Abstract
Backgrounds
Heavy metals cadmium has been used as a yellow pigment due to its bright and lasting color. Considering the toxicity of cadmium, yellow iron oxide has been suggested as a substitute due to its cost-effectiveness. However, cellular and molecular safety information of yellow iron oxide is not fully understood.
Methods
Metal-mediated cellular stress indicated by metallothionein 1 expression were measured by western blotting and qRT-PCR in cadmium- or iron oxide-treated HepG2 cells. Genotoxicity were detected using comet assay and micronuclei assay in HepG2 cells and rat liver tissue. Observed toxicological effects were quantified and scored on a scale bar for integrated analysis.
Results
Yellow iron oxide showed significantly low metallothionein 1 expression and genotoxicity in all results. This result indicates high potential of iron oxide as an alternative to cadmium.
Conclusion
We demonstrated the comparative toxicity of the cadmium and yellow iron oxide in terms of stress-responsive biomarker expression and genotoxicity in HepG2 cells and rat liver tissue. Our study with the integrated strategy suggests usefulness of the yellow iron oxide as a substitute material in cadmium-containing products and reports useful tool to comprehensively assess the toxicity of suspected toxicants or newly developed materials.
Similar content being viewed by others
References
Abdulidha NA, Jaccob AA, AL-Moziel, M.S.G (2020) Protective effects of Co-Q10, Ginkgo biloba, and l-carnitine on brain, kidney, liver, and endocrine system against sub-acute heavy metals toxicity in male rats. Toxicol Environ Health Sci 12(4):331–341. https://doi.org/10.1007/s13530-020-00061-7
Al Khateeb W (2018) Plants genotoxicity as pollution bioindicator in Jordan using comet assay. Physiol Mol Biol Plants 24:89–97
Aly FM, Kotb AM, Hammad S (2018) Effects of Spirulina platensis on DNA damage and chromosomal aberration against cadmium chloride-induced genotoxicity in rats. Environ Sci Pollut Res Int 25:10829–10836
Beattie JH, Marion M, Denizeau F (1987) The modulation by metallothionein of cadmium-induced cytotoxicity in primary hepatocyte cultures. Toxicology 44:329–339
Cha SH, Suh CK (2010) Heme oxygenase-1 mediated protective effect of methyl gallate on cadmium-induced cytotoxicity in cultured mouse mesangial cells. Mol Cell Toxicol 6:127–133
Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26:249–261
Corcuera LA et al (2015) Genotoxicity of Aflatoxin B1 and Ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay. Food Chem Toxicol 76:116–124
Dai S et al (2013) Quantification of metallothionein on the liver and kidney of rats by subchronic lead and cadmium in combination. Environ Toxicol Pharmacol 36:1207–1216
Dudley RE, Svoboda DJ, Klaassen CD (1982) Acute exposure to cadmium causes severe liver injury in rats. Toxicol Appl Pharmacol 65:302–313
Duruibe JMOCO, Egwurugwu J (2017) Heavy metal pollution and human biotoxic effects. 2
el Azzouzi B et al (1994) Cadmium induces apoptosis in a human T cell line. Toxicology 88:127–139
el Jihen H, Imed M, Fatima H, Abdelhamid K (2009) Protective effects of selenium (Se) and zinc (Zn) on cadmium (Cd) toxicity in the liver of the rat: effects on the oxidative stress. Ecotoxicol Environ Saf 72:1559–1564
Elarabany N, Bahnasawy M (2019) Comparative and Interactive Biochemical Effects of Sub-Lethal Concentrations of Cadmium and Lead on Some Tissues of the African Catfish (Clarias gariepinus). Toxicol Res 35(3):249–255. https://doi.org/10.5487/TR.2019.35.3.249
Godt J et al (2006) The toxicity of cadmium and resulting hazards for human health. J Occup Med Toxicol 1:22
Habeebu SS, Liu J, Klaassen CD (1998) Cadmium-induced apoptosis in mouse liver. Toxicol Appl Pharmacol 149:203–209
Hartwig A (1998) Carcinogenicity of metal compounds: possible role of DNA repair inhibition. Toxicol Lett 102–103:235–239
Himeno S, Sumi D, Fujishiro H (2019) Toxicometallomics of Cadmium, Manganese and Arsenic with Special Reference to the Roles of Metal Transporters. Toxicological Research 35(4):311–317. https://doi.org/10.5487/TR.2019.35.4.311
