Abstract
Formaldehyde is a ubiquitous toxic organic compound recently classified as a carcinogen by the International Agency for Research on Cancer and one of the major factors causing sick building syndrome. In this study, we have investigated the effects of formaldehyde on mRNA expression in rat lung tissues by applying genomics. Rats were exposed to ambient air and two different concentrations of formaldehyde (0, 5, 10 ppm) for 2 weeks at 6 h/day and 5 days/week in an inhalation chamber. Malondialdehyde (MDA) assay and carbonyl spectrometric assay were conducted to determine lipid peroxidation and protein oxidation levels and Comet assays were used for genotoxicity evaluation. Level of MDA, carbonyl insertion and DNA damage in the lungs of rats exposed to FA were found to be dose dependently increased. Gene expression was evaluated by using a bio-array hybridization analysis. A total of 21 (2 up- and 19 down-regulated) genes were identified as biomarkers for formaldehyde effects. Several differentiated gene groups were found. Genes involved in apoptosis, immunity, metabolism, signal transduction, transportation, coagulation and oncogenesis were found to be up- and down-regulated. Among these genes, the mRNA expressions of cytochrome P450, hydroxymethylbilane synthase, glutathione reductase, carbonic anhydrase 2, natriuretic peptide receptor 3, lysosomal associated protein transmembrane 5, regulator of G-protein signaling 3, olfactomedin related ER localized protein, and poly (ADP-ribose) polymerase-1 were confirmed by quantitative RT-PCR analysis. In summary, the MDA lipid peroxidation and the carbonyl protein oxidation assays showed that cytotoxic effects increased with increasing formaldehyde levels. Genomic analysis showed that 21 genes were up- or down-regulated. Of these genes, nine were confirmed by quantitative RT-PCR and could be potential biomarkers for human diseases associated with formaldehyde exposure.
Similar content being viewed by others
References
Adibhatla RM, Hatcher JF (2006) Phospholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Rad Biol Med 40:376–387
Adibhatla RM, Hatcher JF, Dempsey RJ (2006) Forum original research communication; phospholipase A2, hydroxyl radical, and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal 5:647–654
Agarwal R, Chase SD (2002) Rapid fluorimetric-liquid chromatographic determination of malondialdehyde in biological samples. J Chromatogr B Analyt Technol Biomed Life Sci 775:121–126
Cheng G, Shi Y, Sturla SJ, Jalas JR, McIntee EJ, Villalta PW, Wang M, Hecht SS (2003) Reactions of formaldehyde plus acetaldehyde with deoxyguanosine and DNA: formation of cyclic deoxyguanosine adducts and formaldehyde cross-links. Chem Res Toxicol 16:145–152
Corvi R (2002) Genomics: an in vitro toxicology point of view. Altern Lab Anim 2:129–131
Cosma GN, Marchok AC (1988) Benzo[a]pyrene-and formaldehyde-induced DNA damage and repair in rat tracheal epithelial cells. Toxicol 51:309–320
Cosma GN, Jamasbi R, Marchok AC (1988) Growth inhibition and DNA damage induced by benzo[a]pyrene and formaldehyde in primary cultures of rat tracheal epithelial cells. Mutat Res 201:161–168
Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R (2003) Protein carbonyl groups as biomarkers of oxidative stress. Clinica Chimica Acta 329:23–38
Emri G, Schaefer D, Held B, Herbst C, Zieger W, Horkay I, Bayerl C (2004) Low concentrations of formaldehyde induce DNA damage and delay DNA repair after UV irradiation in human skin cells. Exp Dermatol 13:305–315
Erat M, Ciftci M (2006) Effect of melatonin on enzyme activities of glutathione reductase from human crythrocytes in vitro and from rat erythrocytes in vivo. Eur J Pharmacol 537:59–63
Fagan JM, Sleczka BG., Sohar I (1999) Quantitation of oxidative damage to tissue proteins. Int J Biochem Cell Biol 31:751–757
Grafström RC (1990) In vitro studies of aldehyde effects related to human respiratory carcinogenesis. Mutat Res 238:175–184
Grafström RC, Fornace AJ Jr, Autrup H, Lechner JF, Harris CC (1983) Formaldehyde damage to DNA and inhibition of DNA repair in human bronchial cells. Science 220:216–218
