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

Julia E. Rager,¹ Benjamin C. Moeller,² Melanie Doyle-Eisele,³ Dean Kracko,³ James A. Swenberg,^1,2,4 and Rebecca C. Fry^1,2,4

¹Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, and ²Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; ³Lovelace Respiratory Research Institute, Albuquerque, New Mexico, USA; ⁴Center for Environmental Health and Susceptibility, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

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.

Key words: apoptosis, epigenetics, formaldehyde, microRNA, primate, systems biology.

Environ Health Perspect 121:339–344 (2013). http://dx.doi.org/10.1289/ehp.1205582 [Online 15 January 2013]

Address correspondence to R.C. Fry, Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, 135 Dauer Dr., CB 7431, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 USA. Telephone: (919) 843-6864. E-mail: rfry@unc.edu

Supplemental Material is available online (http://dx.doi.org/10.1289/ehp.1205582).

We thank L. Smeester for her help with the RNA processing.

This research was supported in part by National Institutes of Health (grants P30-ES010126, P42-ES005948, ES019315, and T32-ES007126) and by the Texas Commission for Environmental Quality (grant 582-12-21861) to J.A.S. The American Chemistry Council provided funding for the animal exposures conducted at the Lovelace Respiratory Research Institute.

The authors declare they have no actual or potential competing financial interests.

Received 6 June 2012; Accepted 14 January 2013; Online 15 January 2013.