Toxicological Sciences最新文献

{"title":"Integration of human microbiota (SIHUMIx) and zebrafish models reveals microbiome-mediated host responses to azoxystrobin.","authors":"Chloe Wray, Victor Castañeda-Monsalve, Beatrice Engelmann, Ulrike E Rolle-Kampczyk, Nicole Schweiger, Sebastian Gutsfeld, Debjyoti Ghosh, Siraz Kader, Charles R Tyler, Nico Jehmlich, Tamara Tal","doi":"10.1093/toxsci/kfag022","DOIUrl":"10.1093/toxsci/kfag022","url":null,"abstract":"<p><p>The gut microbiome is essential for neurodevelopment via bidirectional gut-brain axis signaling, yet environmental chemicals can potentially disrupt this communication by altering community structure and xenobiotic metabolism. In this study, we investigated whether the fungicide azoxystrobin, a known metabolic disruptor, modulates microbiome composition and function to influence neurobehavior. We utilized a simplified human gut microbiota model (SIHUMIx) and a vertebrate host model (larval zebrafish) to elucidate microbiome-mediated mechanisms of xenobiotic neurotoxicity. SIHUMIx was exposed to azoxystrobin for 7 days at 10% of the acceptable daily intake, followed by recovery. Integrated metaproteomic and metabolomic analyses revealed functional reprogramming of the microbiota, characterized by upregulation of vitamin and cofactor biosynthesis, nutrient acquisition, and detoxification pathways, and decreases in carbohydrate fermentation and amino acid turnover, consistent with reduced short-chain fatty acid levels. Microbiome-depleted and SIHUMIx-inoculated larvae were exposed to azoxystrobin at 4 days post fertilization, and neurobehavioral outcomes were assessed after 24 h using the Visual and Acoustic Motor Response assay. Azoxystrobin exposure disrupted non-associative habituation learning independent of microbiome status but induced dark-phase hyperactivity only in colonized larvae, indicating a microbiome-dependent phenotype. Targeted metabolomics revealed lower serotonin levels in microbiome-depleted larvae relative to colonized controls and that azoxystrobin exposure reduced serotonin in colonized larvae toward depleted levels. These results suggest that microbiota-dependent serotonergic signaling may modulate host responses to azoxystrobin. This integrated ex vivo-in vivo approach supports the concept that the microbiome is a key determinant of neurotoxic responses and underscores the importance of incorporating microbiome-mediated effects into chemical risk assessment frameworks.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147378484","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":"In vitro and preclinical assessment of drug interactions between fluoroquinolones and a non-steroidal anti-inflammatory drug predicting risk of seizure.","authors":"Yuki Seki, Ikue Mihara, Taroumaru Okawa, Atsuko Ojima, Kazumasa Aoyama, Masaki Mikamoto, Yuka Morimitsu, Takeo Kamakura, Yasuaki Goto, Aoi Odawara, Yukiko Oshiro, Tomohiko Taniguchi, Motohiro Shiotani, Takashi Yoshinaga, Shoji Asakura, Yuto Ishibashi, Naoki Matsuda, Ikuro Suzuki, Norimasa Miyamoto","doi":"10.1093/toxsci/kfag039","DOIUrl":"https://doi.org/10.1093/toxsci/kfag039","url":null,"abstract":"<p><p>Seizures are a common reason for drugs to fail during development, but they are difficult to predict preclinically. Enoxacin, a fluoroquinolone, rarely causes convulsions as a monotherapy, but convulsions have been seen after combination therapy with fenbufen, a non-steroidal anti-inflammatory drug. The interaction between the drugs is thought to result from inhibition of GABAA receptors, which are not their primary targets. Here we show that, among 15 marketed fluoroquinolones and one active metabolite, six, including enoxacin, inhibited GABA-evoked depolarization in cells expressing human GABAA receptors when administered with felbinac, the active metabolite of fenbufen. Within these six except for a prodrug possessed a piperazinyl group at the seventh position of the quinolone ring. We also administered enoxacin or norfloxacin plus felbinac to rats and determined the cerebrospinal fluid concentrations of each drug when convulsions occurred. As we previously reported, an increase in network burst frequency recorded from primary cultured rat cortical neurons on microelectrode arrays is a risk marker for seizures, so we tested whether this assay could predict seizures induced by drug interactions between fluoroquinolones and felbinac. When co-administered with felbinac, only those fluoroquinolones that inhibited GABA currents in patch-clamp tests increased network burst frequency. Principal component analysis using 17 microelectrode array parameters supported that the mechanism of action was due to GABA antagonism in rodent neurons. Thus, the microelectrode array assay predicted seizure risks from the combination of enoxacin and the active metabolite of fenbufen and identified other fluoroquinolones with seizure risk potential.