Toxicological Sciences最新文献

Kupffer cell expression of macrophage receptor with collagenous structure modulates macrophage gene induction and limits acute liver injury. 巨噬细胞胶原结构受体（MARCO）的表达调节巨噬细胞基因诱导，限制急性肝损伤。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf037

Lauren G Poole, Zimu Wei, Anthony Schulte, Holly M Cline, Matthew P Bernard, John P Buchweitz, Mitchell R McGill, James P Luyendyk

{"title":"Kupffer cell expression of macrophage receptor with collagenous structure modulates macrophage gene induction and limits acute liver injury.","authors":"Lauren G Poole, Zimu Wei, Anthony Schulte, Holly M Cline, Matthew P Bernard, John P Buchweitz, Mitchell R McGill, James P Luyendyk","doi":"10.1093/toxsci/kfaf037","DOIUrl":"10.1093/toxsci/kfaf037","url":null,"abstract":"Macrophages displaying a pro-repair and anti-inflammatory polarization have been implicated in resolution of acute liver injury. Macrophage receptor with collagenous structure (MARCO) expression marks tolerogenic hepatic macrophages and is expressed by pro-resolution macrophages in the injured liver. We tested the hypothesis that MARCO promotes repair of the acetaminophen (APAP)-injured liver. Robust and sustained induction of MARCO mRNA and protein expression was evident in livers of mice challenged with a hepatotoxic dose of APAP (i.e. 300 mg/kg), whereas hepatic MARCO induction failed in mice with APAP-induced liver failure (i.e. 600 mg/kg). Serum proteomics identified a significant increase in serum MARCO levels in surviving acute liver failure (ALF) patients, but not in ALF patients who died. MARCO expression was high in F480+ liver macrophages, and MARCO deficiency reduced macrophage expression of pro-resolution markers such as Gpnmb and Mertk during the repair phase (i.e. 48 h). The results suggested a delay in necrosis resolution along with a trend toward increased mortality in APAP-challenged MARCO-/- mice. Notably, a robust increase in peak hepatic injury (i.e. 6- to 24-h post-APAP challenge) was evident in MARCO-/- mice, which could not be ascribed to differences in NAPQI/APAP-adduct generation nor changes in hepatic neutrophil/macrophage numbers. Interestingly, a reduction in hepatic CD11c+ cells, shown previously to limit APAP-induced liver injury, was evident 24 h after APAP challenge in MARCO-/- mice. The results indicate that MARCO deficiency worsens APAP-induced acute liver injury in mice and provide experimental and initial translational evidence linking MARCO induction to positive outcomes in acute liver injury.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"417-427"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674618","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}

引用次数: 0

Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice. 围产期大麻暴露对小鼠雌性生殖参数的跨代影响。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf043

Mingxin Shi, Yeongseok Oh, Debra A Mitchell, James A MacLean, Ryan J McLaughlin, Kanako Hayashi

{"title":"Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.","authors":"Mingxin Shi, Yeongseok Oh, Debra A Mitchell, James A MacLean, Ryan J McLaughlin, Kanako Hayashi","doi":"10.1093/toxsci/kfaf043","DOIUrl":"10.1093/toxsci/kfaf043","url":null,"abstract":"The use of cannabis during pregnancy and nursing is a growing public health concern, and the multigenerational impacts of perinatal cannabis exposure remain largely unknown. To address this knowledge gap, we sought to examine the long-term consequences of perinatal cannabis use on reproductive function and how it might impact subsequent generations. Pregnant female mice were exposed to control vehicle or cannabis extract [25, 100, or 200 mg/ml Δ9-tetrahydrocannabinol (THC) in the cannabis extract] from gestational day 1 to postnatal day 21 (twice/day), encompassing the duration of pregnancy through weaning. Based on plasma THC concentrations in F0 females, we chose 100 and 200 mg/ml THC in the cannabis extract for subsequent studies. The selected doses and exposure conditions did not disrupt pregnancy or nursing in F0 females. Pregnancy and neonatal outcomes, including gestational length, litter size, and sexual ratio, were not affected by cannabis exposure. However, cannabis-exposed neonatal F1 pups were smaller. Cannabis exposure delayed vaginal opening as a sign of puberty onset and disrupted estrous cyclicity in F1 females. However, its effects were minor in F2 and F3 females. F1-F3 females showed no abnormal ovarian and uterine histology or plasma estradiol-17β levels and could produce normal offspring without pregnancy issues. These results suggest that the developmental stages of the hypothalamus and pituitary are likely perturbed by gestational and nursing cannabis exposure in F1 females. However, they are not sufficient to compromise adult reproductive function. The present results indicate limited transgenerational effects of perinatal cannabis exposure on female reproductive parameters.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"358-368"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744037","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}

