Genotoxicity Induced by Low Dose and Mixed Exposure to Haloacetaldehydes, an Emerging Class of Drinking Water Disinfection By-products

Abstract

Haloacetaldehydes(HALs) are the third largest disinfection by-products(DBPs) class by mass in drinking water. Most of them alone in high doses are more cytotoxic and genotoxic than regulated DBPs. However, the toxic effects of mixed exposure to HALs at environmentally relevant levels are still unknown. Given that genotoxicity is critical for risk assessment, we employed multiple genotoxic tests including the Salmonella typhimurium revertant mutation assay(Ames assay), the single cell gel electrophoresis(SCGE) assay, the cytoplasmic blocking micronucleus(CBMN) assay, and the γ-H2AX assay to investigate the genotoxicity of HALs based on the HALs concentrations and components detected in the finished drinking water of Shanghai, China. The results demonstrated the concentrations of HALs were low, ranging from 0.04 µg/L to 4.47 µg/L, and the total concentration was 10.85 µg/L. Although the mutagenicity of HALs was negative even at 1000-fold concentrations in the real world, mixed exposure to 100 and 1000-fold concentrations HALs resulted in DNA and chromosomal damage in human hepotocyte(HepG2) cells. HALs significantly increased the levels of reactive oxygen species(ROS) and γ-H2AX and activated nuclear factor erythroid-derived factor 2-related factor 2(NRF2) pathway-related protein expressions in HepG2 cells. The antioxidant NAC could ameliorate NRF2 pathway-related protein expression and DNA damage caused by HALs, suggesting that the genotoxicity of mixed exposure to HALs involved cellular oxidative stress and NRF2 pathway activation.

Keywords

Unregulated disinfection by-product / Haloacetaldehyde / Mixed exposure / Genotoxicity

References

[1] King W D, Marrett L D. Cancer Causes Control, 199, 7(6): 596.

[2] Srivastav A L, Patel N, Chaudhary V K. Environ. Pollut., 2020, 267: 115474.

[3] Bove G E, Rogerson P A, Vena J E. Int. J Health Geogr., 2007, 6: 18.

[4] Costet N, Villanueva C M, Jaakkola J J K, Kogevinas M, Cantor K P, King W D, Lynch C F, Nieuwenhuijsen M J, Cordier S. Occup. Environ. Med., 2011, 68(5): 379.

[5] Smith R B, Edwards S C, Best N, Wright J, Nieuwenhuijsen M J, Toledano M B. Environ. Health Perspect, 201, 124(5): 681.

[6] Plewa M J, Richardson S D. J. Environ. Sci.(China), 2017, 58: 1.

[7] Jeong C H, Postigo C, Richardson S D, Simmons J E, Kimura S Y, Mariñas B J, Barcelo D, Liang P, Wagner E D, Plewa M J. Environ. Sci. Technol., 2015, 49(23): 13749.

[8] Muellner M G, Wagner E D, McCalla K, Richardson S D, Woo Y-T, Plewa M J. Environ. Sci. Technol., 2007, 41(2): 645.

[9] Plewa M J, Muellner M G, Richardson S D, Fasano F, Buettner K M, Woo Y-T, McKague A B, Wagner E D. Environ. Sci. Technol., 2008, 42(3): 955.

[10] Plewa M J, Wagner E D, Jazwierska P, Richardson S D, Chen P H, McKague A B. Environ. Sci. Technol., 2004, 38(1): 62.

[11] Wagner E D, Plewa M J. J. Environ. Sci.(China), 2017, 58: 64.

[12] Krasner S W, Weinberg H S, Richardson S D, Pastor S J, Chinn R, Sclimenti M J, Onstad G D, Thruston AD. Environ. Sci. Technol., 200, 40(23): 7175.

[13] Koudjonou B, Lebel G L, Dabeka L. Chemosphere, 2008, 72(6): 875.

[14] Sadiq R, Rodriguez M J. J. Environ. Manage., 2004, 73(1): 1.

