Chemical Research in Toxicology最新文献

{"title":"Uncovering the Hidden Risks: How PLA and PLGA Microplastics Disrupt Gut Microbiota and Metabolic Health","authors":"Bei Gao,&nbsp;Lixia Chen,&nbsp;Weichen Xu,&nbsp;Guangyuan Liu,&nbsp;Mengru Wei,&nbsp;Weishou Shen,&nbsp;Pengcheng Tu and Jinjun Shan*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00556","DOIUrl":"10.1021/acs.chemrestox.5c00556","url":null,"abstract":"<p >Biodegradable plastics are often promoted as an eco-sustainable alternative to conventional polymers. However, their potential to degrade into microplastics still poses significant health risks. Commonly used materials such as polylactic acid (PLA) and poly(lactic-<i>co</i>-glycolic acid) (PLGA) have been widely adopted across various industries. While the toxicity of PLA microplastics has been studied extensively, the biological effects of PLGA microplastics remain largely unknown. Through metagenomic sequencing and untargeted metabolomic profiling, we evaluated the impacts of both PLA and PLGA microplastics on gut bacteria, fungi, virulence factors, microbial metabolic pathways, and metabolites in feces, serum, and liver tissue in this study. Our results demonstrate that both types of biodegradable microplastics disrupt gut microbiota and host metabolic homeostasis. PLA exposure provoked more pronounced changes in gut bacteria, fungi, virulence factors, and fecal and hepatic metabolites. In contrast, microbial metabolic pathways and serum metabolites were more strongly affected by PLGA. Several altered features were common to both microplastics, including enrichment of hepatic metabolic pathways related to valine, leucine, and isoleucine biosynthesis; one-carbon pool by folate; glycine, serine, and threonine metabolism; pantothenate and CoA biosynthesis; taurine and hypotaurine metabolism; and cysteine and methionine metabolism. Other disturbances were material-specific, such as UMP biosynthesis pathways, which were altered exclusively by PLA, while palmitate biosynthesis and unsaturated fatty acid biosynthesis were affected only by PLGA. These findings advance our understanding of the distinct and shared health risks posed by different biodegradable microplastics, providing a clearer basis for assessing their long-term safety.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1302–1310"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the Reactive Metabolites of Colony-Stimulating Factor 1 Receptor Inhibitor PLX5622 in Liver Microsomes and Mice","authors":"Shenzhi Zhou,&nbsp;Thomas Lee,&nbsp;Xingyu Ji,&nbsp;Kevin R. Mackenzie and Feng Li*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00282","DOIUrl":"10.1021/acs.chemrestox.6c00282","url":null,"abstract":"<p >Colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase involved in cell growth and differentiation, particularly in macrophages and microglia. CSF1R inhibitors are under investigation for various diseases, including cancer, autoimmune/inflammatory diseases, and neurodegenerative disorders. PLX5622 is a highly specific, brain-penetrant, and orally bioavailable CSF1R inhibitor that is being evaluated in a clinical trial for rheumatoid arthritis and considered as an attractive candidate for the treatment of Alzheimer’s disease (AD). Drug metabolism significantly influences both the efficacy and safety of therapeutic agents. In particular, bioactivation leading to the formation of reactive metabolites is often implicated in adverse drug effects. In this study, we investigated the metabolism and potential bioactivation of PLX5622 in mouse and human liver microsomes (MLM/HLM) and mice using LC-MS-based metabolomic approaches. Reduced glutathione (GSH) and methoxyamine (NH₂OMe) were used to capture reactive intermediates. In total, 12 PLX5622-GSH adducts and five NH₂OMe adducts were identified in both HLM and MLM, along with 22 nontrapped metabolites generated from demethylation, hydroxylation, and carbon–carbon cleavage reactions. PLX5622-GSH-related adducts in mice were also assessed and 8 GSH adducts were detected in mouse liver, confirming the occurrence of bioactivation in vivo. Using recombinant human cytochrome P450 (CYP) enzymes and selective chemical inhibitors in liver microsomes, CYP3A was determined to be the primary enzyme responsible for the metabolic activation of PLX5622. These insights into the metabolic pathways of PLX5622 are valuable for further study of its safety and potential drug interactions of CYP3A. Future studies using human primary hepatocytes or physiologically human-relevant models such as liver-on-a-chip systems are warranted to confirm clinical relevance and better predict in vivo outcomes.