引用次数: 0

Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing. 发展中的神经系统建模：在DNT测试中使用NAMs的神经科学观点。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf028

Andrew J Newell, Heather B Patisaul

{"title":"Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing.","authors":"Andrew J Newell, Heather B Patisaul","doi":"10.1093/toxsci/kfaf028","DOIUrl":"10.1093/toxsci/kfaf028","url":null,"abstract":"There is widespread concern that environmental exposures constitute an underappreciated but significant contribution to rising rates of neurodevelopmental disorders (NDDs). There is also international consensus that regulatory frameworks for developmental neurotoxicity (DNT) testing are woefully inadequate, prompting reappraisal of DNT testing methods. One approach aims to make testing more efficient, less animal-intensive, and higher throughput through in vitro evaluation of DNT. These new approach methodologies (NAMs) promise to accelerate and standardize DNT testing through interrogation of fundamental mechanisms of neurodevelopment. While in the early stages of development, they have significant, well-publicized shortcomings, including little to no accounting for cellular or genetic diversity, cell-extrinsic signaling molecules, sex as a biological variable, developmental stage, or relevance to NDDs. One of the most advanced NAM platforms is a collection of 17 in vitro assays termed the DNT in vitro battery (IVB). While it models some aspects of neurodevelopmental processes, it fails to capture others. Proper brain ontogeny, and consequently normal behavior and cognition, relies on the integrity of fundamental mechanisms, their temporal/spatial fidelity, and the magnitude of their expression. These fundamental mechanisms are regulated by factors not considered by the DNT IVB, including diverse cell types and neurotransmitters. While the DNT IVB could prove to be an important tool in DNT hazard detection, we identify key areas, including cell-extrinsic neurotransmitter signaling, diversity of neural progenitors, interneurons, and biological sex, that should be prioritized for development and inclusion in future refinements to meaningfully enhance biological coverage and relevance to human cognition and behavior.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"245-273"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558060","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}

引用次数: 0

A mixture parameterized biologically based dosimetry model to predict body burdens of polycyclic aromatic hydrocarbons in developmental zebrafish toxicity assays. 在斑马鱼发育毒性试验中预测多环芳烃身体负荷的混合参数化生物学剂量学模型。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf039

Christian I Rude, Jordan N Smith, Ricky P Scott, Katherine J Schultz, Kim A Anderson, Robyn L Tanguay

{"title":"A mixture parameterized biologically based dosimetry model to predict body burdens of polycyclic aromatic hydrocarbons in developmental zebrafish toxicity assays.","authors":"Christian I Rude, Jordan N Smith, Ricky P Scott, Katherine J Schultz, Kim A Anderson, Robyn L Tanguay","doi":"10.1093/toxsci/kfaf039","DOIUrl":"10.1093/toxsci/kfaf039","url":null,"abstract":"Polycyclic aromatic hydrocarbons (PAHs) are a group of environmental toxicants found ubiquitously as complex mixtures in human-impacted environments. Developmental zebrafish exposures have been used widely to study PAH toxicity, but most studies report nominal exposure concentrations. Nominal exposure concentrations can be unreliable dose metrics due to differences in toxicant bioavailability resulting from disparate exposure methodologies and chemical properties. Toxicokinetic modeling can predict toxicant tissue doses to facilitate comparison between exposures of different chemicals, methodologies, and biological models. We parameterize a biologically based dosimetry model for developmental zebrafish toxicity assays for 9 PAHs. The model was optimized with measurements from media, tissue, and plastic plate walls throughout a static developmental exposure to a mixture of 10 PAHs of high abundance within the Portland Harbor Superfund Site. Plate binding, volatilization, zebrafish permeability, and tissue-media partitioning coefficients vary widely between PAHs. Model predictions accounted for 83% and 54% of 48 hpf body burdens within a factor of 2 resulting from exposures to mixtures and individual PAHs, respectively. Accounting for solubility significantly improves model performance. Competition for active sites in metabolizing enzymes may change biotransformation kinetics between individual PAH and mixture exposures. Area under the curve estimations of concentrations in zebrafish resulted in altered hazard rankings from nominal exposure concentrations. Future work will be oriented to generalizing the model to other PAHs. This PAH dosimetry model improves the interpretability of developmental zebrafish toxicity assays by providing time-resolved body burdens from nominal exposure concentrations.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"326-343"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674608","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}

