Carcinogenicity of chromium and chemoprevention: a brief update

Figures & data

Figure 1 Possible mechanisms of Cr(VI)- and Cr(III)-induced carcinogenicity and chemoprevention of antioxidants.

Abbreviations: Cr(VI), hexavalent chromium; Cr(III), trivalent chromium; GSH, glutathione; ROS, reactive oxygen species; EGCG, epigallocatechin-3-gallate; NAC, N-acetylcysteine; MCE, methanolic Carum copticum extract (seeds).

Table 1 Summary of carcinogenicity for Cr(III) and Cr(VI)

Category	Cr(III)	Cr(VI)
In vitro studies	• Causes DNA damage and genetic mutations in cells^Citation22 • Less toxic than Cr(VI) in HepG2 cells and human fibroblasts;^Citation51,Citation52 more toxic than Cr(VI) in yeast and Jurkat cells^Citation22	• Causes DNA damage and genetic mutations in cells, different mechanisms than Cr(III)^Citation27,Citation28 • Cannot damage DNA directly: requires reductive activation in cells^Citation29,Citation30 • Chronic exposure to Cr(VI):  ○ Induces DNA lesions (SSB, alkali-labile sites, DPCs, DNA–amino acid cross-links, chromium–DNA adducts, formation of protein–Cr[III]–DNA cross-links)^Citation33^–^Citation36  ○ Increases generation of miR21, decreases expression of PDCD4 in BEAS-2B cells^Citation47,Citation48  ○ Cytotoxic and genotoxic to hawksbill sea turtle cells, causes chromosome aberrations in metaphases^Citation43  ○ Zinc chromate/lead chromate causes DNA DSBs, chromosome aberrations, aneuploidy in WTHBF6 cells (also in human bronchial fibroblasts for ZnCrO4), resulting in chromosome instability, gene mutations, progression toward tumorigenesis^Citation37^–^Citation40,Citation42
In vivo studies	• Carcinogenicity in animals is uncertain • Chronic exposure provides little evidence of adverse effects, did not induce in-life toxicity or increase in nonneoplastic lesion incidence^Citation48	• Chronic exposure to potassium dichromate, lead chromate, SDD accounted for high carcinogenic activity in animal models:  ○ DNA damage^Citation53  ○ Hepatic oxidative stress/hepatocyte apoptosis^Citation53  ○ Development of fibrosarcomas or rhabdomyosarcomas^Citation54  ○ Renal tumors^Citation54  ○ Small intestinal adenoma/carcinoma^Citation55,Citation56  ○ Squamous-cell papilloma or carcinoma of oral mucosa^Citation55
Epidemiology studies	• Evidence inadequate to indicate human exposure associated with increased cancer risk^Citation63,Citation64	• Cr(VI) exposure can occur at:  ○ High concentrations occupationally (chromate production, chromate-pigment production, chromium-plating industries)^Citation38,Citation60,Citation61  ○ Chronic low concentrations via inhalation from ambient air pollution or ingestion from contaminated water^Citation62 • Occupational exposure to high concentrations increases risk of lung and sinonasal cavity cancers in humans, may also be stomach carcinogen^Citation60,Citation61 • Absorption into human lung cells brings about BDAs, ODD in P53 gene, and adenine/guanine mutations^Citation59 • Zinc chromate is potent carcinogen^Citation38 • Exposure to lead chromate may not contribute to lung cancer^Citation60

Abbreviations: Cr(VI), hexavalent chromium; Cr(III), trivalent chromium; SSB, single-strand breaks; DPCs, DNA–protein cross-links; DSBs, DNA double-strand breaks; SDD, sodium dichromate dehydrate; BDAs, bulky DNA adducts; ODD, oxidative DNA damage.