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1450–1461"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACSS2 Inhibition Alleviates Cisplatin-Induced Acute Kidney Injury: Insights from Targeted Metabolomics","authors":"Wanting Chen,&nbsp;Xian Zhao,&nbsp;Jiaxin Zheng,&nbsp;Zhiru Zheng,&nbsp;Fengxia Qin,&nbsp;Zunjian Zhang,&nbsp;Fengguo Xu* and Pei Zhang*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00148","DOIUrl":"10.1021/acs.chemrestox.6c00148","url":null,"abstract":"<p >Cisplatin (DDP) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent nephrotoxicity. Although metabolic dysregulation is a hallmark of DDP-induced acute kidney injury (AKI), the specific changes in fatty acid oxidation (FAO)-associated metabolic programs and the enzymes linking metabolic disturbances to cell death remain incompletely defined. In this study, targeted metabolomic profiling of the kidney revealed a marked blockade of FAO, evidenced by the accumulation of fatty acids and a decrease in downstream acylcarnitines. Among FAO-related enzymes, acyl-CoA synthetase short-chain family member 2 (ACSS2) emerged as the most significantly downregulated enzyme, which was further confirmed in an ischemia/reperfusion AKI model. ACSS2 overexpression in HK-2 cells aggravated DDP-induced inflammation and apoptosis, whereas ACSS2 knockdown significantly reduced cytotoxicity and pro-inflammatory cytokine production. Furthermore, pharmacological inhibition of ACSS2 in vivo alleviated DDP-induced AKI characterized by reduced oxidative stress and improved renal function. Together, these findings indicate that targeting ACSS2 may represent a promising therapeutic strategy to mitigate DDP-induced renal injury.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1377–1388"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiparametric and Pathomimetic In Vitro Platform Mimicking Human Hepatic Steatosis, Lipotoxicity, and Associated Metabolic Stress","authors":"Jyoti Sharma,&nbsp; and ,&nbsp;Priyankar Dey*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00049","DOIUrl":"10.1021/acs.chemrestox.6c00049","url":null,"abstract":"<p >Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatocellular lipid accumulation and lipotoxicity. However, there are currently limited well-characterized <i>in vitro</i> models that mimic these early pathogenic mechanisms in terms of molecular and metabolomic features. Here, we developed a customized fatty acid conjugate that facilitates efficient lipid accumulation in the cultured hepatocytes without loss of viability. This conjugate reflects the prominent fatty acids found in the serum of patients with chronic metabolic syndrome, MASLD. This conjugate consistently induces the formation of steatotic bodies in HepG2 cells within a short exposure. The model was validated using a comprehensive analytical framework that measured inflammatory markers (e.g., iNOS, TNF-α, IL-6, IL-1β, and MCP-1), alongside intracellular triglyceride and cholesterol accumulation, intracellular oxidative stress, and lipid peroxidation. The lipid conjugate significantly alters hepatocellular metabolism, as observed by intracellular untargeted metabolomic profiling. The mRNA expression of hepatocellular lipogenic genes (e.g., CD26, SERBP, FASN, SCD5, DAGT1/2) was elevated, indicating impaired lipid homeostasis under lipotoxic conditions. Pathway analysis revealed enrichment of metabolic pathways related to steroid and bile acid biosynthesis, as well as glycerolipid metabolism, consistent with compensatory lipid-metabolism responses. These coordinated metabolic changes confirm that the early MASLD-like metabolic phenotype is recapitulated in this <i>in vitro</i> model. Collectively, these results confirm this fatty acid conjugate as a physiologically relevant <i>in vitro</i> model for MASLD, suitable for therapeutic screening and mechanistic research.