引用次数: 0

An analytical screening platform to differentiate acute and prolonged exposures of per- and polyfluoroalkyl substances on invasive cellular phenotypes. 一个分析筛选平台，以区分急性和长期暴露的PFAS侵袭细胞表型。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf044

Ryan A Lidgett, Abel A Miranda Buzetta, J Ian Baker, Pearl Dang, Amy L Oldenburg, Matthew R Lockett

{"title":"An analytical screening platform to differentiate acute and prolonged exposures of per- and polyfluoroalkyl substances on invasive cellular phenotypes.","authors":"Ryan A Lidgett, Abel A Miranda Buzetta, J Ian Baker, Pearl Dang, Amy L Oldenburg, Matthew R Lockett","doi":"10.1093/toxsci/kfaf044","DOIUrl":"10.1093/toxsci/kfaf044","url":null,"abstract":"Per- and polyfluoroalkyl substances (PFAS) are \"forever chemicals\" and pervasive environmental contaminants associated with cancer. Epidemiological studies found that an increased incidence of hormone-sensitive breast cancer is correlated with PFAS exposure. Cell-based assays provide a well-controlled experimental platform to quantify cellular responses as a function of exposure. Given the nearly 15,000 known PFAS on the Environmental Protection Agency's toxicity database (DSSTox), in vitro models are the only feasible approach to screen this large molecular library. One of the hallmarks of cancer is increased migration and invasion, processes that are the gateway to metastasis. Using a paper-based invasion assay developed in our lab, we compared the invasion of the MCF7 and M231 cell lines after acute and prolonged exposures to 2 legacy PFAS compounds, individually and in an equimolar mixture: perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). The acute exposures quantified cellular movement after a 24-h period in the presence of the molecule of interest. The prolonged exposures in this work exposed 5 consecutive cell passages to the PFAS. We hypothesized that prolonged PFAS exposures would select for invasive subpopulations. These prolonged exposures increased the invasion of MCF7 and M231 cells compared to acute exposures of the same PFAS concentration (10 µM). The prolonged exposures to PFOA and PFOS at environmentally relevant concentrations (10 nM) did not increase invasion. Our results highlight the need to assess different exposure durations in vitro and that the paper-based invasion assay is a reasonable screening tool.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"369-379"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744033","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}

引用次数: 0

Establishing a context of use for three-dimensional cardiac tissue derived from human-induced pluripotent stem cell-derived cardiomyocytes using inotropes. 建立使用人诱导多能干细胞衍生心肌细胞的三维心脏组织的背景。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf033

Yoshiko Okai, Emily Pfeiffer Kaushik, Tomoya Sameshima, Nicole Feric, Rishabh Singh, Isabella Pallotta, Danielle R Bogdanowicz, Marietta M Gustilo, Kosuke Harada, Kevin S Baker, Tadahiro Shinozawa

{"title":"Establishing a context of use for three-dimensional cardiac tissue derived from human-induced pluripotent stem cell-derived cardiomyocytes using inotropes.","authors":"Yoshiko Okai, Emily Pfeiffer Kaushik, Tomoya Sameshima, Nicole Feric, Rishabh Singh, Isabella Pallotta, Danielle R Bogdanowicz, Marietta M Gustilo, Kosuke Harada, Kevin S Baker, Tadahiro Shinozawa","doi":"10.1093/toxsci/kfaf033","DOIUrl":"10.1093/toxsci/kfaf033","url":null,"abstract":"Safety attrition due to drug-induced inotropic changes remains a significant risk factor for drug development. Mitigating these events during early screening remains challenging. Several in vitro predictive models have been developed to address these issues, with varying success in detecting drug-induced inotropic changes. In this study, we compared traditional two-dimensional human-induced pluripotent stem cell-derived cardiomyocytes (2D hiPSC-CMs) with three-dimensional engineered cardiac tissues (3D ECTs) to assess their ability to detect drug-induced inotropic changes in 17 drugs with known mechanisms of action. The models were exposed to various test compounds, and their responses were evaluated by measuring either the active force or maximum contraction speed. The 3D ECTs successfully detected all the tested positive inotropes, whereas the 2D hiPSC-CMs failed to detect the 2 compounds. Both models demonstrated high predictability for negative inotropy and showed similar results for detecting non-active compounds, except for higher concentrations of phentolamine, zimelidine, and tamsulosin. Irregular beating was less likely to occur in the 3D ECTs, suggesting that 3D ECTs provided superior detection of contractility compared to 2D hiPSC-CMs. Genetic analysis revealed a more mature phenotype for the 3D ECTs compared to the 2D hiPSC-CMs, and the compound-related target expression was comparable to that in the adult human heart tissues. The 3D ECTs captured inotropic changes more accurately and thus represented a more translatable model than the 2D hiPSC-CMs. Overall, contractility assessment using the 3D ECTs could be advantageous for profiling candidate compounds and mechanistic investigations of hemodynamic changes during in vivo or clinical studies.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"401-416"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143982163","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}

