Toxicological Sciences最新文献

{"title":"Serum Glutamate dehydrogenase activity enables sensitive and specific diagnosis of hepatocellular injury in humans.","authors":"Jiri Aubrecht, David Potter, John Michael Sauer, Roscoe Warner, Kent Johnson, Mitchell R Mcgill, Katrina Peron, Nicholas M P King","doi":"10.1093/toxsci/kfae143","DOIUrl":"https://doi.org/10.1093/toxsci/kfae143","url":null,"abstract":"<p><p>Serum activities of alanine- and aspartate- aminotransferases (ALT and AST) are considered the \"gold standard\" biomarkers of hepatocyte injury in clinical practice and drug development. However, due to expression of ALT and AST in myocytes, the diagnosis of hepatocellular injury in patients with underlying muscle diseases, including drug-induced muscle injury, is severely limited. Thus, we proposed glutamate dehydrogenase (GLDH) as a liver-specific alternative to serum ALT and AST. In fact, our exploratory studies showed that GLDH has comparable performance to ALT for detecting hepatocyte injury without interference from concomitant muscle injury. Here, we report the results of studies confirming the reference intervals in a healthy human population and sensitivity and specificity of GLDH for detection of hepatocyte injury in human subjects. In human subjects, we could not perform liver biopsies due to ethical reasons, we also confirmed the relationship of GLDH and histopathologic lesions using 32 model toxicants in rats. Furthermore, we have shown that injury to tissues that are known to express appreciable levels of GLDH does not affect serum GLDH measurements, indicating excellent liver specificity of serum GLDH. Finally, we observed faster elimination of GLDH than ALT in humans, indicating that decreasing GLDH values could be considered an early sign of recovery. This study provides comprehensive evidence of excellent sensitivity and liver specificity of GLDH for diagnosis of hepatocellular injury, including evaluation of reference intervals that is essential for interpretation of serum GLDH in human subjects.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591369","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":"Bioinformatic Workflows for Deriving Transcriptomic Points of Departure: Current status, Data Gaps, and Research Priorities.","authors":"Jason O'Brien, Constance Mitchell, Scott Auerbach, Liam Doonan, Jessica Ewald, Logan Everett, Adam Faranda, Kamin Johnson, Anthony Reardon, John Rooney, Kan Shao, Robert Stainforth, Matthew Wheeler, Deidre Dalmas Wilk, Andrew Williams, Carole Yauk, Eduardo Costa","doi":"10.1093/toxsci/kfae145","DOIUrl":"https://doi.org/10.1093/toxsci/kfae145","url":null,"abstract":"<p><p>There is a pressing need to increase the efficiency and reliability of toxicological safety assessment for protecting human health and the environment. While conventional toxicology tests rely on measuring apical changes in vertebrate models, there is increasing interest in the use of molecular information from animal and in vitro studies to inform safety assessment. One promising and pragmatic application of molecular information involves the derivation of transcriptomic points of departure (tPODs). Transcriptomic analyses provide a snapshot of global molecular changes that reflect cellular responses to stressors and progression toward disease. A tPOD identifies the dose level below which a concerted change in gene expression is not expected in a biological system in response to a chemical. A common approach to derive such a tPOD consists of modeling the dose-response behavior for each gene independently and then aggregating the gene-level data into a single tPOD. While different implementations of this approach are possible, as discussed in this manuscript, research strongly supports the overall idea that reference doses produced using tPODs are health protective. An advantage of this approach is that tPODs can be generated in shorter term studies (e.g., days) compared to apical endpoints from conventional tests (e.g., 90-day sub-chronic rodent tests). Moreover, research strongly supports the idea that reference doses produced using tPODs are health protective. Given the potential application of tPODs in regulatory toxicology testing, rigorous and reproducible wet and dry laboratory methodologies for their derivation are required. This review summarizes the current state of the science regarding the study design and bioinformatics workflows for tPOD derivation. We identify standards of practice and sources of variability in tPOD generation, data gaps, and areas of uncertainty. We provide recommendations for research to address barriers and promote adoption in regulatory decision making.