Toxicology and Industrial Health

Qi, Cong; Xu, Xinwei; Zhang, Lan; Gao, Jiahui; Shan, Guosheng; Liang, Guangqiao; Ye, Yang; Li, Fang

doi: 10.1177/07482337261453434pmid: 42189662

Environmental pollutants are an important cause of depression. Dibromoacetonitrile (DBAN) is a disinfection by-product, which is neurotoxic and induces oxidative stress. This study aimed to elucidate whether and how DBAN provoked depression-like behavior. Mitogen-activated protein kinase phosphatase-1 (MKP-1) and P38 mitogen-activated protein kinase (MAPK) are key factors in depression. In mice, 8-week gavage with 20 mg/kg DBAN caused depressive symptoms, serotonin (5-HT) loss, hippocampal neuronal damage, and elevated MKP-1/P38 MAPK signaling; 80 mg/kg proved lethal. DBAN disturbed the intestinal flora of mice. Depression-related bacteria Firmicutes increased. Bacteroidota showed a decreasing trend, and the relative abundance of Bifidobacterium also showed a decreasing trend. Co-treatment with antioxidant N-acetylcysteine (NAC, 150 mg/kg) prevented mortality, restored 5-HT and norepinephrine, normalized MKP-1/P38 phosphorylation, and alleviated behavioral deficits. 10 μM DBAN raised reactive oxygen species (ROS), upregulated MKP-1, increased the phosphorylation levels of P38 and c-Jun amino-terminal kinase (JNK), and decreased the phosphorylation levels of the extracellular signal-regulated kinase (ERK1/2) in HT22 cells. Following HT22 cell MKP-1 knockdown and DBAN exposure, HT22 cells exhibited decreased MKP-1 expression along with decreased P38 and JNK phosphorylation levels. Still, the levels of ERK1/2 phosphorylation were not significantly affected. NAC exerts a prophylactic protective effect against these adverse outcomes.

Coskun, Mazlume Piril; Celik, Ayla; Arslan, Hakan

doi: 10.1177/07482337261453776pmid: 42224505

The potential of the neonicotinoid insecticide dinotefuran to induce oxidative DNA damage was evaluated in human peripheral blood lymphocyte cultures at three concentrations (0.05, 0.15, and 0.30 µg/mL) using the single-cell gel electrophoresis assay (COMET). Its ability to interact with DNA was further examined through molecular docking analysis. The comet assay results revealed statistically significant increases (p < 0.001) in both the genetic damage index (GDI) and the percentage of heavily damaged cells (DCP) at all tested concentrations compared with the negative control. DNA damage within individual cells caused by genotoxic agents can thus be effectively detected using the comet assay, as demonstrated in our study. Additionally, the optimized molecular structure, total energy, molecular orbital energies, molecular electrostatic potential (MEP) maps, and global reactivity parameters of dinotefuran were obtained using the DFT/B3LYP/6-311G(d,p) method. The fully optimized energy was predicted, and geometric parameters were compared with available single-crystal structure data. Computational studies employing density functional theory (DFT) and MEP analyses provided detailed insights into the geometric and electronic characteristics of dinotefuran, suggesting that the compound possesses significant chemical reactivity and potential for biological activity upon interaction with DNA. Molecular docking studies with the B-DNA dodecamer (PDB ID: 1BNA) yielded a minimum binding energy of −6.24 kcal/mol. Dinotefuran was found to form four conventional hydrogen bonds, two carbon-hydrogen bonds, and one π-donor hydrogen bond with DNA, primarily involving guanosine, cytosine, and thymidine bases. These interactions are consistent with the experimental evidence of genetic-oxidative DNA damage, indicating that dinotefuran can establish strong molecular interactions with DNA.

Shan, Yaohui; Liu, Xu; Ge, Wei; Zhang, Qifu; Yan, Sai

doi: 10.1177/07482337261445494pmid: 42041115

ObjectiveMitochondrial dysfunction is the key factor in rotenone-induced neurotoxicity in dopaminergic neurons. This study aimed to investigate the role and potential mechanism of the mitochondrial DNA encoded peptide Humanin (HN) in alleviating rotenone-induced neurotoxicity.MethodsRotenone was added to the cultured PC12 cells to induce neurotoxicity. PC12 cells were preincubated with HN, which has a protective effect. Cell counting kit-8 (CCK-8) was used to evaluate PC12 cell viability. Flow cytometry to detect the content of reactive oxygen species (ROS) in PC12 cells. Western blot analysis was used to detect the expression of superoxide dismutase 2 (SOD2), acetylated SOD (Ac-SOD), sirtuin 3 (SIRT3), nuclear factor erythroid 2-related factor 2 (Nrf2), heme-oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The corresponding kits were used to measure the NAD+/NADH ratio and SOD content separately.ResultsHN pretreatment significantly increased PC12 cell survival, reduced ROS formation, and increased the NAD+/NADH ratio. It also increased the expression of SIRT3, Nrf2, HO-1, and NQO1 proteins and decreased the expression of Ac-SOD protein under rotenone exposure. At the same time, it also activated the Nrf2/HO-1 signaling pathway, which depends on HN-mediated SIRT3 activation.ConclusionThese results suggest that HN plays a protective role in rotenone-induced neurotoxicity by suppressing oxidative stress and activating the antioxidant response via the Nrf2/HO-1 pathway, which is regulated by SIRT3 in PC12 cells.

Phetchahwang, Phichamon; Paricharttanakul, N. Monique; Lirdprapamongkol, Kriengsak; Svasti, Jisnuson

doi: 10.1177/07482337261461640pmid: N/A

Perfluorooctane sulfonate (PFOS) is a man-made chemical widely used in many products and acts as an endocrine-disrupting chemical (EDC). PFOS has spread to the environment through industrial manufacturing processes and disposal of PFOS-containing products. There is growing evidence that environmental pollutants may have promoting effects on cancer cell aggressiveness, rapid growth, and metastasis. Thyroid cancer is an endocrine-related cancer that can respond to EDCs. This study aimed to explore the effect of PFOS on the growth and metastatic potential (invasion capability) of FTC-133 human thyroid cancer cells. PFOS exposure for 72 h (1 pM to 10 µM) did not stimulate growth of FTC-133 cells. However, PFOS exposure at low concentration (1 nM) enhanced invasion capability of the cells, with no correlation to the expression level of estrogen receptors. FTC-133 cells exposed to 1 nM PFOS displayed increasing phosphorylation of multiple invasion-related signaling proteins, including Akt, ERK, and EphA2. Our study revealed that PFOS at low concentration may influence thyroid cancer progression by increasing the metastatic potential of cancer cells.