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1334–1348"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148255808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoplastics at the Placenta–Fetal Interface: Emerging Chemical Toxicology Concerns","authors":"Rasin Puthiyavalappil*,&nbsp;Praveena Prabhakaran and Jebiti Haribabu,&nbsp;","doi":"10.1021/acs.chemrestox.6c00015","DOIUrl":"10.1021/acs.chemrestox.6c00015","url":null,"abstract":"<p >The interaction of nanoplastics with trophoblasts can potentially disrupt fetal development. The additives associated with nanoplastics, their surface chemistry, and protein corona may lead to oxidative stress and affect the cellular functions. Detailed studies revealing a clear mechanism using an advanced placental model is essential to assess developmental toxicity and guide risk assessment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1267–1269"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting Aquatic Species Sensitivity Distributions Using Machine Learning in a Regulatory Setting","authors":"Jordi Minnema,&nbsp;Markus Viljanen,&nbsp;Emiel Rorije,&nbsp;Willie J.G.M. Peijnenburg and Pim N. H. Wassenaar*,&nbsp;","doi":"10.1021/acs.chemrestox.5c00466","DOIUrl":"10.1021/acs.chemrestox.5c00466","url":null,"abstract":"<p >The assessment of chemical risks is increasingly challenged by insufficient toxicological data available for the large number of marketed substances. Recent advancements in artificial intelligence (AI) and machine learning (ML) offer promising avenues to bridge these data gaps through model-based predictions. However, the integration of these methodologies into risk assessment practices remains limited, largely due to issues surrounding (regulatory) trust in the model outcomes. We developed an ML model to predict the ecotoxicity of chemicals across a broad range of aquatic species. These predictions are utilized to construct Species Sensitivity Distributions (SSDs), which constitute a key tool in environmental risk assessment. Trust of risk assessors in the SSDs is essential for use in chemical risk assessment, especially for modeled SSDs. Hence, besides quantitative performance evaluation, we also performed an extensive qualitative validation encompassing aspects such as interpretability and transparency. However, to truly advance the development of ML models for risk assessment, it is crucial to foster interdisciplinary collaboration to enhance the applicability of these technologies within regulatory frameworks. Therefore, this study emphasizes the importance of regulatory acceptance when developing new ML models for SSD predictions. We highlight future opportunities for ML in SSD prediction, while also addressing the challenges of qualitative model validation. As such, this work aims to stimulate the discussion on advancing in silico methodologies beyond the current state of the art and bridging the gap between the technological efforts made in the field of AI and the regulatory needs of chemical risk assessors.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1288–1301"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.5c00466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"20-Hydroxyeicosatetraenoic Acid Ameliorates Nickel Nanoparticle-Induced Epithelial-Mesenchymal Transition by Modulating the FFAR1/NF-kB Pathway","authors":"Jiali Yuan,&nbsp;Huihui Yang,&nbsp;Shuai Zhang,&nbsp;Zhenyu Yan,&nbsp;Jing Li,&nbsp;Yiqun Mo,&nbsp;Qunwei Zhang and Zhenyao Huang*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00048","DOIUrl":"10.1021/acs.chemrestox.6c00048","url":null,"abstract":"<p >Nickel nanoparticles (Nano-Ni) are widely utilized in industrial and biomedical applications due to their unique physicochemical properties. However, their expanded usage increases risks of occupational and environmental exposure. In this study, we established a mouse exposure model via single intratracheal instillation of Nano-Ni and analyzed the perturbation characteristics of lung tissue metabolic profiles using untargeted metabolomics. Subsequently, the biological function of the key metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) was explored in Nano-Ni-exposed lung epithelial cells to elucidate the underlying mechanisms of metabolic alterations in Nano-Ni-induced pulmonary fibrosis. Our results showed that exposure to Nano-Ni induced marked alveolar architecture destruction, interstitial thickening, and upregulated expression of fibrotic markers in mouse lung tissues. Metabolomics identified arachidonic acid metabolism as the most disrupted pathway, with 20-HETE