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584276","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":"Tolvaptan Safety in Autosomal Dominant Polycystic Kidney Disease; Focus on Idiosyncratic Drug Induced Liver Injury Liabilities.","authors":"Sean Hammond, Xiaoli Meng, Jane Barber, Merrie Mosedale, Amy Chadwick, Paul B Watkins, Dean J Naisbitt","doi":"10.1093/toxsci/kfae142","DOIUrl":"https://doi.org/10.1093/toxsci/kfae142","url":null,"abstract":"<p><p>Tolvaptan is a vasopressin V2 receptor antagonist which has proven to be an effective and mostly well-tolerated agent for the treatment of autosomal dominant polycystic kidney disease (ADPKD). However, its administration is associated with rare but serious idiosyncratic liver injury, which has warranted a black box warning on the drug labels and frequent monitoring of liver blood tests in the clinic. This review outlines mechanistic investigations that have been conducted to date and constructs a working narrative as explanation for the IDILI events that have occurred thus far. Potential risk factors which may contribute to individual susceptibility to DILI reactions are addressed, and key areas for future investigative/clinical development are highlighted.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568520","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":"Peripubertal exposure to oxyfluorfen, a diphenyl herbicide, delays pubertal development in the male rat by antagonizing androgen receptor activity.","authors":"A S Murr, A R Buckalew, G Devane, J R Bailey, J L Ford, L E Gray, T E Stoker","doi":"10.1093/toxsci/kfae144","DOIUrl":"https://doi.org/10.1093/toxsci/kfae144","url":null,"abstract":"<p><p>We recently identified the herbicide oxyfluorfen as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), a key step in thyroid hormone synthesis, using in vitro assays. We also observed a suppression of serum T4 and T3 in juvenile rats exposed orally to oxyfluorfen for 4-8 days. The purpose of the present study was to further evaluate effects of an extended 31-day oral exposure using a male pubertal rat study (15 to 500 mg/kg). Oxyfluorfen delayed puberty at all doses (1.3 -3.5 days) suppressing ventral prostate at 62.5 mg/kg and above and seminal vesicle weights at 31.25 mg/kg and above with no effect on testosterone or luteinizing hormone. Serum T4 and T3 were suppressed by all doses up to 80%, with a linear increase in serum TSH. Based on delayed puberty without changes in testosterone, we hypothesized that oxyfluorfen interferes with androgen receptor (AR) function. Results from our Hershberger study, with oxyfluorfen (62.5 and 125 mg/kg) co-treated with testosterone proprionate (TP , 1 mg/kg) for 10 days showed 3 of 5 of the androgenic tissue weights were suppressed compared to TP alone indicating AR antagonism. We next confirmed this effect in an in vitro AR transcriptional activation reporter assay (0-20 μM) with 125 pM 5αDH-11-ketotestosterone and found concentration-dependent inhibition of AR luminescence activity (EC50 1.75 µM) without cytotoxicity. Here, we confirmed the endocrine disrupting effects of oxyfluorfen using both in vitro and in vivo evaluations of the thyroid hormone and AR pathways. This abstract doesn't necessarily reflect U.S. EPA policy.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568513","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":"Associations between per- and polyfluoroalkyl substance exposures and metabolic dysfunction associated steatotic liver disease (MASLD) in adult National Health and Nutrition Examination Survey 2017 to 2018.","authors":"Niharika Samala, Manjiri Kulkarni, Rachana S Lele, Tyler C Gripshover, Jaime Lynn Wise, Shesh N Rai, Matthew C Cave","doi":"10.1093/toxsci/kfae106","DOIUrl":"10.1093/toxsci/kfae106","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants previously associated with elevated liver enzymes in human cohorts and steatotic liver disease in animal models. We aimed to evaluate the associations between PFAS exposures, and liver enzymes and vibration controlled transient elastography (VCTE) biomarkers of metabolic dysfunction associated steatotic liver disease (MASLD) in adult National Health and Nutrition Examination Survey (NHANES) 2017 to 2018. VCTE was determined by FibroScan. Serum PFAS (n = 14), measured by mass spectrometry, were analyzed individually and by principal component (PC). Univariate and multivariable associations were determined between PFAS exposures and liver disease outcome variables: alanine aminotransferase (ALT), controlled attenuation parameter (CAP), liver stiffness measurement (LSM), FibroScan-based Score (FAST), using R. About 1,400 participants including 50% women with a mean age of 48 ± 19 years and a mean BMI of 29 ± 7 kg/m2 were analyzed. Four PFAS clustered to PC1, whereas 3 PFAS clustered to PC2. PC1 was significantly associated with ALT (β = 0.028), CAP (β = 0.041), LSM (β = 0.025), and FAST (β = 0.198) in univariate analysis. Individual PFAS exposures were oftentimes inversely associated with these measurements in multivariate analysis. In adult NHANES 2017-2018, PFAS may not be a significant burden for MASLD, because of the inconsistent associations between the environmental PFAS exposures and biomarkers of liver steatosis, inflammation, and fibrosis. More data are required to better understand the relationships between PFAS exposures and liver disease.