Background/Aim: Formaldehyde is classified as carcinogenic to humans, making it a major concern, particularly in occupational settings. Fat-soluble vitamins, such as vitamins A, D, and E, are documented as antigenotoxic and antimutagenic and also correlate with the cell antioxidant potential. This study investigates the influence of these vitamins on genotoxicity biomarkers of formaldehyde-exposed hospital workers. Methods: The target population were hospital workers exposed to formaldehyde (n = 55). Controls were nonexposed individuals (n = 80). The most used genotoxicity biomarkers were the cytokinesis-block micronucleus assay for lymphocytes and the micronucleus test for exfoliated buccal cells. Vitamins A and E were determined by high-performance liquid chromatography with a diode array detector (HPLC-DAD) and vitamin D receptor (VDR) polymorphisms by real-time PCR. Results: Significant correlations were found between genotoxicity biomarkers and between vitamins A and E in controls. Multiple regression showed that vitamin A was significantly associated with a higher mean of nucleoplasmic bridges (p < 0.001), and vitamin E was significantly associated with a decreased frequency of nuclear buds (p = 0.045) in the exposed group. No effect of vitamin D was observed. The VDRBsmI TT genotype carriers presented higher means of all the genotoxicity biomarkers; however, we found no significant associations. Conclusions: The study suggests that vitamin levels may modulate direct signs of genotoxicity.

1.
Wiseman H: Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action. FEBS Lett 1993;326:285-288.
2.
Yong LC, Brown CC, Schatzkin A, Dresser CM, Slesinski MJ, Cox CS, et al: Intake of vitamins E, C, and A and risk of lung cancer. The NHANES I epidemiologic followup study. First National Health and Nutrition Examination Survey. Am J Epidemiol 1997;146:231-243.
3.
Awodele O, Olayemi SO, Alimba CG, Egbejiogu C, Akintonwa A: Protective effect of vitamin C and or vitamin E on micronuclei induction by rifampicin in mice. Tanzan J Health Res 2010;12:150-154.
4.
Raimondi S, Johansson H, Maisonneuve P, Gandini S: Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis 2009;30:1170-1180.
5.
Sram RJ, Farmer P, Singh R, Garte S, Kalina I, Popov TA, et al: Effect of vitamin levels on biomarkers of exposure and oxidative damage - the EXPAH study. Mutat Res 2009;672:129-134.
6.
Fenech MF: Dietary reference values of individual micronutrients and nutriomes for genome damage prevention: current status and a road map to the future. Am J Clin Nutr 2010;91:1438S-1454S.
7.
Thomas P, Wu J, Dhillon V, Fenech M: Effect of dietary intervention on human micronucleus frequency in lymphocytes and buccal cells. Mutagenesis 2011;26:69-76.
8.
Awodele O, Olayemi S, Alimba C, Egbejiogu C, Akintonwa A: Protective effect of vitamin C and or vitamin E on micronuclei induction by rifampicin in mice. Tanzan J Health Res 2010;12:1-7.
9.
Garcion E, Wion-Barbot N, Montero-Menei C, Berger F, Wion D: New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 2002;13:100-105.
10.
Orlow I, Roy P, Reiner AS, Yoo S, Patel H, Paine S, et al: Vitamin D receptor polymorphisms in patients with cutaneous melanoma. Int J Cancer 2012;130:405-418.
11.
Kállay E, Bareis P, Bajna E, Kriwanek S, Bonner E, Toyokuni S, et al: Vitamin D receptor activity and prevention of colonic hyperproliferation and oxidative stress. Food Chem Toxicol 2002;40:1191-1196.
12.
Uitterlinden AG, Fang Y, Van Meurs JBJ, Pols HAP, Van Leeuwen JPTM: Genetics and biology of vitamin D receptor polymorphisms. Gene 2004;338:143-156.
13.
Maruyama R, Aoki F, Toyota M, Sasaki Y, Akashi H, Mita H, et al: Comparative genome analysis identifies the vitamin D receptor gene as a direct target of p53-mediated transcriptional activation. Cancer Res 2006;66:4574-4583.
14.
Shahbazi S, Alavi S, Majidzadeh-A K, Ghaffarpour M, Soleimani A, Mahdian R: Bsm I but not Fok I polymorphism of VDR gene is contributed in breast cancer. Med Oncol 2013;30:393.
15.
Fenech M, Kirsch-Volders M, Natarajan AT, Surralles J, Crott JW, Parry J, et al: Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 2011;26:125-132.
16.