exhibiting the most pronounced downregulation. In both BEAS-2B and A549 cell lines, exogenous 20-HETE supplementation significantly attenuated Nano-Ni-induced epithelial-mesenchymal transition (EMT). Furthermore, Nano-Ni exposure reduced mRNA and protein levels of free fatty acid receptor 1 (FFAR1) both in vivo and in vitro. Pretreatment with the FFAR1 agonist GW9508 mitigated Nano-Ni-induced EMT and the activation of NF-κB signaling pathway in both cell lines. Critically, FFAR1 inhibition largely abolished the suppressive effects of 20-HETE on EMT and NF-κB signaling. Altogether, our study suggests that 20-HETE may affect the EMT process in lung epithelial cells at least in part through regulating the FFAR1/NF-κB pathway, thereby potentially contributing to the process of Nano-Ni-induced lung fibrosis. These findings point to a possible role of specific metabolites in Nano-Ni-induced pulmonary fibrosis and may provide novel mechanistic insights into the inhalation toxicity of nanomaterials.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1320–1333"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"pH Tunes the DNA Repair Efficiency and Strand Preference of the AlkB Family Enzymes","authors":"Samuel D. Howarth,&nbsp;Quentin J. Mylie,&nbsp;Evans Boateng-Boakye,&nbsp;Vincent Falkowski,&nbsp;Ambar Oliver Mella,&nbsp;Rafael Fermin,&nbsp;Zhiyuan Peng,&nbsp;Xin Bush,&nbsp;Yi-Tzai Chen,&nbsp;Jian Ma,&nbsp;Bongsup Cho and Deyu Li*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00202","DOIUrl":"10.1021/acs.chemrestox.6c00202","url":null,"abstract":"<p >AlkB-family Fe(II)/2-oxoglutarate-dependent dioxygenases repair alkylated nucleic acid lesions through oxidative dealkylation and play important roles in genome maintenance. 1-Methyl-2′-deoxyadenosine (1mA) and 3-methyl-2′-deoxycytidine (3mC) are well-established substrates of AlkB, ALKBH2, and ALKBH3. Although these enzymes have been extensively studied, the influence of proton concentration (pH) on their catalytic behavior and strand preference remains poorly defined. Here, we systematically examined how pH modulates the activity of the prototypical bacterial AlkB and the human homologues ALKBH2 and ALKBH3 using defined DNA substrates in both single-stranded (ssDNA) and double-stranded (dsDNA) contexts containing 1mA and 3mC lesions. Across a broad pH range, all three enzymes mainly exhibit bell-shaped activity profiles with distinct optima. The prevailing view in the field is that AlkB preferentially repairs these lesions in ssDNA, ALKBH2 favors dsDNA, and ALKBH3 prefers ssDNA. However, our results demonstrate that pH influences the catalytic efficiency and strand utilization in a substrate- and enzyme-dependent manner. AlkB maintains a consistent ssDNA preference for 3mC but exhibits variable strand preference for 1mA at different pH values. ALKBH2 retains a strong dsDNA preference for 1mA across all conditions but shows a clear pH-dependent strand switch for 3mC, favoring ssDNA under acidic conditions and preferring dsDNA at neutral to alkaline pH conditions. In contrast, ALKBH3 consistently favors ssDNA for 3mC but exhibits pH-dependent strand preference for 1mA. Our results show that the reported strand preferences largely hold at pH 7.0–8.0 but are not complete, as strand utilization and pH optima vary by enzyme and substrate. The observations demonstrate that proton availability strongly influences AlkB-family catalysis and is an important factor in how these enzymes process damaged DNA. These findings may also aid the optimization of AlkB-based protein engineering and sequencing technologies.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1418–1430"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.6c00202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitation of E-Cigarette Aerosol Mass in Liquid Impinger Solution Using the 13C of E-Liquids: Application for Metal Analyses","authors":"Mark R. Salazar,&nbsp;Tran B. Nguyen and Brett A. Poulin*,&nbsp;","doi":"10.1021/acs.chemrestox.6c00163","DOIUrl":"10.1021/acs.chemrestox.6c00163","url":null,"abstract":"<p >Liquid impingers, i.e., bubbling gaseous or aerosol samples through a liquid-based collection solution, are often used in electronic cigarette (e-cigarette) research to capture aerosols for metal analysis. However, a key limitation is the accurate quantitation of the mass of aerosol collected in the