引用次数: 0

NAPQI is absent in the mouse brain after sub-hepatotoxic and hepatotoxic doses of acetaminophen. 亚肝毒性和肝毒性剂量对乙酰氨基酚后，小鼠脑内NAPQI缺失。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf034

Nyera A Ali, Stefanie Kennon-McGill, Larry D Parker, Laura P James, William E Fantegrossi, Mitchell R McGill

引用次数: 0

A workflow for human health hazard evaluation using transcriptomic data and Key Characteristics-based gene sets. 使用转录组学数据和基于关键特征的基因集进行人类健康危害评估的工作流程。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-06-01 DOI: 10.1093/toxsci/kfaf036

Han-Hsuan D Tsai, King D Oware, Fred A Wright, Weihsueh A Chiu, Ivan Rusyn

{"title":"A workflow for human health hazard evaluation using transcriptomic data and Key Characteristics-based gene sets.","authors":"Han-Hsuan D Tsai, King D Oware, Fred A Wright, Weihsueh A Chiu, Ivan Rusyn","doi":"10.1093/toxsci/kfaf036","DOIUrl":"10.1093/toxsci/kfaf036","url":null,"abstract":"Key characteristics (KCs) are properties of chemicals that are associated with different types of human health hazards. KCs are used for systematic reviews in support of hazard identification. Transcriptomic data are a rich source of mechanistic data and are frequently interpreted through \"enriched\" pathways/gene sets. Such analyses may be challenging to interpret in regulatory science because of redundancy among pathways, complex data analyses, and unclear relevance to hazard identification. We hypothesized that by cross-mapping pathways/gene sets and KCs, the interpretability of transcriptomic data can be improved. We summarized 72 published KCs across 7 hazard traits into 34 umbrella KC terms. Gene sets from Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) were mapped to these, resulting in \"KC gene sets.\" These sets exhibit minimal overlap and vary in the number of genes. Comparisons of the same KC gene sets mapped from Reactome and KEGG revealed low similarity, indicating complementarity. Performance of these KC gene sets was tested using publicly available transcriptomic datasets of chemicals with known organ-specific toxicity: benzene and 2,3,7,8-tetrachlorodibenzo-p-dioxin tested in mouse liver and drugs sunitinib and amoxicillin tested in human-induced pluripotent stem cell-derived cardiomyocytes. We found that KC terms related to the mechanisms affected by tested compounds were highly enriched, while the negative control (amoxicillin) showed limited enrichment with marginal significance. This study's impact is in presenting a computational approach based on KCs for the analysis of toxicogenomic data and facilitating transparent interpretation of these data in the process of chemical hazard identification.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"310-325"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670973","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}

引用次数: 0

A mixture of organophosphate esters sex-specifically impacts monocyte-macrophages in Sprague-Dawley rats. 一种有机磷酯的混合物性别特异性地影响了Sprague-Dawley大鼠的单核巨噬细胞。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-28 DOI: 10.1093/toxsci/kfaf078

Braeden H Giles, Nivetha Kamalavannan Subramaniam, Vincenza Caruana, Nikola Kukolj, Bernard Robaire, Koren K Mann

