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Carbonyl compounds in the gas phase are critical determinants of wood smoke toxicity

ABSTRACT: Epidemiological studies identified air pollution as one of the prime causes for human morbidity and mortality due to harmful effects mainly on the cardiovascular and respiratory system. Damage to the lung leads to several severe diseases such as fibrosis, chronic obstructive pulmonary disease and cancer. Noxious environmental aerosols are comprised of a gas and particulate phase representing highly complex chemical mixtures composed of myriads of compounds. Although some critical pollutants, foremost particulate matter (PM), could be linked to adverse health effects, a comprehensive understanding of relevant biological mechanisms and detrimental aerosol constituents is still lacking. Here, we employed a systems toxicology approach focusing on wood combustion, an important source for air pollution, and demonstrate a key role of the gas phase, specifically carbonyls, to drive adverse effects. Transcriptional profiling and biochemical analysis of human lung cells exposed at the air-liquid-interface determined the DNA damage and stress response as well as perturbation of cellular metabolism as major key events. Connectivity mapping revealed a high similarity of gene expression signatures induced by wood smoke and agents prompting DNA-protein crosslinks (DPCs). Indeed, various gaseous aldehydes were detected in wood smoke, which promote DPCs, initiate similar genomic responses and are responsible for DNA damage provoked by wood smoke. Hence, systems toxicology enables the discovery of critical constituents of complex mixtures i.e. aerosols and highlights the role of carbonyls on top of particulate matter as important health hazard.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228624 | GEO | 2023/09/01

REPOSITORIES: GEO

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Project description:The polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP), was compared to dibenzo[def,p]chrysene (DBC) and combinations of three environmental PAH mixtures (coal tar, diesel particulate and cigarette smoke condensate) using a two stage, FVB/N mouse skin tumor model. DBC (4 nmol) was most potent, reaching 100% tumor incidence with a shorter latency to tumor formation, less than 20 weeks of 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion compared to all other treatments. Multiplicity was 4 times greater than BaP (400 nmol). Both PAHs produced primarily papillomas followed by squamous cell carcinoma and carcinoma in situ. Diesel particulate extract (1 mg SRM 1650b; mix 1 ) did not differ from toluene controls and failed to elicit a carcinogenic response. Addition of coal tar extract (1 mg SRM 1597a; mix 2) produced a response similar to BaP. Further addition of 2 mg of cigarette smoke condensate (mix 3) did not alter the response of mix 2. PAH-DNA adducts measured in epidermis 12 h post initiation and analyzed by 32P post- labeling, did not correlate with tumor incidence. PAH dependent alteration in transcriptome of skin 12 h post initiation was assessed by microarray. Principal component analysis (sum of all treatments) of the 922 significantly altered genes (p<0.05), showed DBC and BaP to cluster distinct from PAH mixtures and each other. BaP and mixtures up-regulated phase 1 and 2 metabolizing enzymes while DBC did not. The carcinogenicity with DBC and two of the mixtures was much greater than would be predicted based on published Relative Potency Factors (RPFs). Gene expression was measured in mouse skin 12 hours after initiation with PAH carcinogens. The following initiation treatments were applied to mice (N=4 or 5 per biological replicates treatment); toluene vehicle control (200 M-NM-<l), BaP 400 nmol (100 M-NM-<g), DBC 4 nmol (1.2 M-NM-<g), or to mixtures of environmental PAH mixtures containing diesel particulate extract, coal tar extract, or cigarette smoke condensate.

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Carbonyl compounds in the gas phase are critical determinants of wood smoke toxicity

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