Abstract
Although it is recognized that cadmium (Cd) causes renal tubular dysfunction, the mechanism of Cd-induced nephrotoxicity is not yet fully understood. Mode of action (MOA) is a developing tool for chemical risk assessment. To establish the mechanistic MOA of Cd-induced renal tubular dysfunction, the Comparative Toxicogenomics Database (CTD) was used to obtain genomics data of Cd-induced nephrotoxicity, and Ingenuity® Pathway Analysis (IPA) software was applied for bioinformatics analysis. Based on the perturbed toxicity pathways during the process of Cd-induced nephrotoxicity, we established the MOA of Cd-induced renal tubular dysfunction and assessed its confidence with the tailored Bradford Hill criteria. Bioinformatics analysis showed that oxidative stress, DNA damage, cell cycle arrest, and cell death were the probable key events (KEs). Assessment of the overall MOA of Cd-induced renal tubular dysfunction indicated a moderate confidence, and there are still some evidence gaps to be filled by rational experimental designs.
Highlights
Cadmium (Cd) is one of the most toxic metals and naturally exists in the environment
The top 10 toxicity pathways with the smallest p-value were as follows: nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress response, aryl hydrocarbon receptor signaling, endoplasmic reticulum (ER) stress pathway, hypoxia signaling in the cardiovascular system, ferroptosis signaling pathway, unfolded protein response, mitotic roles of polo-like kinase, hypoxia-inducible factor-1-alpha (HIF1α) signaling, apoptosis signaling, and cyclins and cell cycle regulation (Figure 2A and Supplementary Figures 1–10)
We used the toxicogenomics data from Comparative Toxicogenomics Database (CTD) to understand the perturbed pathways involved in Cdinduced nephrotoxicity, and we initially constructed the Mode of action (MOA) of Cd-induced renal tubular dysfunction
Summary
Cadmium (Cd) is one of the most toxic metals and naturally exists in the environment. Anthropogenic activities, including agricultural and industrial activities, contribute greatly to the pollution by Cd. The exposure sources in the general population include food, drinking water, smoking, and air. Dietary exposure is the main source in the general population, whereas occupational exposure in individuals working in alloy production, battery production, pigment production and use, plastics production, and smelting and refining mostly involves the respiratory tract (Faroon et al, 2012). Cd can accumulate in the human body due to its long biological half-life (10–30 years) (Kjellström and Nordberg, 1978; Nawrot et al, 2006; Amzal et al, 2009). Cd is distributed throughout the body via blood circulation and accumulates mainly in the kidneys and liver—the major target organs of Cd toxicity. Cd is mostly found in the form of complexes consisting of low-molecular weight protein [mainly metallothionein
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