{"title":"A mixture of organophosphate esters sex-specifically impacts monocyte-macrophages in Sprague-Dawley rats.","authors":"Braeden H Giles, Nivetha Kamalavannan Subramaniam, Vincenza Caruana, Nikola Kukolj, Bernard Robaire, Koren K Mann","doi":"10.1093/toxsci/kfaf078","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf078","url":null,"abstract":"Exposure to individual organophosphate esters (OPEs) has been linked to immune dysfunction. However, the effect of OPEs as environmentally relevant mixtures on the immune system remain poorly understood. This study examines how parental exposure to an OPE mixture impacts the immune status of Sprague-Dawley rats and their offspring. Sprague-Dawley rats were fed a control or OPE-supplemented diet containing 13 OPEs detected in > 85% of Canadian homes. Only male offspring of OPE-exposed animals showed a significant reduction in CD43lowHis48hi splenic monocyte-macrophages. There were no significant changes in CD43lowHis48hi splenic monocyte-macrophages in the F0 generation or in female offspring. However, the OPE mixture significantly altered serum cytokine levels in both sexes and generations, with females and offspring experiencing more pronounced changes. Notably, female progeny had elevated levels of chemokines associated with monocyte recruitment. In vitro follow-up studies revealed that the OPE mixture delays monocyte-to-macrophage transition and monocyte migration in both sexes. These results indicate that an environmentally relevant OPE mixture disrupts immune function by affecting monocyte recruitment and differentiation but does not reveal clear sex differences. However, when combined with cytokine findings, these results support a hypothesis that OPE exposure causes male-specific decreases in CD43lowHis48hi monocyte-macrophages that are absent in females due to compensatory inflammation. Impact statement: These studies demonstrate that an environmentally relevant mixture of organophosphate esters can alter basal immune status in the offspring of exposed animals. This work will be useful for risk assessment studies and regulations protecting human health.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175003","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}

引用次数: 0

Profiling the Cytotoxic Effects of Naled and Other Pesticides in Primary Human Placental Cytotrophoblasts. Naled和其他农药对人胎盘原代细胞滋养细胞的细胞毒作用分析。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-05-28 DOI: 10.1093/toxsci/kfaf038

Lin Li, Hao Chen, Unurzul Jigmeddagva, Ngantu Le, Mirhan Kapidzic, Stephanie Gee, Alizah Ali, Justine Levan, Romane Person, Jessica Chen, Amanda Gutierrez, Chinomnso N Okorie, Mengjing Wang, Tracey J Woodruff, Susan J Fisher, Stephanie L Gaw, Joshua F Robinson

{"title":"Profiling the Cytotoxic Effects of Naled and Other Pesticides in Primary Human Placental Cytotrophoblasts.","authors":"Lin Li, Hao Chen, Unurzul Jigmeddagva, Ngantu Le, Mirhan Kapidzic, Stephanie Gee, Alizah Ali, Justine Levan, Romane Person, Jessica Chen, Amanda Gutierrez, Chinomnso N Okorie, Mengjing Wang, Tracey J Woodruff, Susan J Fisher, Stephanie L Gaw, Joshua F Robinson","doi":"10.1093/toxsci/kfaf038","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf038","url":null,"abstract":"Placental cytotrophoblasts (CTBs) play critical roles in placentation, including implantation, barrier-function, uterine invasion and maternal endovascular remodeling. Impairment of CTB function is linked with common pregnancy complications. In this context, environmental chemicals can contribute to CTB dysfunction. Evidence suggests that prenatal exposures to pesticides affect the placenta and contribute to pregnancy complications and adverse developmental outcomes. Despite being restricted in the European Union, dimethyl 1,2-dibromo-2,2 dichloroethyl phosphate (naled), a common organophosphate pesticide, is widely used in vector control and agriculture in the United States and abroad. In this study, we investigated the placentotoxic activity of naled in 2nd trimester primary human CTBs. We assessed the cytotoxicity of naled and 67 pesticides using the neutral red lysosomal cellular uptake assay and the lactate dehydrogenase release assay. Naled was one of the most toxic compounds (∼15th percentile), impairing viability and inducing cell death at levels similar to federally restricted pesticides (methoxychlor and triclosan) and at lower concentrations than other commonly used compounds in the organophosphate class (e.g., chlorpyrifos, dichlorvos, and malathion). Naled significantly altered expression of 297 genes (unadjusted p < 0.01, absolute fold change > 1.5 with 10 µM or 30 µM), including molecules important in regulating the environmental stress response and developmental processes. Using a benchmark modeling approach, we identified specific genes and related pathways that may serve as early indicators of naled-response in CTBs at physiologically-relevant exposure levels. Thus, our data suggests that naled may alter critical human CTB functions in vivo.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161167","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}

引用次数: 0