[15] Henson C M, Emmert G L, Simone P S. Chemosphere, 2014, 117: 586.

[16] Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E. Environ. Mutagen, 1983, 5(Suppl.1): 1.

[17] Warr T J, Parry E M, Parry J M. Mutat. Res., 1993, 287(1): 29.

[18] Sood C, O’Brien P J. Biochem. Pharmacol., 1993, 46(9): 1621.

[19] Benesic A, Schwerdt G, Mildenberger S, Freudinger R, Gordjani N, Gekle M. Kidney Int., 2005, 68(5): 2029.

[20] Pandya G A, Moriya M. Biochemistry, 199, 35(35): 11487.

[21] Biernat J, Ciesiołka J, Górnicki P, Adamiak R W, Kryzosiak W J, Wiewiórowski M. Nucleic Acids Res., 1978, 5(3): 789.

[22] Crebelli R, Conti G, Conti L, Carere A. Mutat. Res., 1984, 138(1): 33.

[23] Guengerich F P, Mason P S, Stott W T, Fox T R, Watanabe P G. Cancer Res., 1981, 41(11): 4391 Pt 1

[24] Liviac D, Creus A, Marcos R. Water Res., 2010, 44(8): 2638.

[25] Wang Z, Hu H, Hu M, Zhang X, Wang Q, Qiao Y, Liu H, Shen L, Zhou P, Chen Y. Radiat. Environ. Biophys., 2014, 53(2): 283.

[26] Niu H, Chang H C, Cho I C, Chen C H, Liu C S, Chou W T. Applied Surface Science, 2014, 310: 62.

[27] Dong L, Jiang Z, Yang L, Hu F, Zheng W, Xue P, Jiang S, Andersen M E, He G, Crabbe M J C, Qu W. J. Hazard Mater., 2022, 426: 128010.

[28] Wang S, Tian D, Zheng W, Jiang S, Wang X, Andersen M E, Zheng Y, He G, Qu W. Environ. Sci. Technol., 2013, 47(3): 1678.

[29] Standard Examination Methods for Drinking Water-Collection and Preservation of Water Samples, https://openstd.samr.gov.cn/bzgk/gb/newGbInfo?hcno=CA71F3AD8B8B22D908B7ED0FBCF703DF

[30] Serrano M, Silva M, Gallego M. J. Chromatogr. A, 2011, 1218(46): 8295.

[31] Koudjonou B K, LeBel G L. Chemosphere, 200, 64(5): 795.

[32] Kubo S, Kaji H. Sci. Rep., 2018, 8(1): 13462.

[33] Wang S, Zheng W, Liu X, Xue P, Jiang S, Lu D, Zhang Q, He G, Pi J, Andersen M E, Tan H, Qu W. Environ. Sci. Technol., 2014, 48(22): 13478.

[34] Sgro L A, Simonelli A, Pascarella L, Minutolo P, Guarnieri D, Sannolo N, Netti P, D’Anna A. Environ. Sci. Technol., 2009, 43(7): 2608.

[35] Uhl M, Helma C, Knasmüller S. Mutat. Res., 1999, 441(2): 215.

[36] Fenech M. Nat. Protoc., 2007, 2(5): 1084.

[37] McNamee J P, Flegal F N, Greene H B, Marro L, Wilkins R C. Radiat. Prot. Dosimetry, 2009, 135(4): 232.

[38] Mariotti L G, Pirovano G, Savage K I, Ghita M, Ottolenghi A, Prise K M, Schettino G. PLoS One, 2013, 8(11): e79541.

[39] Rothe G, Valet G. J. Leukoc. Biol., 1990, 47(5): 440.

[40] Wang S, Zhang H, Zheng W, Wang X, Andersen M E, Pi J, He G, Qu W. Environ. Sci. Technol., 2013, 47(9): 4768.

[41] Zuo Z, Wu T, Lin M, Zhang S, Yan F, Yang Z, Wang Y, Wang C. Environ. Sci. Technol., 2014, 48(9): 5179.

