Abstract
Occupational and environmental exposure to cadmium is associated with the development of urothelial cancer. The metallothionein (MT) family of genes encodes proteins that sequester metal ions and modulate physiological processes, including zinc homeostasis. Little is known about the selectivity of expression of the different MT isoforms. Here, we examined the effect of cadmium exposure on MT gene and isoform expression by normal human urothelial (NHU) cell cultures. Baseline and cadmium-induced MT gene expression was characterized by next-generation sequencing and RT-PCR; protein expression was assessed by Western blotting using isoform-specific antibodies. Expression of the zinc transporter-1 (SLC30A1) gene was also assessed. NHU cells displayed transcription of MT-2A, but neither MT-3 nor MT-4 genes. Most striking was a highly inducer-specific expression of MT-1 genes, with cadmium inducing transcription of MT-1A, MT-1G, MT-1H, and MT-1M. Whereas MT-1G was also induced by zinc and nickel ions and MT-1H by iron, both MT-1A and MT-1M were highly cadmium-specific, which was confirmed for protein using isoform-specific antibodies. Protein but not transcript endured post-exposure, probably reflecting sequestration. SLC30A1 transcription was also affected by cadmium ion exposure, potentially reflecting perturbation of intracellular zinc homeostasis. We conclude that human urothelium displays a highly inductive profile of MT-1 gene expression, with two isoforms identified as highly specific to cadmium, providing candidate transcript and long-lived protein biomarkers of cadmium exposure.
Highlights
Occupational and environmental exposure to cadmium has increased as a result of the burning of fossil fuels and widespread use of the “heavy” metal in anthropological activities, such as battery production, electroplating, smelting, and soldering
The results revealed that MT isoform expression was inducer-specific, and that abundance of both MT-1A and MT-1M transcript and protein was highly cadmium-specific, highlighting their potential as biomarkers of exposure
Exposure of nondifferentiated normal human urothelial (NHU) cells to cadmium revealed that cell growth was unaffected by concentrations ≤ 10 μM CdCl2 whilst exposure to 20 μM CdCl2 resulted in distinct cytotoxicity
Summary
Occupational and environmental exposure to cadmium has increased as a result of the burning of fossil fuels and widespread use of the “heavy” metal in anthropological activities, such as battery production, electroplating, smelting, and soldering (reviewed [1]). Cadmium ions accumulate in the body in an almost irreversible manner [2], as the metal cannot be metabolized to a less toxic species [3] and has a low excretion rate [4]. The bladder stores concentrated urine prior to voiding, meaning that the urothelial lining of the bladder (which functions as one of the tightest epithelial barriers [16]) is potentially exposed to excreted xenobiotics [16,17,18]. It is currently not known whether exposure to urinary cadmium is limited by the presence of an intact urinary barrier
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