impinger solution for metal data normalization, which is necessary for comparison with prevaped e-liquid metal concentrations and for comparison across studies. To address this gap, we developed a novel approach to quantitate collected aerosol mass in a simple liquid impinger by leveraging the carbon-13 (¹³C) of aerosolized e-liquids, which enabled the parallel determination of aerosol mass and metal concentration by inductively coupled plasma mass spectrometry (ICP-MS). The method demonstrated low limits of detection and quantitation, excellent solution stability (≤4 months), and high accuracy and precision across spiked quality control samples, diverse e-liquid formulations, and multiple aerosol collection techniques (84.4–101% recovery with ≤4.6% relative percent deviation). Compared with an aerosol condensate collection method, the liquid impinger was equally effective at collecting metals, with metal concentrations on a mass-per-puff (ng/puff) basis within ∼7% for chromium (Cr), nickel (Ni), iron (Fe), copper (Cu), zinc (Zn), antimony (Sb), and lead (Pb). Aerosol metal concentrations on a mass-per-mass basis (ng/g) quantified using the ¹³C-derived aerosol mass from the liquid impinger were strongly correlated with (R² ≥ 0.97) but consistently greater than those from the condensate collection approach, due to differences in aerosol collection efficiency between methods. The liquid impinger enabled parallel aerosol mass and metal quantitation, offering a new approach for future e-cigarette aerosol studies, with potential application for investigations into future liquid impinger collection optimizations, e-liquid-to-aerosol metal transfer, and redox-sensitive speciation (e.g., Fe, Cu, Cr, Sb).</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"39 7","pages":"1400–1409"},"PeriodicalIF":4.1,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Exposure to Environmentally Relevant Palladium Nanoparticles Reprograms Oxidative, Reproductive, and Genomic Stress Pathways in Zebrafish (<i>Danio rerio</i>).","authors":"Anila Pottanthara Ashokan, Murugesh Eswaran, Thiruppathi Govindhan, Ramesh Mathan","doi":"10.1021/acs.chemrestox.6c00021","DOIUrl":"10.1021/acs.chemrestox.6c00021","url":null,"abstract":"<p><p>Palladium nanoparticles (Pd NPs), extensively used in automobile catalytic converters, are increasingly released into the environment and represent an emerging nanopollution concern for aquatic ecosystems. This study examined the chronic effects of environmentally relevant Pd NP exposure on the freshwater vertebrate model <i>Danio rerio</i>, integrating bioaccumulation analysis, oxidative stress profiling, histopathology, and bulk RNA-seq transcriptomics with computational cell-type inference analyses. Adult zebrafish were exposed for 42 days to low (0.4 ng/L) and high (22 ng/L) Pd NP concentrations. Inductively coupled plasma-mass spectrometry confirmed dose-dependent Pd bioaccumulation in whole-body tissues. Biochemical analyses indicated a disruption of gonadal redox homeostasis, characterized by altered activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and lipid peroxidation, indicating sustained oxidative stress. Histological examination of ovaries and testes demonstrated progressive structural damage, including follicular atresia, delayed oocyte maturation, and impaired spermatogenesis, highlighting reproductive vulnerability. Transcriptomic profiling showed concentration-dependent transcriptional changes under Pd NP exposure, including reduced expression of mitochondrial energy metabolism genes and increased expression of DNA repair, cell cycle regulation, steroid biosynthesis, and stress-response pathways. High-dose Pd exposure strongly increased the expression of cell cycle and stress-response genes, including ccnb1 (41 to 8296 TPM), cdc25b (41 to 1937 TPM), and tp53 (110 to 604 TPM), while mitochondrial energy metabolism genes were consistently suppressed. Notably, <i>PI3K</i>-<i>AKT</i>-<i>mTOR</i>, <i>p53</i>, and cell cycle signaling axes exhibited biphasic regulation, reflecting compensatory and maladaptive stress responses. This study identifies potential ecological and human health risks associated with palladium nanoparticle dispersal and emphasizes the need for safer catalyst design and stricter environmental management of platinum group nanoparticles.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}