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Persistent binding of 3-methylcholanthrene to mouse lung DNA and its correlation with susceptibility to pulmonary
Abstract:
A/J, C3H/HeJ, DBA/2J, and C57BL/6J mice have different susceptibilities to polycyclic aromatic hydrocarbon-induced pulmonary neoplasia, whereas the livers from these animals are uniformly resistant to the carcinogenic actions of these substances. After i.v. injection of [3H]-3-methylcholanthrene, radiolabel was detected in the DNA of both lung and liver of all these strains. The DNA was digested to deoxyribonucleosides and chromatographed on Sephadex LH-20. The amounts of nucleoside-bound adducts detected varied markedly with the different tissues and strains. These adducts were undetectable in liver DNA by 28 days. Although all lung preparations showed some reduction in adducts by 28 days, the amounts in A/J lung were always highest; this correlated with its high susceptibility to neoplastic transformation. In all preparations, radioactivity eluted from Sephadex LH-20 with the column void volume or with underivatized nucleosides. Tissue, but not strain differences were observed in these chromatographic profiles. The predominance of these early-eluting peaks in liver, rather than lung, suggests that they may represent noncarcinogenic lesions. This radiolabeled material remains uncharacterized, but some possibilities are discussed.
Insights
Different mouse strains show varying susceptibility to polycyclic aromatic hydrocarbon-induced lung tumors. DNA adducts in lung tissue correlate with tumor development, while liver adducts are transient and uncharacterized.
Area of Science:
- Toxicology
- Carcinogenesis
- Molecular Biology
Background:
- Polycyclic aromatic hydrocarbons (PAHs) are environmental carcinogens.
- Mouse strains exhibit differential susceptibility to PAH-induced pulmonary neoplasia.
- Liver tissues are generally resistant to PAH carcinogenicity, unlike lung tissues.
Purpose of the Study:
- To investigate the formation and persistence of PAH-DNA adducts in different mouse strains and tissues.
- To correlate DNA adduct levels with susceptibility to lung cancer induced by PAHs.
- To characterize the nature of PAH-DNA adducts in lung and liver tissues.
Main Methods:
- Intravenous injection of radiolabeled 3-methylcholanthrene (a PAH) into A/J, C3H/HeJ, DBA/2J, and C57BL/6J mice.
- DNA extraction from lung and liver tissues at various time points post-injection.
- Digestion of DNA to deoxyribonucleosides and chromatographic separation using Sephadex LH-20.
- Quantification of radiolabeled nucleoside-bound adducts.
Main Results:
- Radiolabeled PAH adducts were detected in both lung and liver DNA across all mouse strains.
- Adduct levels varied significantly between tissues and strains, with A/J lung showing the highest amounts.
- Liver DNA adducts became undetectable by 28 days, while lung adducts persisted but were reduced.
- Uncharacterized radioactivity eluted early from Sephadex LH-20, predominantly in liver samples, suggesting non-carcinogenic lesions.
Conclusions:
- Lung DNA adduct levels in mice correlate with susceptibility to PAH-induced pulmonary neoplasia.
- Transient and potentially non-carcinogenic adducts are formed in the liver.
- Further characterization of uncharacterized radiolabeled material is needed to understand PAH metabolism and toxicity.
