The role of formaldehyde in cell proliferation and death

Abstract

Accumulating public attentions have been paid to the neurotoxicity of formaldehyde during aging and carcinogenesis induced by environmental and occupational formaldehyde exposure. The cytotoxicity and carcinogenesis by formaldehyde manifestly reveal two distinct cellular functions of formaldehyde: inducing cell death and promoting cell proliferation. The degree of the disturbance of the formaldehyde baseline determines the effect of formaldehyde on cells. This chapter classifies the dose ranges of formaldehyde based on its role in cell proliferation and death and discusses the mechanisms underlying the nonlinear dose- and time-dependent effects of formaldehyde, which would give light to our knowledge on the physiological and pathological effects of formaldehyde. Short-term small interruption on the formaldehyde baseline, i.e., formaldehyde elimination by formaldehyde capturers and low concentration of formaldehyde (<0.1 mM), provides a pro-proliferative environment for cancer cell lines by activating extracellular-regulated protein kinase (ERK) pathways and raising genomic instability, which contributes to the carcinogenesis of formaldehyde. The moderate concentration of formaldehyde (0.1-1 mM) further increases the formaldehyde-induced DNA damage (DNA adducts and DNA-protein cross-links), which overwhelms the cellular DNA repair capacity and triggers programmed cell death, especially apoptosis. In addition, moderate concentration of formaldehyde induces oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proteotoxicity, and excitotoxicity delivered by prolonged Ca2+ releasing in neurons, which subsequently lead to apoptosis. Formaldehyde plays a role in autophagy and cell senescence, as well. High concentration of formaldehyde (> 1 mM) induces necrosis. Particularly, neuronal cells are more sensitive to the toxicity of formaldehyde. The necrosis-inducing dose of formaldehyde also depends on cell density.