Abstract 72: Gene-specific H3K4 trimethylation changes in healthy human subjects exposed to carcinogenic metal components of air particles

Abstract

Abstract Ambient and occupational exposure to air particulate matter (PM) has been consistently associated with increased risk of lung cancer. Epidemiological studies strongly indicate that the metal components of PM may be responsible for PM carcinogenicity, but the underlining mechanisms are poorly understood. H3K4 trimethylation (H3K4me3) is known to be modified by exposure to carcinogenic metals in-vitro and correlates with transcriptional activation when found in gene promoter regions. In a pilot study on workers of a steel-plant production, we investigated whether PM metal components, such as nickel and arsenic, had an effect on H3K4me3 in the promoter regions of target genes, including tumor suppressors and genes whose expression is increased following metal exposures, such as NIMA-related kinase 6 (NEK6) genes and carbonic anhydrase IX (CA9). We obtained blood samples on the first (sample 1) and last (sample 2) day of a working-week from 10 subjects. We used gene-specific analysis by chromatin immunoprecipitation (ChIP)-real-time PCR in blood leukocytes to investigate whether H3K4 trimethylation changes, at different levels of exposure to airborne metals in PM, can influence transcription of CA9 and NEK6 genes. We found that both for CA9 and NEK6, there was a difference between sample 1 and sample 2 in all subjects, with a higher level in sample 2; furthermore, in sample 2, we found a positive trend for H3K4me3 in CA9 and NEK6 genes with increasing levels of exposure to metals in PM compared to one unexposed control. The observed tendency is consistent with the fact that carcinogenic metals alter patterns of gene expression leading to activation of genes that may be relevant to the carcinogenic process. These findings indicate that different levels of exposure to PM metal components can induce changes in H3K4 trimethylation that up-regulates transcription of CA9 and NEK6 genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 72. doi:10.1158/1538-7445.AM2011-72