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147514910","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":"Serine Hydrolase Targets of a Sarin Surrogate Anticholinesterase and Oxime Mediated Reactivation in Rat Brain.","authors":"Chiquita Y Price, Edward C Meek, Matthew K Ross, Janice E Chambers","doi":"10.1093/toxsci/kfag024","DOIUrl":"https://doi.org/10.1093/toxsci/kfag024","url":null,"abstract":"<p><p>While acetylcholinesterase (AChE) is the primary inhibitory target for organophosphate (OP) insecticides and chemical warfare nerve agents, research supports the concept that the wide range of systems affected by OPs are not solely dependent on the anticholinesterase activity of OPs but are attributable to the inhibition of other serine hydrolases. Oxime reactivators play an integral role in the treatment of acute OP exposure by returning function to OP-inhibited AChE. Our laboratory has synthesized and patented a platform of oxime reactivators (US Patent 9,227,937) that have provided central neuroprotection through returning function to OP-inhibited AChE in the brain and preservation of neuronal and glial structures from damage in a rat model; the current U.S. approved oxime, pralidoxime (2-PAM), does not provide central neuroprotection. Thus, returning function to other OP-inhibited serine hydrolases by these novel oximes could provide additional secondary neuroprotection. Rat brain proteins were studied using activity-based protein profiling (ABPP) for serine hydrolase targets of a highly relevant sarin surrogate, nitrophenyl isopropyl methylphosphonate (NIMP), alone or in combination with Oxime 20, our lead novel AChE reactivator. ABPP indicated that NIMP significantly inhibited 6 serine hydrolases and of these were the well-known serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which are important in endocannabinoid signaling. Oxime 20 administration after NIMP treatment showed only limited remediation of the inhibition experienced by these targets. The impact of this study is the identification of secondary serine esterase targets that could be explored for esterase reactivating therapeutics for the treatment of OP poisoning.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147445351","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":"Progeny effects of rotenone exposure depend on parental toxicity.","authors":"Christina M Bergemann, Danielle F Mello, Rojin Chitrakar, Kinsey Fisher, Shefali R Bijwadia, Javier Huayta, Ian T Ryde, Rick Presman, Zhiqing Huang, Amy H Herring, Susan K Murphy, L Ryan Baugh, Joel N Meyer","doi":"10.1093/toxsci/kfag011","DOIUrl":"10.1093/toxsci/kfag011","url":null,"abstract":"<p><p>Parental exposure to toxicants can affect progeny health. However, laboratory studies often employ exposures that result in loading of pollutants to gametes or toxic effects to parents, which could indirectly affect germ cell or gamete health. Here, we took advantage of the biology of Caenorhabditis elegans to carry out a study in which we minimized the potential for maternal loading of toxicants, and used an exposure paradigm that either did (high concentration) or did not (low concentration) significantly impact the health of the P0 generation. We hypothesized that parental exposure to mitochondrial toxicants during germ cell and gamete development, at levels not causing P0 toxicity, would result in altered mitochondria and organismal health in offspring. In the P0 generation, a high rotenone concentration altered growth, mitochondrial respiration, gene expression, induction of the mitochondrial unfolded protein response, and susceptibility to dopaminergic neurodegeneration induced by a chemical rechallenge later in life. However, we observed minor or no effects in P0 at a low concentration. In high-exposure F1 offspring, we observed altered embryo size, larval developmental stage distribution, spare respiratory capacity, heat shock protein expression, and dopaminergic neurodegeneration after a secondary rotenone challenge. The only effects observed in the F1 offspring of the low exposure were a 1.7% decrease in egg size (size later in development was normal), and moderate evidence of a slightly increased sensitivity to heat shock protein expression and dopaminergic neurodegeneration caused by a secondary later-in-life rotenone exposure. We recommend that parental toxicity be carefully assessed to contextualize offspring outcomes.