Attenuation of Polycyclic Aromatic Hydrocarbon (PAH)-Mediated Pulmonary DNA Adducts and Cytochrome P450 (CYP)1B1 by Dietary Antioxidants, Omega-3 Fatty Acids, in Mice

Abstract

Numerous human and animal studies have reported positive correlation between carcinogen-DNA adduct levels and cancer occurrence. Therefore, attenuation of DNA adduct levels would be expected to suppress tumorigenesis. In this investigation, we report that the antioxidants omega 3-fatty acids, which are constituents of fish oil (FO), significantly decreased DNA adduct formation by polycyclic aromatic hydrocarbons (PAHs). B6C3F1 male mice were fed an FO or corn oil (CO) diet, or A/J male mice were pre-fed with omega-3 fatty acids eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA). While the B6C3F1 mice were administered two doses of a mixture of seven carcinogenic PAHs including benzo(a)pyrene (BP), the A/J mice were treated i.p. with pure benzo[a]pyrene (BP). Animals were euthanized after 1, 3, or 7 d after PAH treatment. DNA adduct levels were measured by the 32P-postlabeling assay. Our results showed that DNA adduct levels in the lungs of mice 7 d after treatment were significantly decreased in the FO or EPA/DHA groups compared with the CO group. Interestingly, both qPCR and Western blot analyses revealed that FO, DHA and EPA/DHA significantly decreased the expression of cytochrome P450 (CYP) 1B1. CYP1B1 plays a critical role in the metabolic activation of BP to DNA-reactive metabolites. qPCR also showed that the expression of some metabolic and DNA repair genes was induced by BP and inhibited by FO or omega-3 fatty acids in liver, but not lung. Our results suggest that a combination of mechanism entailing CYP1B1 inhibition and the modulation of DNA repair genes contribute to the attenuation of PAH-mediated carcinogenesis by omega 3 fatty acids.

Kernel extreme learning with harmonized bat algorithm for prediction of pyrene toxicity in rats

“…Although PAHs are inert, CYPs that depend on metabolism can cause them to manifest their toxicities. By releasing reactive metabolites leading onto proteomic/DNA adduct generation, PAHS toxins were made manifest 52 …”

“…By releasing reactive metabolites leading onto proteomic/DNA adduct generation, PAHS toxins were made manifest. 52 Nuclear receptors, including PXR, CAR and AhR, that are activated control the expression of the CYP gene. This research discovered a correlation between PXR and CAR mRNA levels and increased CYP1A1/2 and CYP2B1/2 mRNA following pyrene therapy.…”

Lung cancer risk in workers occupationally exposed to polycyclic aromatic hydrocarbons with emphasis on the role of DNA repair gene

“…These findings suggested reduction in DNA repair ability as a result of exposure to high concentration of PAHs resulting in accumulation of albumin adducts that may lead to DNA damages and mutations, which may eventually become malignant. Recently, Zhou et al ( 2022 ) showed that the expression of some metabolic and DNA repair genes was induced by BP and inhibited by FO or omega-3 fatty acids in liver, but not lung.…”

Lung Organoids in Smoking Research: Current Advances and Future Promises

“…The tobacco-specific nitrosamines N-nitrosonornicotine (NNN) and nicotine-derived nitrosamine ketone (NNK) may cause reproductive damage and exhibit potent carcinogenic effects in rat and human models [ 34 , 35 , 36 , 37 ]. Polycyclic aromatic hydrocarbons (PAHs) are immunosuppressive, carcinogenic, mutagenic, and cause reproductive damage [ 38 , 39 , 40 , 41 ]. Benzene is another toxic component in cigarette smoke that causes anemia, reproductive damage, bone marrow damage, and exerts carcinogenic potential [ 42 , 43 , 44 , 45 , 46 ].…”