Toxicological Sciences最新文献

Metabolic syndrome is increasing worldwide, particularly in rural communities, where residents have a higher risk of exposure to pesticides. We investigated whether six commonly used agricultural pesticides on corn and soy fields possess adipogenic and metabolic disruption activity. Exposure to two of these pesticides, the herbicides acetochlor and metolachlor, induced adipogenesis in vitro in mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure induced morphological malformations and lethality in zebrafish larvae with an EC50 of 7.8 µM and LC50 of 12 µM. Acetochlor exposure at 10 nM resulted in lipid accumulation in zebrafish larvae when simultaneously fed a high cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we preformed transcriptomic and lipidomic analysis of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consistent with this prediction, Gpx activity was efficiently repressed by acetochlor in zebrafish, whereas lipid peroxidation was increased. We propose that acetochlor disrupts lipid homeostasis by inhibiting Gpx activity, resulting in accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contain the chloroacetamide group, inhibition of Gpx activity may represent a novel, common molecular initiating event of metabolic disruption.

Air pollution, particularly fine particulate matter with an aerodynamic diameter of ≤ 2.5 μm (PM2.5), has been recognized for its adverse effects on multiple organs beyond the lungs. Among these, the bone began to garner significant attention. This review covers epidemiological, animal and cell studies on PM2.5 exposure and bone health as well as studies on PM2.5-induced diseases with skeletal complications. Emerging evidence from epidemiological studies indicates a positive association between PM2.5 exposure and the incidence of osteoporosis and fractures, along with a negative association with bone mineral density. Experimental studies have demonstrated that PM2.5 can disrupt the metabolic balance between osteoclasts and osteoblasts through inflammatory responses, oxidative stress, and endocrine disruption, thereby triggering bone loss and osteoporosis. Additionally, this review proposes a secondary mechanism by which PM2.5 may impair bone homeostasis via pathological alterations in other organs, offering new perspectives on the complex interactions between environmental pollutants and bone health. In conclusion, this contemporary review underscores the often-overlooked risk factors of PM2.5 in terms of its adverse effects on bone and elucidates the mechanisms of both primary and secondary toxicity. Further attention should be given to exploring the molecular mechanisms of PM2.5-induced bone impairment and developing effective intervention strategies. With global climate change, increasing ozone pollution, emerging pollutants, and multifactorial exposure to environmental factors, these issues are likely to become of greater concern in the near future.

Drug-induced liver injury (DILI) is the most common trigger for acute liver failure and the leading cause of attrition in drug development. In this study, we developed an in silico framework to screen drug-induced hepatocellular toxicity (INSIGHT) by integrating the post-treatment transcriptomic data from both rodent models and primary human hepatocytes. We first built an early prediction model using logistic regression with elastic net regularization for 123 compounds and established the INSIGHT framework that can screen for drug-induced hepatotoxicity. The 235 signature genes identified by INSIGHT were involved in metabolism, bile acid synthesis, and stress response pathways. Applying the INSIGHT to an independent transcriptomic dataset treated by 185 compounds predicted that 27 compounds show a high DILI risk, including zoxazolamine and emetine. Further integration with cell image data revealed that predicted compounds with high DILI risk can induce abnormal morphological changes in the endoplasmic reticulum and mitochondrion. Clustering analysis of the treatment-induced transcriptomic changes delineated distinct DILI mechanisms induced by these compounds. Our study presents a computational framework for a mechanistic understanding of long-term liver injury and the prospective prediction of DILI risk.

Emerging epidemiological evidence indicates perfluorooctane sulfonic acid (PFOS) is increasingly associated with asthma and respiratory viral infections. Animal studies suggest PFOS disrupts lung development and immuno-inflammatory responses, but little is known about the potential consequences on respiratory health and disease risk. Importantly, PFOS exposure during the critical stages of lung development may increase disease risk later in life. Thus, we hypothesized that developmental PFOS exposure will affect lung inflammation and alveolar/airway development in a sex-dependent manner. To address this knowledge gap, timed pregnant Balb/cJ dams were orally dosed with a PFOS (1.0 or 2.0 mg/kg/d) injected mealworm or a vehicle control daily from gestational day (GD) 0.5 to postnatal day (PND) 21, and offspring were sacrificed at PND 22-23. PFOS-exposed male offspring displayed increased alveolar septa thickness. Occludin was also downregulated in the lungs after PFOS exposure in mice, indicative of barrier dysfunction. BALF macrophages were significantly elevated at 2.0 mg/kg/d PFOS in both sexes compared with vehicles, whereas BALF cytokines (TNF-α, IL-6, KC, MIP-1α, MIP-1β, and MCP-1) were suppressed in PFOS-exposed male offspring compared with vehicle controls. Multiplex nucleic acid hybridization assay showed male-specific downregulation of cytokine gene expression in PFOS-exposed mice compared with vehicle mice. Overall, these results demonstrate PFOS exposure exhibits male-specific adverse effects on lung development and inflammation in juvenile offspring, possibly predisposing them to later-in-life respiratory disease. Further research is required to elucidate the mechanisms underlying the sex-differentiated pulmonary toxicity of PFOS.

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established 3D human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels. This approach enabled the measurement of concentration responses and margins of exposure for 2 physiologically relevant metrics of proarrhythmic risk (i.e. action potential duration and triangulation assessed by optical mapping) across concentrations spanning 3 orders of magnitude. The combination of both metrics enabled accurate proarrhythmic risk assessment of 4 compounds with a range of known proarrhythmic risk profiles (i.e. quinidine, cisapride, ranolazine, and verapamil) and demonstrated close agreement with their known clinical effects. Action potential triangulation was found to be a more sensitive metric for predicting proarrhythmic risk associated with the primary mechanism of concern for pharmaceutical-induced fatal ventricular arrhythmias, delayed cardiac repolarization due to inhibition of the rapid delayed rectifier potassium channel, or hERG channel. This study advances human-induced pluripotent stem cell-based 3D cardiac tissue models as new approach methodologies that enable in vitro proarrhythmic risk assessment with high precision of quantitative metrics for understanding clinically relevant cardiotoxicity.