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992395","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":"Demyelination and impaired oligodendrogenesis in the corpus callosum following lead exposure.","authors":"Luke L Liu, Uzay Emir, Huiying Gu, Lara T Sang, Stephen J Sawiak, Jason R Cannon, Yansheng Du, Wei Zheng","doi":"10.1093/toxsci/kfae100","DOIUrl":"10.1093/toxsci/kfae100","url":null,"abstract":"<p><p>The corpus callosum is an oligodendrocyte-enriched brain region, replenished by newborn oligodendrocytes from oligodendrocyte progenitor cells (OPCs) in subventricular zone (SVZ). Lead (Pb) exposure has been associated with multiple sclerosis, a disease characterized by the loss of oligodendrocytes. This study aimed to investigate the effects of Pb exposure on oligodendrogenesis in SVZ and myelination in the corpus callosum. Adult female mice were used for a disproportionately higher prevalence of multiple sclerosis in females. Acute Pb exposure (one ip-injection of 27 mg Pb/kg as PbAc2 24 hr before sampling) caused mild Pb accumulation in the corpus callosum. Ex vivo assay using isolated SVZ tissues collected from acute Pb-exposed brains showed a diminished oligodendrogenesis in SVZ-derived neurospheres compared with controls. In vivo subchronic Pb exposure (13.5 mg Pb/kg by daily oral gavage 4 wk) revealed significantly decreased newborn BrdU+/MBP+ oligodendrocytes in the corpus callosum, suggesting demyelination. Mechanistic investigations indicated decreased Rictor in SVZ OPCs, defective self-defense pathways, and reactive gliosis in the corpus callosum. Given the interwined pathologies between multiple sclerosis and Alzheimer's disease, the effect of Pb on myelination was evaluated in AD-modeled APP/PS1 mice. Myelin MRI on mice following chronic exposure (1,000 ppm Pb in drinking water as PbAc2 for 20 wk) revealed a profound demyelination in the corpus callosum compared with controls. Immunostaining of the choroid plexus showed diminished signaling molecule (Klotho, OTX2) expressions in Pb-treated animals. These observations suggest that Pb caused demyelination in the corpus callosum, likely by disrupting oligodendrogenesis from SVZ OPCs. Pb-induced demyelination represents a crucial pathogenic pathway in Pb neurotoxicity, including multiple sclerosis.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992396","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":"Adolescent exposure to a mixture of per- and polyfluoroalkyl substances (PFAS) depletes the ovarian reserve, increases ovarian fibrosis, and alters the Hippo pathway in adult female mice.","authors":"Kendra L Clark, Jitu W George, John S Davis","doi":"10.1093/toxsci/kfae103","DOIUrl":"10.1093/toxsci/kfae103","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals known for their environmental persistence and resistance to biodegradation. This study investigated the impact of adolescent exposure to a PFAS mixture on adult ovarian function. Female CD-1 mice were orally exposed to vehicle control or a PFAS mixture (comprised of perfluorooctanoic acid, perfluorooctanesulfonic acid, undecafluoro-2-methyl-3-oxahexanoic acid, and perfluorobutanesulfonic acid) for 15 d. After a 42-d recovery period, reproductive hormones, ovarian fibrosis, and ovarian gene and protein expression were analyzed using ELISA, Picrosirius red staining, qPCR, and immunoblotting, respectively. Results revealed that PFAS exposure did not affect adult body or organ weight, although ovarian weight slightly decreased. PFAS-exposed mice exhibited a disturbed estrous cycle, with less time spent in proestrus than control mice. Follicle counting indicated a reduction in primordial and primary follicles. Serum analysis revealed no changes in steroid hormones, follicle-stimulating hormone, or anti-Müllerian hormone, but a significant increase in luteinizing hormone was observed in PFAS-treated mice. Ovaries collected from PFAS-treated mice had increased mRNA transcripts for steroidogenic enzymes and fatty acid synthesis-related genes. PFAS exposure also increased collagen content in the ovary. Additionally, serum tumor necrosis factor-α levels were higher in PFAS-treated mice. Finally, transcripts and protein abundance for Hippo pathway components were upregulated in the ovaries of the PFAS-treated mice. Overall, these findings suggest that adolescent exposure to PFAS can disrupt ovarian function in adulthood.