Exposure to ultrafine particulate matter induces NF-κß mediated epigenetic modifications.

Exposure to ultrafine particulate matter (PM0.1) is positively associated with the etiology of different acute and chronic disorders; however, the in-depth biological imprints that link these submicron particles with the disturbances in the epigenomic machinery are not well defined. Earlier, we showed that exposure to these particles causes significant disturbances in the mitochondrial machinery and triggers PI-3-kinase mediated DNA damage responses. In the present study, we aimed to further understand the epigenomic insights of the ultrafine PM exposure. The higher levels of intracellular reactive oxygen species and depleted Nrf-2 in ultrafine PM exposed cells reconfirmed its potential to induce oxidative stress. Importantly, the observed increase in the levels of NF-κß and associated cytokines among exposed cells suggested the activation of NF-κß mediated inflammatory loop which potentially serves as a platform for initiating epigenetic insinuations. This fact was strongly supported by the altered miRNA expression profile of the ultrafine PM exposed cells. These NF-κß induced miRNA alterations were also found to be associated with other epigenetic targets as the exposed cells showed higher expression levels of DNA methyltransferases which positively corresponded with the global changes in DNA methylation levels. Upon further analysis, significant alterations in histone code were also reported in ultrafine PM exposed cells. Conclusively our results suggested that NF-κß acts as an inflammatory switch that possesses the potential to induce genome-wide epigenetic modification upon ultrafine PM exposure.

Air pollution associated epigenetic modifications: Transgenerational inheritance and underlying molecular mechanisms.

Air pollution is one of the leading causes of deaths in Southeast Asian countries including India. Exposure to air pollutants affects vital cellular mechanisms and is intimately linked with the etiology of a number of chronic diseases. Earlier work from our laboratory has shown that airborne particulate matter disturbs the mitochondrial machinery and causes significant damage to the epigenome. Mitochondrial reactive oxygen species possess the ability to trigger redox-sensitive signaling mechanisms and induce irreversible epigenomic changes. The electrophilic nature of reactive metabolites can directly result in deprotonation of cytosine at C-5 position or interfere with the DNA methyltransferases activity to cause alterations in DNA methylation. In addition, it also perturbs level of cellular metabolites critically involved in different epigenetic processes like acetylation and methylation of histone code and DNA hypo or hypermethylation. Interestingly, these modifications may persist through downstream generations and result in the transgenerational epigenomic inheritance. This phenomenon of subsequent transfer of epigenetic modifications is mainly associated with the germ cells and relies on the germline stability of the epigenetic states. Overall, the recent literature supports, and arguably strengthens, the contention that air pollution might contribute to transmission of epimutations from gametes to zygotes by involving mitochondrial DNA, parental allele imprinting, histone withholding and non-coding RNAs. However, larger prospective studies using innovative, integrated epigenome-wide metabolomic strategy are highly warranted to assess the air pollution induced transgenerational epigenetic inheritance and associated human health effects.