Formaldehyde and Epigenetic Alterations: MicroRNA Changes in the Nasal Epithelium of Nonhuman Primates

Abstract

Background: Formaldehyde is an air pollutant present in both indoor and outdoor atmospheres. Because of its ubiquitous nature, it is imperative to understand the mechanisms underlying formaldehyde-induced toxicity and carcinogenicity. MicroRNAs (miRNAs) can influence disease caused by environmental exposures, yet miRNAs are understudied in relation to formaldehyde. Our previous investigation demonstrated that formaldehyde exposure in human lung cells caused disruptions in miRNA expression profiles in vitro.Objectives: Using an in vivo model, we set out to test the hypothesis that formaldehyde inhalation exposure significantly alters miRNA expression profiles within the nasal epithelium of nonhuman primates.Methods: Cynomolgus macaques were exposed by inhalation to approximately 0, 2, or 6 ppm formaldehyde for 6 hr/day for 2 consecutive days. Small RNAs were extracted from nasal samples and assessed for genome-wide miRNA expression levels. Transcriptional targets of formaldehyde-altered miRNAs were computationally predicted, analyzed at the systems level, and assessed using real-time reverse transcriptase polymerase chain reaction (RT-PCR).Results: Expression analysis revealed that 3 and 13 miRNAs were dysregulated in response to 2 and 6 ppm formaldehyde, respectively. Transcriptional targets of the miRNA with the greatest increase (miR-125b) and decrease (miR-142-3p) in expression were predicted and analyzed at the systems level. Enrichment was identified for miR-125b targeting genes involved in apoptosis signaling. The apoptosis-related targets were functionally tested using RT-PCR, where all targets showed decreased expression in formaldehyde-exposed samples.Conclusions: Formaldehyde exposure significantly disrupts miRNA expression profiles within the nasal epithelium, and these alterations likely influence apoptosis signaling.

Epigenetic alterations induced by genotoxic occupational and environmental human chemical carcinogens: A systematic literature review

“…miRNAs have been demonstrated to be dysregulated upon in vitro exposure to formaldehyde in human lung epithelial A549 cells [138], and in the olfactory bulb [139] of mice, nasal epithelium cells of non-human primates (macaques) [140], and in the nose and WBCs of rats [141] exposed in vivo to formaldehyde by inhalation. The five most differentially expressed miRNAs in the human lung cells were miR-33, miR-450, miR-330, miR-181a, and miR-10b (all down-regulated), the predicted mRNA targets of which are associated with inflammatory response pathways; specifically, the IL-8 pathway.…”

Air toxics and epigenetic effects: ozone altered microRNAs in the sputum of human subjects

“…miRNAs can be found in sputum obtained from the central airways (35,38), a site where O 3 induces a robust inflammatory response and produces changes in immune cell responses following controlled inhalational exposures (5,17). Although there are known links between miRNA expression changes and air pollutants (19,37), very few studies have assessed genomewide changes in miRNA expression profiles resulting from air toxicant exposure in vivo. Of the studies that have examined the role of miRNAs in pollutant-induced effects, it appears that pollutants with oxidizing potential have the ability to alter miRNA expression profiles (37).…”

“…Although there are known links between miRNA expression changes and air pollutants (19,37), very few studies have assessed genomewide changes in miRNA expression profiles resulting from air toxicant exposure in vivo. Of the studies that have examined the role of miRNAs in pollutant-induced effects, it appears that pollutants with oxidizing potential have the ability to alter miRNA expression profiles (37). Ozone is a potent oxidizing pollutant and therefore has good potential to alter miRNA expression profiles.…”

Formaldehyde induces toxicity in mouse bone marrow and hematopoietic stem/progenitor cells and enhances benzene-induced adverse effects

“…Inflammation at distal sites can alter hematopoiesis in BM releasing immature cells into the circulation in order to effect repair (Denburg and van Eeden 2006;Schuettpelz and Link 2013), and chronic pro-inflammatory signaling can lead to HSC exhaustion (Schuettpelz and Link 2013). Altered expression of miRNAs and mRNAs related to immune system/inflammation signaling was reported in both the nose and WBC of FA-exposed rats suggesting that miRNAs may, in part, regulate immune/inflammatory responses (Rager et al 2013).…”