Effect of formaldehyde on cell proliferation and death Be ´ la Szende* and Erno ˝ Tyiha ´k 1{ * 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary { Institute of Plant Protection of the Hungarian Academy of Sciences, Budapest, Hungary Abstract Formaldehyde (HCHO) may reach living organisms as an exogenous agent or produced within cells. The so-called formaldehydogenic compounds like S-adenosyl-L-methionine, N-hydroxymethyl-L-arginine, 19-methyl ascorbigen, meth- anol, E-N-trimethyl lysine and methylamine are special exogenous sources of HCHO. Endogenous HCHO can be formed from hydroxymethyl groups during enzymatic methylation and demethylation processes. HCHO, as a highly reactive compound, is considered to be involved in the induction of apoptosis, consequently in the pathogenesis of atherosclerosis and neurodegenerative processes. The biological action of HCHO is dose-dependent. In vitro studies on tumour cell and endothelial cell cultures showed that HCHO in the concentration of 10.0 mM caused necrotic cell death, 1.0 mM resulted in enhanced apoptosis and reduced mitotic activity, while 0.5 and 0.1 mM enhanced cell proliferation and reduced apoptotic activity. Among formaldehydogenic compounds N-hydroxymethyl-L-arginine, 1’-methyl ascorbigen and the HCHO donor resveratrol may be considered as potential inhibitors of cell proliferation. Endogenous HCHO in plants apparently play a role in regulation of apoptosis and cell proliferation. The genotoxic and carcinogentic effects of HCHO is due to production of DNA–protein cross-links. Low doses of HCHO, reducing apoptotic activity may also accumulate cells with such cross- links. Experimental data point to the possible therapeutic use of methylated lysine residues and methylated arginine residues in the case of neoplasms. Keywords: apoptosis; cell proliferation; formaldehyde; formaldehydogenic compound Introduction HCHO (formaldehyde), one of the simplest compounds, may reach living organisms as an exogenous agent or as an endogenous metabolite that is constantly being produced within cells and released into the intercellular space. HCHO is generally, and erroneously, considered toxic. The most commonly known use of this chemical is in the preservation of tissues or whole organs for anatomical, histological or pathohisto- logical purposes. The saturated 40% solution of HCHO is called formalin and is used for the above-mentioned purposes in a diluted (4–8%) form (Walker, 1964). In these concentrations, HCHO quickly causes denaturation of the cells and tissues, although preserving the cellular and even subcellular structures for microscopic or electron microscopic studies, respectively. Because of this property, HCHO has long been considered as a strong poison. HCHO had also been used in the past as a disinfectant and as a surgical antiseptic and astringent. Massive ingestion of formalin is practically impossible, due to its penetrating odour and irritating effect on the mucous membranes. For the same reasons, suicidal attempts with HCHO are sporadic and mostly ineffective (Aggarwal et al., 2004; Pandey et al., 2000). In the last decade, studies on ‘endogenous’ HCHO produced at the cellular level have increased knowledge on the biological effects of small amounts of HCHO. HCHO, deriving as a metabolite from various, so-called formaldehydogenic compounds, may also influence cellular functions when these formaldehydogenic com- pounds are applied to living organisms in a proper way and dose (Tyiha ´ k et al., 1998a; Ka ´ tay et al., 2009). This review will consider exogenous sources of HCHO, the production of endogenous HCHO, and the mechanism of action of various doses of HCHO on living organisms. Special attention will be paid to the effect of high and low doses, including the most debatable genotoxic and carcinogenic properties of HCHO. The possible therapeutic use of compounds generating or capturing HCHO will also be reviewed. Sources of HCHO Exogenous sources HCHO is widely used in various industrial processes, with production of certain paints, plywood and even cosmetics involving the use of HCHO. Consequently, workers dealing with these materials are exposed to HCHO, mainly present in gaseous form in the working area (Bosetti et al., 2008). Pathologists, anatomists and medical technical assistants are exposed to HCHO inhalation and skin contamination because formalin is still the most widely used tissue fixative in anatomical, histological and pathohistological practice (Pandey et al., 2000). Part of a series marking the 70th birthday of the Cell Biology International Editor-in-Chief Denys Wheatley 1 To whom correspondence should be addressed (email bjena@med.wayne.edu). Abbreviations: HCHO, formaldehyde; MA, methylamine; SAM, S-adenosyl-L-methionine; SMC, smooth muscle cells; SSAO, semicarbazide-sensitive amine oxidase; TML, trimethyl lysine. Cell Biol. Int. (2010) 34, 1273–1282 (Printed in Great Britain) Review Article E The Author(s) Journal compilation E 2010 Portland Press Limited Volume 34 (12) N pages 1273–1282 N doi:10.1042/CBI20100532 N www.cellbiolint.org 1273