Methylmercury (MeHg) is a global pollutant that readily crosses the blood–brain barrier and placenta, posing significant risks to fetal neurodevelopment. While the cerebellum is a recognized target of MeHg toxicity in adults, the effect of fetal exposure remains poorly defined. In this study, we investigated the neurotoxic effects of low-dose MeHg exposure (0.2 ppm via drinking water) on the cerebellums of prenatal C57BL/6 mice using integrated transcriptomic and proteomic analyses. Cerebellar tissues collected from postnatal day 90–120 (P90–120) mice (n = 3/group) were processed for RNA sequencing and proteomics analysis. Differentially expressed genes (DEGs) and proteins (DEPs) revealed significant changes (n = 4/group) in multiple pathways associated with neurodegeneration, including Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Overlapping transcriptomic and proteomic findings identified potential underlying mechanisms such as chemical carcinogenesis driven by reactive oxygen species and retrograde endocannabinoid signaling, underscoring the central role of oxidative stress in MeHg-induced neurotoxicity. Collectively, these results indicate that prenatal MeHg exposure induces persistent molecular alterations consistent with neurodegenerative processes and synaptic dysfunction, despite the absence of overt behavioral changes at the time of sacrifice. The long-term consequences for delayed symptom onset and the potential contribution of these changes to the etiology of neurodevelopmental disorders warrant further investigation.

The causative agent of Minamata disease, which is characterized primarily by severe central nervous system dysfunction, is methylmercury; however, the mechanisms underlying methylmercury toxicity remain unclear. Ferroptosis is a type of programmed cell death that is mediated by iron-dependent lipid peroxidation and methylmercury has long been suggested to cause neuronal damage via lipid peroxidation, although the detailed mechanism of this action remains unknown. In this study we therefore investigated the involvement of ferroptosis in methylmercury-induced neuronal cell death using C17.2 mouse neural stem cells. First, we examined the effects of various ferroptosis inhibitors (ferrostatin-1, liproxstatin-1, and deferoxamine) on methylmercury-induced cell death. All the inhibitors tested attenuated methylmercury-induced cell death. We then examined the levels of intracellular reactive oxygen species and lipid peroxides, and found that these levels were increased prior to methylmercury-induced cell death. We also examined the levels of a cystine transporter (xCT/SLC7A11) and glutathione peroxidase 4 (GPX4), major factors involved in the suppression of ferroptosis. We found that both mRNA and protein levels of xCT were increased prior to methylmercury-induced cell death, whereas GPX4 mRNA levels were largely unaffected by methylmercury and its protein levels were decreased. C17.2 cells overexpressing FLAG-GPX4 exhibited greater resistance to methylmercury than control cells. These results indicate that methylmercury induces ferroptosis in C17.2 cells by suppressing GPX4 protein levels.

The global consumption of complementary and alternative medicine (CAM) has risen dramatically. However, safety concerns persist owing to contamination with elemental impurities. In this study, we optimized and validated an analytical method for quantifying four toxic metals, As, Cd, Pb, and Hg, in Yataprasen (YTPS) extract, a complex Thai traditional polyherbal formulation. Samples were obtained from natural collection sites and commercial sources, and the contributions of 13 individual herbs to total impurities were evaluated. Inductively coupled plasma mass spectrometry (ICP-MS) was applied following four acid-digestion protocols. Quantification involved external calibration and standard addition, with validation covering LOD, LOQ, linearity, precision, and recovery. Toxicological risk was assessed in accordance with the ICH Q3D(R2) guideline. Digestion with 1 mL of HNO₃ gave the highest accuracy and recovery. Cd and Pb levels showed little variation across methods. Validation demonstrated excellent accuracy (93.6–107.5% recovery), strong linearity (R² > 0.998), and low detection limits (<1.5 µg/kg). A significant difference in elemental impurity concentration was observed between the two sources, with the naturally collected YTPS exhibiting markedly higher levels of all four metals than the commercial one. While external calibration was sufficient for commercial samples, standard addition was required for naturally sourced samples to overcome matrix effects. Component analysis identified Allium sativum L., Cymbopogon nardus (L.) Rendle, and Melia azedarach L. as the major contributors to the impurity burden. Source-dependent variation in elemental impurity concentration was observed in YTPS extracts, with natural collection posing a greater toxicological concern. The validated analytical workflow provides a robust platform for quality control and regulatory assessment of traditional polyherbal formulations.