Viegas S, Ladeira C, Nunes C, Malta-Vacas J, Gomes M, Brito M, et al: Genotoxic effects in occupational exposure to formaldehyde: a study in anatomy and pathology laboratories and formaldehyde-resins production. J Occup Med Toxicol 2010;5:25.
17.
Ladeira C, Viegas S, Carolino E, Prista J, Gomes MC, Brito M: Genotoxicity biomarkers in occupational exposure to formaldehyde - the case of histopathology laboratories. Mutat Res 2011;721:15-20.
18.
Speit G, Ladeira C, Linsenmeyer R, Schütz P, Högel J: Re-evaluation of a reported increased micronucleus frequency in lymphocytes of workers occupationally exposed to formaldehyde. Mutat Res 2012;744:161-166.
19.
Ladeira C, Viegas S, Carolino E, Gomes MC, Brito M: The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxicity biomarkers in workers exposed to formaldehyde. Environ Mol Mutagen 2013;54:213-221.
20.
NIOSH: Manual of Analytical Methods, 1994.
21.
McGlothlin JD: Occupational exposure assessment and control using video exposure monitoring in the pharmaceutical industry. Proceedings of the International Scientific Conference (IOHA - International Occupational Hygiene), Pilanesberg National Park, 2005.
22.
Fenech M, Holland N, Chang WP, Zeiger E, Bonassi S: The HUman MicroNucleus Project - an international collaborative study on the use of the micronucleus technique for measuring DNA damage in humans. Mutat Res 1999;428:271-283.
23.
Tolbert PE, Shy CM, Allen JW: Micronuclei and other nuclear anomalies in buccal smears: a field test in snuff users. Am J Epidemiol 1991;134:840-850.
24.
Jaworowska A, Bazylak G: HPLC Assessment and multivariate predictability of serum retinol and α-tocopherol concentrations in adult female subjects. Open Chem Biomed Methods J 2008;1:11-21.
25.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Formaldehyde, 2-butoxyethanol and 1-tert-butoxypropan-2-ol. IARC Monogr Eval Carcinog Risks Hum 2006;88:1-478.
26.
Pyatt D, Natelson E, Golden R: Is inhalation exposure to formaldehyde a biologically plausible cause of lymphohematopoietic malignancies? Regul Toxicol Pharmacol 2008;51:119-133.
27.
Prado RP, dos Santos BF, Pinto CL, de Assis KR, Salvadori DM, Ladeira MS: Influence of diet on oxidative DNA damage, uracil misincorporation and DNA repair capability. Mutagenesis 2010;25:483-487.
28.
Bonassi S, Znaor A, Ceppi M, Lando C, Chang WP, Holland N, et al: An increased micronucleus frequency in peripheral blood lymphocytes predicts the risk of cancer in humans. Carcinogenesis 2007;28:625-631.
29.
Lal A, Ames BN: Association of chromosome damage detected as micronuclei with hematological diseases and micronutrient status. Mutagenesis 2011;26:57-62.
30.
Gaziev AI, Sologub GR, Fomenko LA, Zaichkina SI, Kosyakova NI, Bradbury RJ: Effect of vitamin-antioxidant micronutrients on the frequency of spontaneous and in vitro gamma-ray-induced micronuclei in lymphocytes of donors: the age factor. Carcinogenesis 1996;17:493-499.
31.
Fenech M, Crott JW: Micronuclei, nucleoplasmic bridges and nuclear buds induced in folic acid deficient human lymphocytes - evidence for breakage-fusion-bridge cycles in the cytokinesis-block micronucleus assay. Mutat Res 2002;504:131-136.
32.
Crott JW, Mashiyama ST, Ames BN, Fenech M: The effect of folic acid deficiency and MTHFR C677T polymorphism on chromosome damage in human lymphocytes in vitro. Cancer Epidemiol Biomark Prev 2001;10:1089-1096.
33.
Mateuca R, Lombaert N, Aka PV, Decordier I, Kirsch-Volders M: Chromosomal changes: induction, detection methods and applicability in human biomonitoring. Biochimie 2006;88:1515-1531.
34.
Thomas P, Umegaki K, Fenech M: Nucleoplasmic bridges are a sensitive measure of chromosome rearrangement in the cytokinesis-block micronucleus assay. Mutagenesis 2003;18:187-194.
35.
De Flora S, Bagnasco M, Vainio H: Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues. Mutagenesis 1999;14:153-172.
36.
Fenech M, Baghurst P, Luderer W, Turner J, Record S, Ceppi M, et al: Low intake of calcium, folate, nicotinic acid, vitamin E, retinol, β-carotene and high intake of pantothenic acid, biotin and riboflavin are significantly associated with increased genome instability - results from a dietary intake and micronucleus index survey in South Australia. Carcinogenesis 2005;26:991-999.