Table 2 Summary of chemoprevention for Cr(III) and Cr(VI) carcinogenicity

Category	Cr(III)	Cr(VI)
In vivo studies	• Few chemoprevention investigations  ○ Selenium in C3H mice with MMTV: Cr(III) weakens antitumorigenic effects of Se, counteracts inhibitory effect on tumor development, shortens tumor latency period, and accelerates tumor-growth rates^Citation107	• Antioxidants with chemopreventive effects against Cr(VI) cyto/genotoxicity:  ○ EDE in Swiss mice: prevents pathological liver and kidney damage^Citation71  ○ NAC in albino Hartley strain GPs: inhibits activation of phospho-Akt, phospho-p65, phospho-IκBα, phospho-ERK, phospho-p38, and phospho-JNK in epidermis^Citation74  ○ GSH in Swiss albino mice and Wistar rats: protects against LP, oxidative stress, and DNA damage, restores GSH cycle in liver and kidney^Citation4,Citation91  ○ EGCG in Hsd:ICR and CD1 mice: protects against genotoxic damage, contributes to elimination of DNA-damaged cells^Citation92,Citation93  ○ Quercetin in nude mice with BEAS-2B and CD1 mice: reduces tumor incidence, targets miR21–PDCD4 signaling, protects against genotoxic damage^Citation46,Citation93  ○ Rutin in CD1 mice: protects against genotoxic damage^Citation93  ○ Curcumin in Wistar rats: direct and indirect antioxidant effects against renal oxidant damage, preserves mitochondrial function^Citation95  ○ Selenium in Wistar rats: prevents against Cr(VI)-induced erythrocyte damage, inhibits LP and oxidative stress, restores GSH cycle in liver and kidney^Citation4,Citation97,Citation98  ○ α-tocopherol in Wistar rats: inhibits LP and oxidative stress, restores GSH cycle in liver and kidney^Citation4  ○ Ginger in Wistar rats: reduces intensity of oxidative stress^Citation98  ○ Vitamins C and E in albino rats and Swiss mice: reduce oxidative damage and decrease LP and sperm mutations and germ cells degenerated^Citation99  ○ Propylthiouracil in mice: reduces oxidative stress and protects against hepatotoxicity^Citation101  ○ Green-tea polyphenol extracts in CD1 mice: reduces amount of MN-PCEs^Citation102,Citation103 Thiol compounds (including LA and DHLA) in ddY and Swiss albino mice: reduce oxidative stress and generation of DPCs, scavenge ROS, alter cell-redox status, boost urinary chromium excretion^Citation104,Citation105
In vitro studies	• Few chemoprevention studies conducted • Antioxidants with chemopreventive effects against Cr(III) cyto/genotoxicity:  ○ Tempol in human lymphocytes: inhibits cyto/genotoxicity^Citation82  ○ Zinc in PBL: inhibits apoptosis, reduces ROS production, reverses changes in mitochondrial membrane potential, ATP levels, activation of caspase 3^Citation90	• Antioxidants with chemopreventive effects against Cr(VI) cyto/genotoxicity:  ○ Apple juice in A549: scavenges hydroxyl radicals, reduces lipid peroxidation, DNA damage, cell apoptosis, NFκB activation^Citation68  ○ Quercetin in BEAS2B: decreases ROS generation, inhibits cell transformation, increases miR21 expression, and inhibits of PDCD4^Citation69  ○ Luteolin in BEAS2B: scavenges ROS^Citation46  ○ EDE in AMJ2-C11: protects against cytotoxicity and oxidative stress^Citation71  ○ Tempol in human lymphocytes: inhibits cyto- and genotoxicity^Citation82  ○ NAC in L02 hepatocytes, H460, HaCaT: inhibits suppression of apoptosis, p53 activation, HSP72 and HIF1α upregulation, prevents ROS-mediated cell death and cytokine expression, decreases rate of cell apoptosis, alleviates mitochondrial and DNA damage^Citation73^–^Citation75  ○ Vitamin C: inhibits increase in DPCs, complete protection against cytotoxicity^Citation76  ○ Lawsonia inermis extract in MDA-MB-435S: scavenges free radicals, inhibits lipid peroxidation^Citation80  ○ Phyllanthus amarus aqueous extract in MDA-MB-435S: inhibits Cr(VI)-induced oxidative toxicity^Citation81  ○ EGCG in BEAS2B: scavenges ROS, protects against DNA damage, inhibits activation of NFκB^7  ○ Melatonin in rat hepatocytes: protects against DSBs, cytotoxicity, lipid peroxidation^Citation88  ○ MCE in BEAS2B, PBL: increases cell viability, decreases DNA damage and ROS level^Citation89

Abbreviations: Cr(VI), hexavalent chromium; Cr(III), trivalent chromium; EDE, Eugenia dysenterica extract (leaf, hydroalcoholic); NAC, N-acetylcysteine; MMTV, murine mammary tumor virus; GPs, guinea pigs; GSH, glutathione; EGCG, epigallocatechin-3-gallate; MN-PCEs, micronucleated polychromatic erythrocytes; LP, lipid peroxidation; LA, α-lipoic acid; DHLA, dihydrolipoic acid; ROS, reactive oxygen species; PBL, peripheral blood lymphocyte; DPCs, DNA–protein cross-links; DSBs, double-strand breaks; MCE, methanolic Carum copticum extract (seeds).

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