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166827","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":"Detection and characterization of alterations in miRNA in urine of firefighters.","authors":"Patrick C Sachs, Julie S Bjerring, James Blando, Robert D Bruno","doi":"10.1093/toxsci/kfag010","DOIUrl":"10.1093/toxsci/kfag010","url":null,"abstract":"<p><p>Firefighters are exposed to high levels of toxic chemicals while fighting fires, and previous studies have established these men and women have a significantly elevated risk for various cancers. Improved risk management for firefighters requires the identification of biomarkers indicative of physiological response. Micro-RNAs (miRNAs) have emerged as promising noninvasive prognostic and diagnostic biomarkers for various diseases. Here, we isolated miRNA from the urine of a large dataset of firefighters, collected pre- and post-fire exposure, as well as from healthy non-firefighter controls. miRNA was analyzed by microarray using the Affymetrix GeneChip miRNA 4.0 array. Analysis revealed 23 human miRNAs were significantly up-regulated and 25 significantly down-regulated in firefighters compared with control samples (analysis 1). Gene targets of these miRNAs were analyzed using the Online Database for Annotation, Visualization, and Integrated Discovery (DAVID) and found to cluster in several pathways and disease associations with smoking, cancer, and inflammatory diseases. Furthermore, we performed a longitudinal analysis of samples from firefighters that provided a sample prior to a fire exposure and immediately after a fire (analysis 2). This analysis found 20 miRNAs that were significantly up-regulated post-fire exposure. Of these, 5 were also up-regulated in firefighters vs control samples (hsa-miR-1268b, hsa-miR-4433b-3p, hsa-miR-4253, hsa-miR-6824-5p, and hsa-miR-3188). Again, analysis of gene targets of these miRNAs found association of mostly the same pathways and disease processes found in analysis 1. These findings are consistent with epidemiological evidence for increased risks associated with firefighting and offer a proof of concept and framework for the use of miRNA in urine as biomarkers for health risk assessment associated with firefighting.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166788","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":"Short-term electrical stimulation promotes partial functional and morphological maturation of human-induced pluripotent stem cell-derived cardiomyocytes enabling cardiotoxicity risk mitigation at early-stage drug discovery for cardiac contractility modulation.","authors":"Hayato Miyoshi, Kaoru Morimura, Reiko Hara, Ritsuko Hori, Eriko Watanabe, Nobuyuki Mochizuki, Ayako Kamei, Rika Yamazaki, Katsuyuki Kazusa","doi":"10.1093/toxsci/kfag018","DOIUrl":"10.1093/toxsci/kfag018","url":null,"abstract":"<p><p>In drug discovery, assessing cardiac contractile force is crucial because of its association with the development of cardiovascular events and heart failure. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a promising in vitro model for drug discovery, particularly for assessing proarrhythmic risk. However, the availability of robust in vitro models to evaluate cardiac contractility has been limited. Here, we demonstrate that subjecting hiPSC-CMs to electrical stimulation for 48 h using a multielectrode array system induces partial functional and morphological maturation, as evidenced by a positive force-frequency relationship, increased conduction velocity of depolarization signals and improved sarcomere orientation with distinct Z-bands compared to unstimulated controls. We confirmed that electrical stimulation enables the evaluation of the positive inotropic effects of drug compounds with diverse pharmacological actions. The functional maturation induced by the electrical stimulation was observed across different facilities. The method also effectively detected prolonged QT intervals. These findings demonstrate the utility of the electrical stimulation for 48 h for hiPSC-CMs using the multielectrode array assay system to assess drug-induced contractile function and detect prolonged QT intervals in a single experiment, thereby enhancing the early-stage assessment of cardiotoxicity in drug discovery.