-challenged with 20 μl of DMBA served as positive controls (solid bars). Panels of mice that were only ear-challenged with 20 μl of DMBA served as negative controls (shaded bars).

Figure 3

Cutaneous tumorigenesis in C3H and C3H.SW mice. C3H and C3H.SW mice were subjected to a DMBA-initiation, TPA-promotion cutaneous carcinogenesis protocol. The cumulative number of tumors was plotted as a function of the number of weeks on the test.

Figure 4

Effect of preimmunization with DMBA on subsequent DMBA–DNA adduct formation in the skin of C3H mice. Mice were immunized with DMBA by painting 100 μg on the abdominal skin. [³H]DMBA was applied to the back skin 5 days later. Skin was removed and [³H]DMBA binding to DNA was assessed 24 hr after that. Positive controls were immunized with DMBA before [³H]DMBA application. Negative controls were not immunized. The data are significant at the P < 0.01 level.