Background:Formaldehyde (FA) is an environmental and occupational chemical carcinogen. Recent studies have shown that exogenous FA causes only a modest increase in DNA adduct formation compared with the amount of adducts formed by endogenous FA, raising the possibility that epigenetic mechanisms may contribute to FA-mediated carcinogenicity.Objectives:We investigated the effects of FA exposure on histone modifications and chromatin assembly. We also examined the role of defective chromatin assembly in FA-mediated transcription and cell transformation.Methods:Cellular fractionation and Western blot analysis were used to measure the levels of histone modifications in human bronchial epithelial BEAS-2B cells and human nasal RPMI2650 cells in the presence of FA. Chromatin immunoprecipitation (ChIP) and micrococcal nuclease (MNase) digest assays were performed to examine the changes in chromatin assembly and accessibility after FA exposure. RNA sequencing (RNA-seq) and real-time polymerase chain reaction (PCR) were used to examine transcriptional dysregulation. Finally, anchorage-independent cell growth ability was tested by soft agar assay following FA exposure.Results:Exposure to FA dramatically decreased the acetylation of the N-terminal tails of cytosolic histones. These modifications are important for histone nuclear import and subsequent chromatin assembly. Histone proteins were depleted in both the chromatin fraction and at most of the genomic loci tested following FA exposure, suggesting that FA compromises chromatin assembly. Moreover, FA increased chromatin accessibility and altered the expression of hundreds of cancer-related genes. Knockdown of the histone H3.3 gene (an H3 variant), which mimics inhibition of chromatin assembly, facilitated FA-mediated anchorage-independent cell growth.Conclusions:We propose that the inhibition of chromatin assembly represents a novel mechanism of cell transformation induced by the environmental and occupational chemical carcinogen FA. https://doi.org/10.1289/EHP1275

Ultraviolet radiation (UVR) from sunlight is the major effector for skin aging and carcinogenesis. However, genes and pathways altered by solar-simulated UVR (ssUVR), a mixture of UVA and UVB, are not well characterized. Here we report global changes in gene expression as well as associated pathways and upstream transcription factors in human keratinocytes exposed to ssUVR. Human HaCaT keratinocytes were exposed to either a single dose or 5 repetitive doses of ssUVR. Comprehensive analyses of gene expression profiles as well as functional annotation were performed at 24 hours post irradiation. Our results revealed that ssUVR modulated genes with diverse cellular functions changed in a dose-dependent manner. Gene expression in cells exposed to a single dose of ssUVR differed significantly from those that underwent repetitive exposures. While single ssUVR caused a significant inhibition in genes involved in cell cycle progression, especially G2/M checkpoint and mitotic regulation, repetitive ssUVR led to extensive changes in genes related to cell signaling and metabolism. We have also identified a panel of ssUVR target genes that exhibited persistent changes in gene expression even at 1 week after irradiation. These results revealed a complex network of transcriptional regulators and pathways that orchestrate the cellular response to ssUVR.

Cancer is a complex disease with acquired genomic and epigenomic alterations that affect cell proliferation, viability and invasiveness. Almost all the epigenetic mechanisms including cytosine methylation and hydroxymethylation, chromatin remodeling and non-coding RNAs have been found associate with carcinogenesis and cancer specific expression profile. Altered histone modification as an epigenetic hallmark is frequently found in tumors. Understanding the epigenetic alterations induced by carcinogens or infectious agents may help us understand early epigenetic changes prior to the development of cancer. In this review, we focus on chromatin remodeling and the associated histone modifiers in the development of cancer; the application of these modifiers as a cancer therapy target in different clinical trial phases is also discussed.

Nanoparticles are of increasing interest and concern as they become more widely used in consumer products, industry and medicine. Nanoparticles differ from their ‘bulk’ materials in physiochemical properties, creating interest and further applications. In addition to being engineered, humans are constantly exposed to nanoparticles (NPs) through ambient air pollution. There is a need for toxicological assessment of these particles as humans come into contact with them every day. The toxicological mechanism and biological fate of these particles are not well known. Findings in the fields of genotoxicity and epigenetics shed light on potential mechanisms for adverse human health effects when exposed to these particles. There is still much work to be done in order to properly assess the risk of NP exposure. Key Concepts: Nanoparticles have different inherent physiochemical properties from bulk materials of the same composition. Studies show that nanoparticles at smaller dimensions induce stronger toxic effects than the same particles at larger dimensions Oxidative stress is increased when exposed to nanoparticles, more free radicals will cause more cellular and DNA damage. Nanoparticles are being investigated for use in clinical settings, specifically diagnostic procedures and drug delivery. Epigenetic modifications are those in which there is no genetic mutation or DNA damage present. Nanoparticles will be constituents of ambient particulate matter, therefore, all life is exposed to varying amounts of nanoparticles daily. Government organisations are working to increase research and development involving nanoparticles in order to better understand their mechanisms of action.

The "Acknowledgments" section was inadvertently omitted from the published text of "Regulation of Chromatin Assembly and Cell Transformation by Formaldehyde Exposure in Human Cells." It is presented here. EHP regrets the error.