37.
Stich HF, Stich W, Rosin MP, Vallejera MO: Use of the micronucleus test to monitor the effect of vitamin A, beta-carotene and canthaxanthin on the buccal mucosa of betel nut/tobacco chewers. Int J Cancer 1984;34:745-750.
38.
Stich HF, Rosin MP, Vallejera MO: Reduction with vitamin A and beta-carotene administration of proportion of micronucleated buccal mucosal cells in Asian betal nut and tobacco chewers. Lancet 1984;1:1204-1206.
39.
Benner SE, Wargovich MJ, Lippman SM, Fisher R, Velasco M, Winn RJ, et al: Reduction in oral mucosa micronuclei frequency following alpha-tocopherol treatment of oral leukoplakia. Cancer Epidemiol Biomarkers Prev 1994;3:73-76.
40.
Piyathilake CJ, Macaluso M, Hine RJ, Vinter DW, Richards EW, Krumdieck CL: Cigarette smoking, intracellular vitamin deficiency, and occurrence of micronuclei in epithelial cells of the buccal mucosa. Cancer Epidemiol Biomarkers Prev 1995;4:751-758.
41.
Majer BJ, Laky B, Knasmüller S, Kassie F: Use of the micronucleus assay with exfoliated epithelial cells as a biomarker for monitoring individuals at elevated risk of genetic damage and in chemoprevention trials. Mutat Res 2001;489:147-172.
42.
Claycombe KJ, Meydani SN: Vitamin E and genome stability. Mutat Res 2001;475:37-44.
43.
Gulec M, Gurel A, Armutcu F: Vitamin E protects against oxidative damage caused by formaldehyde in the liver and plasma of rats. Mol Cell Biochem 2006;290:61-67.
44.
Konopacka M, Widel M, Rzeszowska-Wolny J: Modifying effect of vitamins C, E and beta-carotene against gamma-ray-induced DNA damage in mouse cells. Mutat Res 1998;417:85-94.
45.
Schneider M, Diemer K, Engelhart K, Zankl H, Trommer WE, Biesalski HK: Protective effects of vitamins C and E on the number of micronuclei in lymphocytes in smokers and their role in ascorbate free radical formation in plasma. Free Radic Res 2001;34:209-219.
46.
Sarkar A, Saha BK, Basak R, Mukhopadhyay I, Karmakar R, Chatterjee M: Anticlastogenic potential of 1alpha,25-dihydroxyvitamin D3 in murine lymphoma. Cancer Lett 2000;150:1-13.
47.
Jones KH, York TP, Juusola J, Ferreira-Gonzalez A, Maes HH, Jackson-Cook C: Genetic and environmental influences on spontaneous micronuclei frequencies in children and adults: a twin study. Mutagenesis 2011;26:745-752.
48.
Lowe LC, Guy M, Mansi JL, Peckitt C, Bliss J, Wilson RG, et al: Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer 2005;41:1164-1169.
49.
Valdivielso JM, Fernandez E: Vitamin D receptor polymorphisms and diseases. Clin Chim Acta 2006;371:1-12.
50.
Denzer N, Vogt T, Reichrath J: Vitamin D receptor (VDR) polymorphisms and skin cancer. Dermatoendocrinol 2011;3:205-210.
51.
Kaleta B, Bogaczewicz J, Robak E, Sysa-Jędrzejowska A, et al: Vitamin D receptor gene Bsm I polymorphism in Polish patients with systemic lupus erythematosus. ISRN Endocrinol 2013;2013:e427818.
52.
Schooten FJV, Hirvonen A, Maas LM, Mol BAD, Kleinjans JCS, Bell DA, et al: Putative susceptibility markers of coronary artery disease: association between VDR genotype, smoking, and aromatic DNA adduct levels in human right atrial tissue. FASEB J 1998;12:1409-1417.
53.
Al-Daghri NM, Al-Attas O, Alokail MS, Alkharfy KM, Draz HM, Agliardi C, et al: Vitamin D receptor gene polymorphisms and HLA DRB1*04 cosegregation in Saudi type 2 diabetes patients. J Immunol 2012;188:1325-1332.
54.
Qin X, Lu Y, Qin A, Chen Z, Peng Q, Deng Y, et al: Vitamin D receptor Bsm І polymorphism and ovarian cancer risk: a meta-analysis. Int J Gynecol Cancer 2013;23:1178-1183.
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