Hradil D, Grygar T, Hradilová J, Bezdička P (2003) Clay and iron oxide pigments in the history of painting. Appl Clay Sci 22:223–236
Jin T, Nordberg GF, Nordberg M (1987) Influence of cadmium-metallothionein pretreatment on tolerance of rat kidney cortical cells to cadmium toxicity in vitro and in vivo. Pharmacol Toxicol 60:345–349
Kagi JH (1991) Overview of metallothionein. Methods Enzymol 205:613–626
Kang SH, Kwon JY, Lee JK, Seo YR (2013) Recent advances in in vivo genotoxicity testing: prediction of carcinogenic potential using comet and micronucleus assay in animal models. J Cancer Prev 18:277–288
Kim HS, Kim YJ, Seo YR (2015) An overview of carcinogenic heavy metal: molecular toxicity mechanism and prevention. J Cancer Prev 20:232–240
Kirkland D et al (2007) How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop. Mutat Res 628:31–55
Koyu A, Gokcimen A, Ozguner F, Bayram DS, Kocak A (2006) Evaluation of the effects of cadmium on rat liver. Mol Cell Biochem 284:81–85
Krishna G, Hayashi M (2000) In vivo rodent micronucleus assay: protocol, conduct and data interpretation. Mutat Res 455:155–166
Ladeira C, Koppen G, Scavone F, Giovannelli L (2019) The comet assay for human biomonitoring: Effect of cryopreservation on DNA damage in different blood cell preparations. Mutat Res 843:11–17
Lee J, Lee YM (2020) Effects of heavy metals on the expression of digestive enzyme-coding genes in the brackish water flea Diaphanosoma celebensis. Toxicol Environ Health Sci 12 (4):363–370. https://doi.org/10.1007/s13530-020-00074-2
Meisen U (2000) Process for producing yellow iron oxide pigments. US6689206B2
Milnerowicz H, Sliwinska-Mosson M, Sobiech KA (2017) The effect of ozone on the expression of metallothionein in tissues of rats chronically exposed to cadmium. Environ Toxicol Pharmacol 52:27–37
Morita T et al (1997) Evaluation of the rodent micronucleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) the summary report of the 6th collaborative study by CSGMT/JEMS MMS. Collaborative Study of the Micronucleus Group Test. Mammalian Mutagenicity Study Group. Mutat Res 389:3–122
Namdarghanbari M, Wobig W, Krezoski S, Tabatabai NM, Petering DH (2011) Mammalian metallothionein in toxicology, cancer, and cancer chemotherapy. J Biol Inorg Chem 16:1087–1101
Nautiyal A et al (2019) Quantification of DNA damage in patients undergoing non-contrast and contrast enhanced whole body PET/CT investigations using comet assay and micronucleus assay. Int J Radiat Biol 95(6):710–719
Nemmiche S (2017) Oxidative Signaling Response to Cadmium Exposure. Toxicol Sci 156:4–10
Nigro M et al (2015) n-TiO2 and CdCl2 co-exposure to titanium dioxide nanoparticles and cadmium: Genomic, DNA and chromosomal damage evaluation in the marine fish European sea bass (Dicentrarchus labrax). Aquat Toxicol 168:72–77
Palus J et al (2003) Genotoxic effects of occupational exposure to lead and cadmium. Mutat Res 540:19–28
Park SJ, Youn HS (2009) Suppression of the TRIF-dependent signaling pathway of toll-like receptor by cadmium in RAW264.7 macrophages. Mol Cell Toxicol 5:187–192 https://doi.org/10.1007/s10059-009-0130-z
Patlolla AK, Barnes C, Hackett D, Tchounwou PB (2009) Potassium dichromate induced cytotoxicity, genotoxicity and oxidative stress in human liver carcinoma (HepG2) cells. Int J Environ Res Public Health 6:643–653
Recio L, Hobbs C, Caspary W, Witt KL (2010) Dose-response assessment of four genotoxic chemicals in a combined mouse and rat micronucleus (MN) and Comet assay protocol. J Toxicol Sci 35:149–162
Reinecke SA, Reinecke AJ (2004) The comet assay as biomarker of heavy metal genotoxicity in earthworms. Arch Environ Contam Toxicol 46:208–215
Russo C, Rocco L, Morescalchi MA, Stingo V (2004) Assessment of environmental stress by the micronucleus test and the Comet assay on the genome of teleost populations from two natural environments. Ecotoxicol Environ Saf 57:168–174
Ruttkay-Nedecky B et al (2013) The role of metallothionein in oxidative stress. Int J Mol Sci 14:6044–6066