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228808","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":"Removal of volatile organic compounds by chemical filters significantly inhibited the development of atopic dermatitis symptoms in mice: potential implications for air-conditioning systems in healthcare environments.","authors":"Chiharu Ohira, Kengo Tomita, Yukiko Ota, Keiichi Yano, Mona Amano, Mao Kaneki, Atsushi Yamada, Riku Usui, Yuzo Nagai, Masaki Nagane, Satoshi Takagi, Tomoki Fukuyama","doi":"10.1093/toxsci/kfag009","DOIUrl":"10.1093/toxsci/kfag009","url":null,"abstract":"<p><p>Volatile organic compounds (VOCs) are increasingly implicated in systemic diseases, but their contribution to skin disorders such as atopic dermatitis (AD) remains unclear. This study assessed VOC concentrations in medical environments, their effects on AD development, and the efficacy of VOC removal using chemical filters. Total VOC levels were monitored in 3 types of veterinary hospitals. AD-like lesions were induced in female NC/Nga mice by repeated dermal application of toluene diisocyanate or house dust mite ointment, with or without topical exposure to a VOC mixture (10 μg/ml). Clinical parameters, including dermatitis scores, transepidermal water loss, and skin thickness, were measured weekly, and immunological and histological analyses were performed. VOC monitoring revealed that 1 hospital exhibited concentrations exceeding 400 μg/m³. In the mouse model, direct VOC exposure significantly aggravated keratinocyte inflammation and worsened AD symptoms. Application of chemical filtering systems effectively reduced VOC levels in real clinical settings, and their use in the experimental model suppressed AD development. However, therapeutic application of VOC removal showed only limited effects on systemic immunological markers. These findings suggest that VOCs present in healthcare environments may contribute to the onset and progression of AD. Incorporating VOC-removing filters into air-conditioning systems could serve as a preventive strategy to improve the management of allergic skin diseases.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165949","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":"Multimodal preclinical assessment of glucocorticoid-induced disruption of bone remodeling in Sprague-Dawley rats.","authors":"Anik Tuladhar, Caitlyn Carter, Erin Vaughan, Martin J Voorbach, Pankaj Kumar, Anastasia Marinopoulos, Ayusha Acharya, DeAnne Stolarik, Elizabeth J Sande, Timothy Brayman, Karen E Parrish, Xin Huang, Sjoerd J Finnema, Romy Christmann, Terry R Van Vleet, Brian Enright, Magali Guffroy, Stacey Fossey","doi":"10.1093/toxsci/kfag026","DOIUrl":"10.1093/toxsci/kfag026","url":null,"abstract":"<p><p>Skeletal toxicity is a critical consideration during drug development arising from on-target mechanisms and off-target effects. Standard histopathology used in preclinical toxicity studies lacks sensitivity to detect subtle skeletal alterations. Early detection of bone changes is essential especially for compounds that may interfere with skeletal remodeling, growth, or maintenance. We characterized serum markers of bone formation and turnover (procollagen type I N-terminal propeptide and osteocalcin) and resorption (C-terminal telopeptide of type I collagen) across developmental age group (1 to 8 mo) in naïve Sprague-Dawley rats and evaluated marker responsiveness in a positive-control prednisolone model (2-mo-old rats dosed 14 or 28 d). Biomarkers were interpreted alongside histology, imaging by micro-computed tomography and dual-energy X-ray absorptiometry. Serum biomarkers of bone formation and resorption decreased with age, along with physiological growth plate thinning in naive rats. In prednisolone-treated rats, biomarkers decreased at 14 and 28 d of daily dosing; histology demonstrated reduced growth plate thickness, increased marrow adiposity, and imaging revealed alteration of trabecular microarchitecture and bone mineral density relative to controls. These data indicate that serum bone biomarkers are sensitive to both normal maturational change and pharmacologic suppression of remodeling, and these biomarker shifts correspond with skeletal toxicity, reflecting early structural deterioration induced by glucocorticoid exposure. We show that integrating serum biomarkers with histology and high-resolution imaging enhances early detection of skeletal toxicity in preclinical studies with compounds having known or expected bone effects based on their pharmacology and informs selection of serum sampling time frame and translational monitoring strategies using imaging.