Abstract
Formaldehyde is an environmental and occupational chemical carcinogen implicated in the damage of proteins and nucleic acids. However, whether formaldehyde provokes modifications of RNAs such as 8-oxo-7,8-dihydroguanine (8-oxoG) and the role that these modifications play on conferring long-term adverse health effects remains unexplored. Here, we profile 8-oxoG modifications using RNA-immunoprecipitation and RNA sequencing (8-oxoG RIP-seq) to identify 343 RNA transcripts heavily enriched in oxidations in human bronchial epithelial BEAS-2B cell cultures exposed to 1 ppm formaldehyde for 2 h. RNA oxidation altered expression of many transcripts involved in chromatin modification and p53-mediated DNA-damage responses, two pathways that play key roles in sustaining genome integrity and typically deregulated in tumorigenesis. Given that these observations were identified in normal cells exhibiting minimal cell stress and death phenotypes (for example, lack of nuclear shrinkage, F-actin alterations or increased LDH activity); we hypothesize that oxidative modification of specific RNA transcripts following formaldehyde exposure denotes an early process occurring in carcinogenesis analogous to the oxidative events surfacing at early stages of neurodegenerative diseases. As such, we provide initial investigations of RNA oxidation as a potentially novel mechanism underlying formaldehyde-induced tumorigenesis.
Highlights
Formaldehyde is an environmental and occupational chemical carcinogen implicated in the damage of proteins and nucleic acids
It is worth noting that our relative quantitative analysis of transcripts was constrained as following the selected 6-h recovery period post formaldehyde exposures. By focusing on those transcripts enriched in oxidation, we preferentially identify transcripts that are not efficiently turned over or replaced and are more likely to contribute to sustained influences on cellular processes and cell survival; this is justified by the establishment of RNA oxidations as early indicators of cell mortality occurring hours to days after exposure[31]
The results presented support the growing body of evidence that specific transcripts are more prone to RNA oxidation than others and that transcript oxidation is not a random event
Summary
Formaldehyde is an environmental and occupational chemical carcinogen implicated in the damage of proteins and nucleic acids. The consequences regarding exposure to formaldehyde are well-established; the investigation of causative mechanisms remains challenging because formaldehyde is quickly oxidized in the human body to formic acid, filtered by the kidneys, and excreted from the s ystem[7] Despite these challenges, several recent works, focused on the occupational exposure of formaldehyde in hair salons and tableware manufacturing facilities, have discovered DNA damage in blood comet assays even at low level exposures (< 0.3 ppm) to formaldehyde, which could result in potentially deleterious e ffects[8,9,10]. Studies investigating the effects of formaldehyde exposure at the cellular level have been performed intensively, demonstrating radical damage to lipids, proteins, and D NA14,15 These studies highlight the formation of DNA-adducts and DNA–protein crosslinks in response to formaldehyde in association with carcinogenesis[16]; recent work has suggested that RNA plays an important role in the cellular response to oxidative stress[17,18]. Compromise of these RNA functions could act as a modulating factor between oxidative stress and regulation of cellular pathways, potentially affecting the onset of disease
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