The online version contains supplementary material available at 10.1007/s43188-026-00340-4.

Environmental pollutants, whether naturally occurring or manufactured for commercial use, are pervasive in modern ecosystems. Endocrine disruptors, particulate matter, and micro- and nanoplastics are especially concerning because of their ubiquity, persistence, resistance to degradation, and bioaccumulation. Their global dispersal enables widespread human exposure and poses systemic health risks. The brain, with limited antioxidant capacity and a lipid-rich composition, is highly vulnerable to pollutant-induced injury. It exhibits sex-dependent differences in neurotransmission, neuroanatomy, glial populations, and neuroinflammatory responses, which can shape susceptibility to environmental insults. Yet the direct effects of environmental toxicants on the brain remain incompletely defined, partly because many toxicology studies have used only male animals, lacked sex-stratified analyses, or omitted sex altogether. Converging evidence from epidemiological, animal, and cellular studies links pollutant exposure to sex-dependent neurotoxic outcomes spanning neurodevelopmental and neurodegenerative disorders and functional impairments, reflecting intrinsic differences between male and female brains. This review synthesizes current knowledge on sources and exposure routes of key pollutants-endocrine disruptors, particulate matter, and micro- and nanoplastics-along with their sex-dependent neurotoxic effects and underlying mechanisms. Recognizing sex-dependent vulnerabilities is essential to inform public health policies, targeted interventions, and regulatory strategies to prevent pollutant-associated brain diseases.

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, SAL) is a dopamine-derived tetrahydroisoquinoline, first identified in the urine of a Parkinson's disease patienttreated with L-DOPA. SAL is generated endogenouslyvia bothenzymatic and non-enzymatic Pictet-Spenglercondensation of dopamine with acetaldehyde. It is also found indietary sourcessuchas bananas, mushrooms, and cocoa, as well as in certain microbes. SALhas been detected in cerebrospinal fluid and various brain regions. SAL acts as a neuroactive compound implicated in ethanol's reinforcing effects and has been proposed as an endogenous prolactin-releasing factor. Its structural similarity to the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) haslong provokedsuspicions that SAL may inducedopaminergic neurodegeneration throughgeneration ofreactive oxygen species and subsequent activation ofcell death pathways. However, recent in vitro and in vivo studies reveal a biphasic profile: at low concentrations, SAL exerts neuroprotective effects, whereas at higher concentrations, it becomes neurotoxic. This review therefore summarizes differential pathophysiological roles of SAL based onexperimental and clinicalfindings, highlighting its context-specific, dose-dependent actions in the centralnervous system.

The online version contains supplementary material available at 10.1007/s43188-025-00316-w.

4-Methylbenzophenone (4-MBP), a derivative of benzophenone commonly utilized in consumer products, has elicited significant safety concerns due to its potential to migrate from food packaging materials and its structural similarity to known toxicants. This investigation sought to elucidate the toxicological profile of 4-MBP in female Sprague-Dawley rats following a 7-day repeated oral exposure to doses of 100, 200, and 400mg/kg. The results demonstrated pronounced toxicity, as evidenced by high mortality, decreased body weight, clinical signs of weakness, and increased relative liver weights. Biochemical analysis revealed significant elevations in liver enzymes (AST, ALT, and GGT), lipid dysregulation, and increased glucose levels, which are indicative of hepatic dysfunction. Histopathological examination confirmed hepatocyte hypertrophy and mild renal tubular vacuolation, suggesting hepatotoxicity and nephrotoxicity, respectively. Hematological findings further revealed a decrease in white blood cell counts and alterations in immune cell populations, indicating a compromised immune function. Notably, no significant pulmonary lesions were observed, suggesting organ-specific toxicity. This study provides critical insights into the toxic effects of 4-MBP, identifies hepatotoxic and nephrotoxic risks, and highlights the need for further investigation in the field of regulatory toxicology. The present findings are crucial for determining safe exposure limits and contributing to the regulatory assessment of 4-MBP safety and public health risks.

During drug development, it is crucial to ensure that a drug exhibits effective activity in its target cells and organs. However, regardless of its effectiveness, a drug cannot be administered to patients if it exhibits toxicity in vivo. Based on pharmacokinetics, most drugs are cleared from the liver after entering the body, and only the remaining fraction reaches the target organ to exert therapeutic effects. Consequently, drugs with in vivo toxicity often manifest hepatotoxicity as an initial sign. This highlights the critical importance of hepatotoxicity assessment in drug development. Currently, hepatotoxicity assessments primarily rely on animal models and primary human hepatocytes. However, there are instances in which drugs pass these evaluations, are released to the market, and are later withdrawn because of unforeseen toxicity in patients. To enhance prediction accuracy, emerging hepatotoxicity models—including advanced 3D liver culture systems, in silico approaches such as AI-based models, and improved in vitro assays—are gaining significant attention. This review systematically compares conventional 2D models, animal models, organ-on-a-chip systems, and computational models, highlighting their advantages, limitations, and predictive reliability. By critically evaluating these methodologies, we propose future directions for refining hepatotoxicity assessment strategies, with an emphasis on enhancing translational relevance, reducing reliance on animal testing, and integrating AI-driven predictive models.

