Hexavalent chromium induces chromosome instability in human urothelial cells

Abstract

Numerous metals are well-known human bladder carcinogens. Despite the significant occupational and public health concern of metals and bladder cancer, the carcinogenic mechanisms remain largely unknown. Chromium, in particular, is a metal of concern as incidences of bladder cancer have been found elevated in chromate workers, and there is an increasing concern for patients with metal hip implants. However, the impact of Cr(VI) on bladder cells has not been studied. We compared chromate toxicity in two bladder cell lines; primary human urothelial cells and hTERT-immortalized human urothelial cells. Hexavalent chromium (Cr(VI)) induced a concentration- and time-dependent increase in chromosome damage in both cell lines, with the hTERT-immortalized cells exhibiting more chromosome damage than the primary cells. Chronic exposure to Cr(VI) also induced a concentration-dependent increase in aneuploid metaphases in both cell lines which was not observed after a 24 h exposure. Aneuploidy induction was higher in the hTERT-immortalized cells. When we correct for uptake, Cr(VI) induces a similar amount of chromosome damage and aneuploidy suggesting that the differences in Cr(VI) sensitivity between the two cells lines were due to differences in uptake. The increase in chromosome instability after chronic chromate treatment suggests this may be a mechanism for chromate-induced bladder cancer specifically and may be a mechanism for metal-induced bladder cancer in general.

Mechanisms of chromium-induced toxicity

“…Chromate is known to form adducts in DNA including DNA-protein crosslinks, and crosslinks with amino acids such as cysteine, GSH and ascorbate [50][51][52][53][54][55][56][57][58][59], Most of these adducts involved the reduced Cr(III) which coordinates ligands to DNA in ternary complexes [52,54,59]. Chromate also induces chromosomal damage and formation of oxidized DNA adducts [60][61][62][63]. The cited studies are just a fraction of those in the literature that establish chromate as a mutagenic and genotoxic carcinogen.…”

Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells

“…Moreover, HR repair protects against particulate Cr(VI)-induced chromosome instability (Bryant et al, 2006; Stackpole et al, 2007). However, genomic instability has been proposed as the underlying mechanism of particulate Cr(VI)-induced carcinogenesis, based on a wealth of data demonstrating Cr(VI) induces chromosome instability (Holmes et al, 2008; Qin et al, 2014; Wise et al, 2012; Wise et al, 2016; Xie et al, 2009). …”

Composites Produced from Natural Rubber and Chrome-Tanned Leather Wastes: Evaluation of their In Vitro Toxicological Effects for Application in Footwear and Textile Industries

“…These results reinforced the inference that the majority of the total chromium present in the extracts was in the trivalent oxidation state. Hexavalent chromium is well-known for its genotoxic and carcinogenic effects in human cells [47]. It has been reported that trivalent chromium, at high concentrations, can damages DNA molecules, sister-chromatid exchange, and the appearance of the micronucleus [48].…”