Ototoxicity, or hearing loss and damage to the auditory system caused by certain medications, is a significant clinical challenge. Many commonly used drugs, including antimicrobials, cancer therapies, and loop diuretics, have the potential to induce temporary or permanent ototoxicity. The underlying mechanisms are complex, involving both genetic and environmental factors. Pharmacogenomics, the study of how an individual’s genetic makeup influences their response to drugs, has emerged as a promising field for understanding and mitigating ototoxicity. Developing personalized approaches to prevent and manage ototoxicity is crucial, and this is where the pharmacogenomic basis of ototoxicity becomes crucial. This review aims to provide healthcare professionals with an updated perspective on the genetics of ototoxicity by summarizing the latest research and insights in this rapidly evolving field. It presents a comprehensive overview of the mechanisms and genetic factors associated with drug-induced ototoxicity, with a particular focus on cisplatin and aminoglycoside antibiotics.

Cadmium (Cd) exposure through the respiratory system is associated with various respiratory disorders, including lung cancer. Circular RNAs (circRNAs) are increasingly recognized as critical regulators in carcinogenesis. This study employed high-throughput RNA sequencing and quantitative real-time PCR (qRT-PCR) to identify differentially expressed circRNAs in 16HBE cells (Cd-T) after 30 weeks of cadmium chloride (CdCl₂, 5 μmol/L) exposure. Circ_0008272 knockdown inhibited migration, invasion, proliferation, and colony formation in Cd-T cells, whereas its overexpression enhanced these malignant phenotypes. Bioinformatics analyses and RNA-Protein Interaction Prediction (RPISeq) suggested that circ_0008272 promotes tumor-like behavior in Cd-T cells by modulating histone modification pathways. In conclusion, circ_0008272 acts as a tumor-promoting factor in the Cd-induced malignant transformation of 16HBE cells.

Autophagy has been implicated in the pathophysiology of thyroid cancer and in determining the response of cancer cells to anticancer therapy. Dabrafenib, a BRAF inhibitor, has demonstrated efficacy and safety in several types of cancers. However, it is unknown whether Dabrafenib exerts a protective effect on autophagy in thyroid carcinoma cells. In the current study, our findings demonstrate that treatment with Dabrafenib reduced cell viability and promoted LDH release in SW579 thyroid carcinoma cells. Dabrafenib was then shown to promote autophagy by increasing the level of Beclin1 and the LC3-II/LC3-I ratio while reducing the level of p62. Additionally, exposure to Dabrafenib upregulated the expression of HMGB-1 at both mRNA and protein levels. Interestingly, silencing of HMGB-1 abrogated Dabrafenib-induced autophagy, suggesting that the effects of Dabrafenib are mediated by HMGB-1. Further study revealed that Dabrafenib activated the JAK1/STAT1 signaling pathway and that blockage of the JAK1/STAT1 signaling pathway with its inhibitor Pyridone 6 ameliorated Dabrafenib-induced HMGB-1 upregulation and autophagy, implicating the involvement of the JAK1/STAT1 signaling pathway in this process. Collectively, these findings demonstrate that Dabrafenib induces autophagy in thyroid carcinoma cells via the JAK1/STAT1/HMGB-1 axis. Notably, this effect occurs independently of BRAF V600E mutation status, suggesting a novel therapeutic mechanism.

Antimony ecotoxicity studies are often hindered by the incorrect selection of Sb(III) standards and the application of concentrations that do not reflect real environmental exposure. In this study, we used environmentally relevant concentrations of inorganic Sb in its pentavalent [Sb(V)] and trivalent [Sb(III)] oxidation states, as well as the organic species NMG-Sb(V), which is present in Meglumine Antimoniate, to evaluate the effects of Sb on cell viability in human lung (A549), kidney (HEK293), and liver (HepG2) cell lines. Cell viability was assessed in these cells following treatment with 0.001 to 1 µg/L of Sb(V), 1 to 500 µg/L of Sb(III), and 0 to 1000 mg/L of MA. We also measured ROS production and the expression of the profibrotic markers CTGF, α-SMA, and PAI-1, which are associated with fibrosis activation. No significant changes in cell viability were observed in HepG2 and A549 cells. However, in HEK293 cells, viability decreased by 20-40% at Sb(III) concentrations between 1 µg/L and 1 mg/L. CTGF expression was significantly increased at 17 µg/L of Sb(III), while α-SMA and PAI-1 expression increased at 21 µg/L of Sb(V). These findings suggest that different species of Sb can induce increased expression of mRNA for fibrotic genes in human liver and kidney cell lines at concentrations found in the environment.

Diphenylarsinic acid (DPAA) was responsible for the 2003 arsenic poisoning incident in Japan, in which DPAA-exposed individuals experienced cerebellum-related neurological symptoms. We previously reported that DPAA targets cerebellar astrocytes rather than neurons in rats in vivo and induced the aberrant activation of particular signal transduction pathways, such as the MAP kinase and transcription factor pathway, as well as the oxidative stress response in cultured normal rat cerebellar astrocytes (NRA). Here, we examined the effects of 10 µM DPAA exposure for 96 hr in a panel of nine cell lines (HepG2, U251MG, T98G, 1321N1, SK-N-SH, SH-SY5Y, MCF7, A549, and C6) as well as NRA, and examined the DPAA-susceptible signal transduction pathways: oxidative-stress responsive factors [heme oxygenase-1 (HO-1), Hsp70, superoxide dismutase-1, and catalase), MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK), transcription factors (CREB, c-Jun, and c-Fos), glutathione (GSH), and GSH-related enzymes (glutamate-cysteine ligase and glutathione synthetase). In NRA, DPAA significantly activated these signal transduction pathways. Although there were cell-type specificities in susceptibility to DPAA, multivariate clustering analyses classified NRA, rat glioma-derived C6, and two human glioma-derived cell lines, U251MG and 1321N1, into an identical group. These results suggest that DPAA might affect cellular signal transduction preferentially in astrocytes among the diverse types of cells.