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147356191","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":"Acute exposure to diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) impacts pituitary hormones and inflammatory markers, suggesting altered reproductive aging in adult female mice.","authors":"Yinka Ojo, Karen Weis, Mary Laws, Catheryne Chiang, Ramses Santacruz-Marquez, Francky Maemble Ntomb, Jodi Flaws, Lori Raetzman","doi":"10.1093/toxsci/kfag020","DOIUrl":"10.1093/toxsci/kfag020","url":null,"abstract":"<p><p>Phthalates are ubiquitous endocrine-disrupting chemicals whose exposure is associated with accelerated reproductive aging in humans. We focused on the pituitary gland, the source of the gonadotropins: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH). We hypothesized that the common phthalates di-(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) modulate inflammation in the pituitary and impact gonadotropin expression acutely and during aging. To test this, female CD-1 mice were orally dosed with corn oil or varying concentrations of DEHP and DiNP for 10 days. Pituitary tissues were collected immediately after dosing or 15 months post-dosing, processed, and analyzed by quantitative real-time PCR (qPCR) and immunohistochemistry. We found that acute phthalate exposure did not alter Fshb and Lhb mRNA expression compared with controls, but both DEHP and DiNP reduced FSH immunopositive cell number. Phthalate exposure also decreased Il1b, and increased Il18 and Tnf mRNA levels compared with controls, suggesting an inflammatory imbalance. At 15 months post-dosing, DiNP exposure increased Lhb and Il1b mRNA levels, but repressed Fshb and Nlrp3 mRNA levels compared with controls. Next, using dissociated cultures, we investigated the impact of phthalates and the proinflammatory stimulus lipopolysaccharide (LPS) on inflammation and gonadotropin gene expression directly at the pituitary. Both the DEHP metabolite MEHP and LPS decreased Fshb, but not Lhb mRNA relative to control. MEHP also repressed the induction of Il1b by LPS. Together, these findings suggest that acute exposure to phthalate alters mRNA expression of inflammatory markers and gonadotropins in the pituitary, which could alter the process of reproductive aging.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146228644","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":"Suppression of haptoglobin and loss of striatal neurons in mice chronically exposed to chlorpyrifos-contaminated drinking water.","authors":"Emma Fikse, Faith Anderson, Soyeon Cho, Jessica Landry, Elisa Carloni, Karl Biggs, Kathleen Paul, Thomas Daley, T Y Chang, Arminja Kettenbach, Matthew C Havrda","doi":"10.1093/toxsci/kfag012","DOIUrl":"10.1093/toxsci/kfag012","url":null,"abstract":"<p><p>Exposure to agricultural chemicals is a risk factor for neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Chlorpyrifos (CPF) is an organophosphate insecticide widely used in agricultural and occupational settings. Epidemiological studies have associated CPF exposure with developmental impairments and an increased risk of AD and PD. Experimental characterization of the impact of chronic, systemic CPF exposure is essential for understanding how organophosphates actually influence disease risk. Multiple studies have assessed the effects of gestational exposure to CPF in preclinical models. To model exposure faced by adults, we administered CPF-contaminated drinking water to mice from 6 to 22 mo of age. This chronic exposure led to systemic effects, including reduced levels of the acute-phase protein haptoglobin (HTP) in both plasma and liver. Notably, the combination of aging and CPF exposure resulted in astrogliosis in the hippocampus and striatum, as well as neuronal loss in the striatum, primarily due to the loss of GAD65/67-immunoreactive interneurons. Having identified CPF-driven suppression of HPT in peripheral tissues, we examined HPT expression in brain tissues. We readily detected HPT expression in brain microglia. We then cultivated primary microglia and found that CPF exposure decreased HPT secretion in vitro. These findings indicate systemic and neurotoxic effects resulting from adult exposure to CPF-contaminated water.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146158615","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}