Grafström RC, Fornace AJ Jr, Harris CC (1984) Repair of DNA damage caused by formaldehyde in human cells. Cancer Res 44:4323–4327
Heck H, Casanova M (1999) Pharmacodynamics of formaldehyde: applications of a model for the arrest of DNA replication by DNA-protein cross-links. Toxicol Appl Pharmacol 160:86–100
Kim WJ, Terada N, Nomura T, Takahashi R, Lee SD, Park JH, Kinno A (2002) Effects of formaldehyde on the expression of adhesion molecules in nasal microvascular endothelial cells: the role of formaldehyde in the pathogenesis of sick building syndrome. Clin Exp Allergy 32:287–295
Kita T, Fujimura M, Myou S, Ishiura Y, Abo M, Katayama N, Nishitsuji M, Yoshimi Y, Nomura S, Oribe Y, Nakao S (2003) Potentiation of allergic bronchoconstriction by repeated exposure to formaldehyde in guinea-pigs in vivo. Clin Exp Allergy 33:1747–1753
Künn H, Borchert A (2002) Regulation of enzymatic lipid peroxidation: the interplay of peroxidizing and peroxide reducing enzymes. Free Rad Biol Med 33:154–172
Liteplo RG., Meek ME (2003) Inhaled formaldehyde: exposure estimation, hazard characterization, and exposure-response analysis. J Toxicol Environ Health Part B 6:85–114
Mazzetti MB, Taira MC, Lelli SM, Dascal E, Basabe JC, San Martin de Viale LC (2004) Hexachlorobenzene impairs glucose metabolism in a rat model of porphyria cutanea tarda: a mechanistic approach. Arch Toxicol 78:25–33
Metz B, Kersten GFA, Hoogerhout P, Brugghe HF, Timmermans HAM, De Jong A, Meiring H, Ten Hove J, Hennink WE, Crommelin DJ, Jiskoot W (2004) Identification of formaldehyde-induced modifications in proteins: reactions with model peptides. J Biol Chem 279:6235–6243
Nakazawa H, Ikeda H, Yamashita T, Hara I, Kumai Y, Endo G, Endo Y (2005) A case of sick building syndrome in a Japanese office worker. Ind Health 43:341–345
Oh S, Im H, Oh E, Lee J, Khim J, Mun J, Kim Y, Lee E, Kim J, Sul D (2004) Effects of benzo(a)pyrene on protein expression in Jurkat T-cells. Proteomics 4:3514–3526
Ohtsuka R, Shutoh Y, Fujie H, Yamaguchi S, Takeda M, Harada T, Doi K (2003) Rat strain difference in histology and expression of Th1- and Th2-related cytokines in nasal mucosa after short-term formaldehyde inhalation. Exp Toxicol Pathol 54:287–291
Ross WE, Shipley N (1980) Relationship between DNA damage and survival in formaldehyde-treated mouse cells. Mutat Res 79:277–283
Saito Y, Nishio K, Yoshida Y, Niki E (2005) Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive oxygen species. Toxicology 210:235–245
Savinova OV, Matsukawa N, Smithies O, John SWM (1997) Mouse natriuretic peptide receptor 3 gene maps to proximal chromosome 15. Mamm Genome 8:788
Schneider-Yin X, Szlendak U, Lipniacka AI, Minder EI, Gegor A (2006) Nine novel mutations in the hydroxymethylbilane synthase gene of polish patients with acute intermittent porphyyria. Clin Genet 69:284–286
Singh NP, McCoy MT, Tice RR, Schneider EL (1988). A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191
Tang M, Xie Y, Yi Y, Wang W (2003) Effects of formaldehyde on germ cells of male mice. Wei Sheng Yan Jiu 32:544–548
The International Agency for Research on Cancer (IARC) (1995) 62:217–362
Thrasher JD, Wojdani A, Cheung G., Euser C (1987) Evidence for formaldehyde antibodies and altered cellular immunity in subjects exposed to formaldehyde in mobile home. Arch Environ Health 42:347–350
Yoo H-W, Warner CA, Chen C-H, Desnik RJ (1993) Hydroxymethylbilane synthesis: complete genomic sequence and amplifiable polymorphisms in the human gene. Genomics 15:21–29
Zhong W, Que Hee SS (2004) Formaldehyde-induced DNA adducts as biomarkers of in vitro human nasal epithelial cell exposure to formaldehyde. Mutat Res 563:13–24
Acknowledgments
This research was supported by the grant of Medical Research Center for Environmental Toxico-Genomics and Proteomics and funded by Korea Science and Engineering Foundations and ministry of Science and Technology and by the Ministry of Environment as “The Eco-Technopia 21 project”.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sul, D., Kim, H., Oh, E. et al. Gene expression profiling in lung tissues from rats exposed to formaldehyde. Arch Toxicol 81, 589–597 (2007). https://doi.org/10.1007/s00204-007-0182-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-007-0182-9