[42] Attene-Ramos M S, Wagner E D, Plewa M J. Environ. Sci. Technol., 2010, 44(19): 7206.

[43] Kao T-Y, Chen M-S, Jou J-R, Lin C-P, Tsai T-H, Ho T-C. J. Formos. Med. Assoc., 2015, 114(3): 238.

[44] Postigo C., Jeong C. H., Richardson S. D., Wagner E. D., Plewa M. J., Simmons J. E., Barceló D., Recent Advances in Disinfection By-Products, ACS Symposium Series 1190, American Chemical Society, New York, 2015

[45] Wagner E D, Osiol J, Mitch W A, Plewa M J. Environ. Sci. Technol., 2014, 48(14): 8203.

[46] Wilde E C, Chapman K E, Stannard L M, Seager A L, Brüsehafer K, Shah U-K, Tonkin J A, Brown M R, Verma J R, Doherty A T, Johnson G E, Doak S H, Jenkins G J S. Arch. Toxicol., 2018, 92(2): 935.

[47] Caldwell J C. Mutat. Res., 2012, 751(2): 82.

[48] Smith C J, Perfetti T A, Berry S C, Brash D E, Bus J, Calabrese E, Clemens R A, Fowle J R J, Greim H, MacGregor J T, Maronpot R, Pressman P, Zeiger E, Hayes A W. Mutat. Res. Rev. Mutat. Res., 2021, 787: 108363.

[49] Barbezan A B, Martins R, Bueno J B, Villavicencio A L C H. J. Food Sci., 2017, 82(7): 1518.

[50] Madia F, Kirkland D, Morita T, White P, Asturiol D, Corvi R. Mutat. Res. Genet. Toxicol. Environ. Mutagen, 2020, 854/855: 503199.

[51] Vaca C E, Fang J L, Schweda E K. Chem. Biol. Interact., 1995, 98(1): 51.

[52] Krishna G, Hayashi M. Mutat. Res., 2000, 455(1/2): 155.

[53] Kalweit S, Utesch D, von der Hude W, Madle S. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 1999, 439(2): 183.

[54] Thomas P, Umegaki K, Fenech M. Mutagenesis, 2003, 18(2): 187.

[55] Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe S E. Physiol. Rev., 2014, 94(2): 329.

[56] Xu A, Smilenov L B, He P, Masumura K-I, Nohmi T, Yu Z, Hei T K. Environ. Health Perspect, 2007, 115(1): 87.

[57] Kinner A, Wu W, Staudt C, Iliakis G. Nucleic Acids Res., 2008, 36(17): 5678.

[58] Yang G, Ibuki Y. Chem. Res. Toxicol., 2018, 31(2): 145.

[59] Plewa M J, Simmons J E, Richardson S D, Wagner E D. Environ. Mol. Mutagen, 2010, 51(8/9): 871.

[60] Pals J A, Ang J K, Wagner E D, Plewa M J. Environ. Sci. Technol., 2011, 45(13): 5791.

[61] Palejwala V A, Simha D, Humayun M Z. Biochemistry, 1991, 30(36): 8736.

[62] Kerins M J, Ooi A. Antioxid. Redox Signal, 2018, 29(17): 1756.

[63] LoPachin R M, Gavin T. Chem. Res. Toxicol., 2014, 27(7): 1081.

[64] Beauchamp R O, Andjelkovich D A, Kligerman A D, Morgan K T, Heck H D. Crit. Rev. Toxicol., 1985, 14(4): 309.

[65] Esterbauer H, Schaur R J, Zollner H. Free Radic. Biol. Med., 1991, 11(1): 81.

[66] Hughes T B, Miller G P, Swamidass S J. Chem. Res. Toxicol., 2015, 28(4): 797.

[67] Lopachin R M, Gavin T, Decaprio A, Barber DS. Chem. Res. Toxicol., 2012, 25(2): 239.

[68] Pals J A, Wagner E D, Plewa M J. Environ. Sci. Technol., 201, 50(6): 3215.