Sato M, Bremner I (1993) Oxygen free radicals and metallothionein. Free Radic Biol Med 14:325–337
Schnell RC et al (1978) Effect of acute and chronic cadmium treatment on hepatic drug metabolism in male rats. Arch Toxicol 40:269–277
Schwarz MA et al (1995) Metallothionein protects against the cytotoxic and DNA-damaging effects of nitric oxide. Proc Natl Acad Sci U S A 92:4452–4456
Sharma RK, Agrawal M (2005) Biological effects of heavy metals: an overview. J Environ Biol 26:301–313
Smith CJ, Livingston SD, Doolittle DJ (1997) An international literature survey of “IARC Group I carcinogens” reported in mainstream cigarette smoke. Food Chem Toxicol 35:1107–1130 https://doi.org/10.1016/S0278-6915(97)00063-X
Soichiro Nobuoka TA, Ado K (1982) Yellow iron oxide pigment and method for manufacture thereof. US4459276A
Speit G, Rothfuss A (2012) The comet assay: a sensitive genotoxicity test for the detection of DNA damage and repair. Methods Mol Biol 920:79–90
Takahashi S (2012) Molecular functions of metallothionein and its role in hematological malignancies. J Hematol Oncol 5:41
Takasawa H et al (2015) Results of the International Validation of the in vivo rodent alkaline comet assay for the detection of genotoxic carcinogens: individual data for 1,2-dibromoethane, p-anisidine, and o-anthranilic acid in the 2nd step of the 4th phase Validation Study under the JaCVAM initiative. Mutat Res Genet Toxicol Environ Mutagen 786–788:144–150
Tice RR et al (2000) Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35:206–221
Trabelsi F et al (2016) Genotoxic effects of cadmium in human head and neck cell line SQ20B. Environ Sci Pollut Res Int 23:16127–16136
Turner A (2018) Concentrations and migratabilities of hazardous elements in second-hand children’s plastic toys. Environ Sci Technol 52:3110–3116
Turner A (2019) Cadmium pigments in consumer products and their health risks. Sci Total Environ 657:1409–1418
Wada K, Fukuyama T, Nakashima N, Matsumoto K (2015) Assessment of the in vivo genotoxicity of cadmium chloride, chloroform, and D, L-menthol as coded test chemicals using the alkaline comet assay. Mutat Res Genet Toxicol Environ Mutagen 786–788:114–119
Waisberg M, Joseph P, Hale B, Beyersmann D (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117
Yang CF, Shen HM, Shen Y, Zhuang ZX, Ong CN (1997) Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells). Environ Health Perspect 105:712–716
Zhao Y-Q, Liu G-D, Hou C-C, Han Y-L, Zhu J-Q (2016) Effect of cadmium exposure on antioxidant enzyme catalase in different tissues of Acrossocheilus fasciatus. Molecular & Cellular Toxicology 12:255–263
Acknowledgements
This study was supported by Korea Environment Industry & Technology Institute (KEITI) through The Chemical Accident Prevention Technology Development Program (2017001970001) and Environmental Research Laboratory project (412-112-011), funded by Korea Ministry of Environment (MOE).
Author information
Authors and Affiliations
Contributions
YRS and PK designed the research study. HSK and HYL cared animals, performed overall experimental procedure and analyzed data. HSK also wrote the manuscript. YJ and JIW provides chemical processes for iron oxide materials. DYS and YJ reviewed statical analysis and integrative scoring system of the study.
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflict of interest to declare.
Ethical approval
All animal experiments were performed in accordance with the guidelines from Institutional Animal Care and Use Committee (IACUC). All experimental procedures have been approved by the IACUC of Dongguk University (IACUC-2013–023) and were undertaken in compliance with the National Animal Welfare Law of the Republic of Korea.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Kim, H.S., Lee, H.J., Jung, WY. et al. Integrative comparison of cadmium and iron oxide as yellow pigment in terms of cellular stress and genotoxicity in vitro and in vivo. Mol. Cell. Toxicol. 17, 99–109 (2021). https://doi.org/10.1007/s13273-020-00113-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13273-020-00113-6