# The Double Face of Metals: The Intriguing Case of Chromium
## 6 Toxicity of Chromium(VI)
A serious side effect of chromium intoxication is nephrotoxicity following its elimination via the kidney; high levels of hexavalent chromium are deposited in the kidneys, causing proximal tubule damage [102]. A considerable rise in oxidative stress, nitrosative stress, apoptosis, and inflammation has been demonstrated in the kidney tissue of rats [103]. Cr(VI) toxicity has been suggested to induce cell apoptosis mostly via intrinsic mitochondrial pathways in human tumour cell lines, anterior pituitary cells, hepatocyte cells and in a rat model. In a recent work, [PERSON] et al. (2020) studied the apoptotic mechanism of Cr(VI)-toxicity in human proximal tubular epithelial HK-2 cell line [104]. They found that both intrinsic and extrinsic apoptotic pathways were activated after exposure to 10 \(\upmu\)M Cr(VI). K\({}_{2}\)Cr\({}_{2}\)O\({}_{7}\)-induced nephrotoxicity associated with oxidative stress has been shown to be protected by natural antioxidants. Curcumin pretreatment in rats exerts a protective effect by preserving mitochondrial function against K\({}_{2}\)Cr\({}_{2}\)O\({}_{7}\) renal oxidant damage, through direct and indirect antioxidant effects [105]. [PERSON] (2018) demonstrated the reno-protective effects of eugenol, a naturally occurring substance, on the injury determined by potassium dichromatic intoxication in male rats: it exerted antioxidant activity and also lowered the formation of inflammatory mediators including TNF- [106]. Recently, a multicenter study using human biomonitoring in the assessment of Cr(VI) exposure and associated health risks in occupational settings has been reported [107]. Epidemiological studies demonstrated that chronic exposure to Cr(VI) and exposure to high Cr(VI) concentrations are associated with prostate cancer development and apoptosis induction in nontumorigenic human prostate cells in vitro and in vivo by acting on the epithelial\(-\)mesenchymal transition (EMT) pathway [108,109]. Low doses of Cr(VI) may act in two different ways, by downregulating epithelial protein markers, such as E-cadherin, and upregulating mesenchymal protein markers, such as Snail and N-cadherin, as assessed by [PERSON] et al. [110]. The author suggested inhibition of Cr(VI)-induced EMT signalling as an approach to reduce Cr(VI)-induced prostate tumour progression. Human oral exposure to Cr(VI) seems to determine hepatotoxicity since its accumulation takes place mainly in the liver. Mitochondrion is one of the most sensitive targets of Cr(VI) liver toxicity [111]. [PERSON] et al. (2017) proposed mitochondrial biogenesis as an adaptive mechanism to counteract Cr(VI) hepatotoxicity [112]. These authors found that the antioxidant systems and mitochondrial biogenesis were upregulated by low concentrations of Cr(VI), thus it is conceivable that a compensative mechanism should be generatedto counteract the Cr(VI) insult. On the other end, high and cytotoxic concentrations of Cr(VI) inhibited mitochondrial biogenesis and downregulated the expression of its regulatory factors and antioxidants in HepG2 cells. Thus, pretreatment with \(\alpha\)-tocopherol was proposed to act against the mitochondrial biogenesis imbalance induced by Cr(VI). Recently, [PERSON] et al. (2020) studied the effects of long-term Cr(VI) exposure on liver toxicity in mice [113]. Results indicated that chronic, low concentration Cr(VI) treatment induced liver injury characterized by disorganization of liver structure, liver dysfunction, and inhibition of the antioxidant enzyme system. Moreover, the occurrence of liver fibrosis was observed, as a result of hepatic stellate cell triggering mediated by the increased expression levels of Hedgehog signalling network. Cr(VI) has been classified as a hazardous air pollutant by the USEPA (2004) [114]. Inhalation of chromium dusts or aerosols has been found to induce respiratory diseases and represents an undoubted risk factor for lung cancer [115]. [PERSON] et al.