Cancer cachexia, characterized by progressive skeletal muscle loss, is common in advanced malignancies and correlates with poor prognosis. Cisplatin, a widely used chemotherapeutic, is linked to muscle atrophy, but its mechanisms remain unclear. Recent studies implicate endoplasmic reticulum (ER) stress in muscle disorders; however, its role in chemotherapy-induced muscle atrophy is unknown. This study examined the effects of five anticancer agents—cisplatin, 5-fluorouracil, vincristine, irinotecan, and cyclophosphamide—on mouse skeletal muscle. Quadriceps muscle mass, gene expression related to protein synthesis (IGF-1), degradation (MuRF1, atrogin-1), ER stress (Ddit3/CHOP, Atf4, sXbp-1), and inflammation (TNF-α, IL-1β, COX2) were analyzed. Despite similar body weight loss, cisplatin-treated mice showed a significant reduction in muscle mass compared to dietary-restricted controls. Only cisplatin upregulated MuRF1 and atrogin-1 and downregulated IGF-1. Inflammatory markers were unaffected. Notably, cisplatin induced ER stress genes Ddit3, Atf4, and sXbp1. These findings suggest cisplatin promotes muscle atrophy via ER stress activation and protein degradation, independently of reduced food intake or inflammation. Targeting ER stress may help prevent chemotherapy-induced muscle wasting. Further studies are needed to clarify mechanisms and develop protective strategies.

Over-the-counter (OTC) medicines are available without a prescription and are key to the promotion of self-medication. However, they also pose the risks of misuse, overdose, addiction, and abuse. These risks have recently emerged as global public health concerns. An important aspect of OTC drugs in Japan is that they are often combined with drugs with different effects. Although it has been noted that interactions between depressants and stimulants of the central nervous system (CNS) may promote drug dependence, the details remain unclear due to a lack of basic evidence. Therefore, an assessment was conducted to determine the interaction between CNS depressants, including dextromethorphan, diphenhydramine, and bromovalerylurea, and the CNS stimulant caffeine, by employing a conditioned place preference test in mice. Even at low doses, long-term administration of dextromethorphan and diphenhydramine induced place preference. Long-term administration of high-dose bromovalerylurea also induced this effect. The period required for dextromethorphan, diphenhydramine, bromovalerylurea, and morphine to acquire place preference was shortened by co-administration with caffeine, demonstrating that CNS stimulation enhances the preference of these sedatives in mice. Moreover, the preference for these drugs was suppressed by the dopamine D₁ receptor antagonist SCH23390, and by the dopamine D₂ receptor antagonist sulpiride, suggesting that dopamine is involved in the enhancing effect. These findings underscore the need to reconsider the active ingredients and distribution practices of OTC products, as the prolonged or inappropriate use of OTC medications and polypharmacy increases the risk of dependence.

Recently, α-mercuri-acetaldehyde (HgCH₂CHO) and α-mercuri-acetic acid (HgCH₂COOH) have been proposed as potential causative agents of Minamata disease. However, their toxicological profiles remain largely unknown. This study aimed to characterize the cytotoxicity, cellular uptake, and efflux mechanisms of these compounds in SH-SY5Y neuroblastoma cells and to compare these properties with those of methylmercury (MeHg). Cell viability was assessed after 24 hr of exposure to MeHg (1–10 µM), HgCH₂CHO (10–50 µM), or HgCH₂COOH (10–50 µM) using the CCK-8 assay. The roles of L-type amino acid transporter 1 (LAT1) and multidrug resistance-associated proteins (MRPs) were evaluated using the inhibitors JPH203 (1 µM) and MK571 (10 µM), respectively. Intracellular mercury accumulation was quantified after 24 hr of exposure to 3 µM of each compound using thermal decomposition-amalgamation atomic absorption spectrometry. All compounds exhibited dose-dependent cytotoxicity, with a relative toxicity order of MeHg (LC₅₀: 6.4 µM) > HgCH₂CHO (LC₅₀: 14.6 µM) > HgCH₂COOH (LC₅₀: 39.2 µM). LAT1 inhibition had minimal effect on MeHg toxicity but slightly attenuated that of HgCH₂CHO and HgCH₂COOH. Conversely, MRP inhibition markedly enhanced MeHg toxicity, modestly increased that of HgCH₂CHO, and slightly increased that of HgCH₂COOH. Cellular mercury accumulation was consistent with cytotoxicity patterns, showing 10–20-fold lower levels for HgCH₂CHO and HgCH₂COOH than for MeHg. HgCH₂CHO and HgCH₂COOH were approximately 2–5-fold less cytotoxic than MeHg and exhibited substantially lower intracellular mercury levels. Our findings suggest that HgCH₂CHO and HgCH₂COOH are unlikely to have neurotoxic potential comparable to that of MeHg.