Humans rely heavily on visual function to gather information, and loss of vision has a significant impact on quality of life. However, it is difficult to quantitatively evaluate the effects of chemical compounds on visual function in toxicity studies using animals (such as OECD guideline studies). Consequently, evaluation including ophthalmological and histopathological examinations has played a major role to date. Visually evoked potential (VEP) is a type of brain wave that reflects the activity of the entire visual pathway, including the retina, optic nerve, and visual cortex. We investigated whether VEP could detect the effects of acrylamide, a toxicant known to affect peripheral nerves, on visual function. Acrylamide was administered to rats via drinking water at concentrations of 0 (control) and 200 ppm for 4 weeks, and electroretinograms (ERGs) and VEPs were recorded at weeks 0, 2, and 4. After the 4-week treatment period, the eyes and optic nerves were examined by light microscope. Acrylamide exposure significantly delayed VEP latency, while no effects were observed on the retina and optic nerve by ERG or histopathology. A significant decrease in grip strength in the hindlimbs and degeneration of sciatic nerve fibers were observed in the acrylamide-treated group, indicating that acrylamide damaged peripheral nerves. In conclusion, our study demonstrated that VEP can detect the effects of acrylamide on visual function earlier than histopathological examination, suggesting that VEP could be useful for detecting early-phase effects of chemical compounds on visual function and for evaluating whether morphological changes observed in toxicity studies are toxicologically significant.

OE₂imC₃C, a zwitterionic ionic liquid, has attracted considerable attention as a low-toxicity solvent. However, the effects of OE₂imC₃C on the pharmacokinetics of drugs have not yet been investigated. In this study, we examined the effects of OE₂imC₃C on p-glycoprotein (P-gp) and cytochrome P450 (CYPs), typical factors associated with pharmacokinetic interactions. No notable inhibition of P-gp by OE₂imC₃C was observed at the tested concentrations. OE₂imC₃C inhibited several CYPs (IC₅₀:0.048–0.66 vol% for 70 wt% aq OE₂imC₃C stock solution) and induced the gene expression of several CYPs. Based on these findings, practical guidance for the use of OE₂imC₃C was proposed here. A previous study suggested that OE₂imC₃C does not penetrate the cell membrane, and therefore, we had hypothesized that it does not inhibit CYPs inside cells. However, OE₂imC₃C inhibited CYPs. The related transporter was assumed to be organic cation transporter 1 (OCT1). These results suggest that OE₂imC₃C effect on CYPs should be considered in both in vitro and in vivo experiments. The CYP inhibition was alleviated through structural modification of OE₂imC₃C.

Methylmercury (MeHg) is a potent environmental toxicant that frequently coexists with other heavy metals, raising concerns about combined toxic effects. Increasing evidence indicates that co-exposure to multiple metals can lead to synergistic or greater-than-additive effects; however, the molecular mechanisms underlying such interactions remain poorly understood. Among the tested metals, only co-exposure with Cd markedly enhanced MeHg cytotoxicity. Here, our objective was to evaluate the impact of MeHg co-exposure on cytotoxicity of various heavy metals in HeLa cells. We used cell viability assays, western blot analysis, and reverse-transcription-quantitative polymerase chain reactions to determine toxicity. Co-treatment with MeHg significantly reduced cell viability compared with that of Cd alone. Mechanistically, MeHg suppressed nuclear factor erythroid 2-related factor 2 (NRF2) expression more strongly at earlier time points than Cd alone, thereby impairing antioxidant and detoxification responses. This suppression was accompanied by increased intracellular mercury (Hg) retention, leading to enhanced cytotoxicity. Our results provide a mechanistic basis for metal–metal interactions and highlight the importance of considering co-exposure scenarios in environmental risk assessment.

Cytochrome P450s (P450s) are essential for xenobiotic metabolism, and their inhibition is associated with chemical-induced liver toxicity. While qualitative associations between P450 inhibition and hepatotoxicity have been reported, the quantitative relationship between the degree of inhibition and the severity of hepatotoxicity remains unclear. In this study, we explored the quantitative association between P450 inhibition and hepatotoxicity using lowest observed effect levels (LOELs) from rat repeated-dose toxicity (RDT) studies on 326 chemicals. Inhibitory activities against seven rat P450 isoforms were compared between compounds positive and negative for six liver-related group endpoints (gEPs). The results revealed that inhibitory activity against CYP1A1, CYP2B1, CYP2C6, and CYP3A2 was significantly higher in compounds positive for hepatocellular hypertrophy or dyslipidemia than in negative compounds. Although regression analyses did not show clear linear relationships between P450 inhibition and LOELs, nonparametric trend tests revealed modest monotonic associations, with increased P450 inhibition corresponding to lower LOELs. To identify structural factors influencing inhibition among highly toxic compounds, we compared molecular descriptors between those exhibiting strong or weak P450 inhibition. Descriptors related to aqueous solubility, Verhaar baseline toxicity, and structural complexity were consistently higher in the weak-inhibition group across multiple P450–gEP combinations. These findings suggest that inhibition of CYP1A1, CYP2B1, CYP2C6, and CYP3A2 partly contributes to the severity of hepatocellular hypertrophy and dyslipidemia, whereas highly toxic compounds with low P450 inhibition may exert their toxicity through P450-independent mechanisms.