Sargassum horneri is an edible brown seaweed used as traditional medicine in various East Asian countries, such as China and Korea. Its therapeutic effects, including antioxidant and anti-inflammatory activities, have been reported in animal models of respiratory diseases and allergic disorders. However, its specific effects on liver health remain ambiguous. Therefore, in this study, we aimed to examine the effects of S. horneri extract (SHE) on acetaminophen (APAP)-induced hepatotoxicity, a common clinical cause of drug-induced liver injury. SHE-pretreated male mice were injected with a high dose of APAP. SHE alleviated APAP-induced liver injury and inhibited lipid peroxidation and glutathione (GSH) depletion. It also enhanced the hepatic total antioxidant capacity in APAP-treated mice, exhibiting direct radical scavenging activity against APAP-induced oxidative stress. Levels of the hepatic antioxidant enzymes, superoxide dismutase-1/2 and GSH peroxidase 1, were unaffected by SHE; however, catalase levels decreased by APAP were restored by the extract. Protein levels of the APAP-metabolizing enzymes, uridine 5'-diphospho-glucuronosyltransferase 1a6, sulfotransferase 1a1, GSH S-transferase a1, cytochrome P450 (Cyp)-1a2, Cyp2e1, and Cyp3a, were unaffected; however, Cyp1a activity was reduced by SHE. Plasma concentrations of APAP-GSH and APAP-cysteine conjugates were reduced by SHE in APAP-treated mice, indicating that SHE alleviates APAP hepatotoxicity by inhibiting Cyp1a-mediated metabolic activation of APAP. In conclusion, our results suggest that the increase in cellular antioxidant capacity and inhibition of APAP bioactivation are possible mechanisms underlying the hepatoprotective effects of SHE against high-dose APAP-induced acute liver injury.

Assessment of toxicity and efficacy in the nervous system is essential to ensure the safety of compounds and the efficacy of neurotherapeutics. Recently, technologies using neural organoids to mimic the structural and functional properties of human brain tissue have been developed to improve our understanding of human-specific brain development and to model neurodevelopmental disorders. This approach offers the potential for standardized toxicity testing and large-scale drug screening at the organ level. Here, we review recent advances in neural organoids and explore the possibility of establishing more accurate and efficient systems for toxicological screening applications. Our review provides insights into toxicity and efficacy assessment research using neural organoids.

Bacterial vaginosis (BV) isa microbial dysbiosis that shifts the paradigms of vaginal flora from lactobacilli to opportunistic pathogens. Globally, BV is treated with antibiotic therapy and recurrence rates are > 70% occurring within 6months due to antibiotic resistance against pathogenic bacteria. An incorporation of lactobacilli orally or intravaginally for the recolonization of healthy microbes in vagina is the suggested course of treatment. Although Lactobacilli are suggested as a novel therapeutic for women's BV, evaluation of safety and toxicity have not been well understood previously. Therefore, in this study, we aimed to evaluate the safety profile of Lactobacillus plantarum ATG-K2 in subacute intravaginal animal toxicity in Sprague-Dawley rats under OECD guidelines and GLP regulations. Toxicological assessments were performed in a single-dose toxicity study by intravaginal administration with local tolerance study, 1-week repeated-dose intravaginal toxicity dose range finding (DRF) study, and a 2-week repeated-dose intravaginal toxicity study with a 2-week recovery period. Studies were performed at dose 3-18 × 109CFU/head/day. No toxicological changes in clinical signs, body weight, water and food consumption, urinalysis, hematology, clinical biochemistry, gross findings, or histopathological examination were observed in intravaginal repeated-dose toxicity. And Lactobacillus plantarum ATG-K2 did not show any local tolerance at the same doses as the intravaginal repeated-dose toxicity study. In conclusion, the no-observed-adverse-effect level (NOAEL) of Lactobacillus plantarum ATG-K2 was 12 × 109CFU/head/day and no target organ was identified in female rats. Our findings are the first to suggest that Lactobacillus plantarum is safe for use as an intravaginal treatment with no adverse effects observed in toxicological testing and has potential for application as a therapeutic agent or for other biological uses.