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141983227","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":"Aryl hydrocarbon receptor-dependent toxicity by retene requires metabolic competence.","authors":"Christian I Rude, Lindsay B Wilson, Jane La Du, Priscila M Lalli, Sean M Colby, Katherine J Schultz, Jordan N Smith, Katrina M Waters, Robyn L Tanguay","doi":"10.1093/toxsci/kfae098","DOIUrl":"10.1093/toxsci/kfae098","url":null,"abstract":"<p><p>Polycyclic aromatic hydrocarbons (PAHs) are a class of organic compounds frequently detected in the environment with widely varying toxicities. Many PAHs activate the aryl hydrocarbon receptor (AHR), inducing the expression of a battery of genes, including xenobiotic metabolizing enzymes like cytochrome P450s (CYPs); however, not all PAHs act via this mechanism. We screened several parent and substituted PAHs in in vitro AHR activation assays to classify their unique activity. Retene (1-methyl-7-isopropylphenanthrene) displays Ahr2-dependent teratogenicity in zebrafish, but did not activate human AHR or zebrafish Ahr2, suggesting a retene metabolite activates Ahr2 in zebrafish to induce developmental toxicity. To investigate the role of metabolism in retene toxicity, studies were performed to determine the functional role of cyp1a, cyp1b1, and the microbiome in retene toxicity, identify the zebrafish window of susceptibility, and measure retene uptake, loss, and metabolite formation in vivo. Cyp1a-null fish were generated using CRISPR-Cas9. Cyp1a-null fish showed increased sensitivity to retene toxicity, whereas Cyp1b1-null fish were less susceptible, and microbiome elimination had no significant effect. Zebrafish required exposure to retene between 24 and 48 hours post fertilization (hpf) to exhibit toxicity. After static exposure, retene concentrations in zebrafish embryos increased until 24 hpf, peaked between 24 and 36 hpf, and decreased rapidly thereafter. We detected retene metabolites at 36 and 48 hpf, indicating metabolic onset preceding toxicity. This study highlights the value of combining molecular and systems biology approaches with mechanistic and predictive toxicology to interrogate the role of biotransformation in AHR-dependent toxicity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898292","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":"Mixtures of phthalates disrupt expression of genes related to lipid metabolism and peroxisome proliferator-activated receptor signaling in mouse granulosa cells.","authors":"Hanin Alahmadi, Stephanie Martinez, Rivka Farrell, Rafiatou Bikienga, Nneka Arinzeh, Courtney Potts, Zhong Li, Genoa R Warner","doi":"10.1093/toxsci/kfae105","DOIUrl":"10.1093/toxsci/kfae105","url":null,"abstract":"<p><p>Phthalates are a class of known endocrine-disrupting chemicals that are found in common everyday products. Several studies associate phthalate exposure with detrimental effects on ovarian function, including growth and development of the follicle and production of steroid hormones. We hypothesized that dysregulation of the ovary by phthalates may be mediated by phthalate toxicity towards granulosa cells, a major cell type in ovarian follicles responsible for key steps of hormone production and nourishing the developing oocyte. To test the hypothesis that phthalates target granulosa cells, we harvested granulosa cells from adult CD-1 mouse ovaries and cultured them for 96 h in vehicle control, a phthalate mixture, or a phthalate metabolite mixture (0.1 to 100 μg/ml). After culture, we measured metabolism of the phthalate mixture into monoester metabolites by the granulosa cells, finding that granulosa cells do not significantly contribute to ovarian metabolism of phthalates. Immunohistochemistry of phthalate metabolizing enzymes in whole ovaries confirmed that these enzymes are not strongly expressed in granulosa cells of antral follicles and that ovarian metabolism of phthalates likely occurs primarily in the stroma. RNA sequencing of treated granulosa cells identified 407 differentially expressed genes, with overrepresentation of genes from lipid metabolic processes, cholesterol metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Expression of significantly differentially expressed genes related to these pathways was confirmed using qPCR. Our results agree with previous findings that phthalates and phthalate metabolites have different effects on the ovary, but both interfere with PPAR signaling in granulosa cells.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141992405","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":"Defining VOC signatures of Airway Epithelial Cells with PM2.5 Exposure.","authors":"Angela L Linderholm, Eva Borras, Katyayini Aribindi, Leilani L Jones, Dante E Rojas, Keith Bein, Mitchell M McCartney, Cristina E Davis, Richart W Harper, Nicholas J Kenyon","doi":"10.1093/toxsci/kfae141","DOIUrl":"https://doi.org/10.1093/toxsci/kfae141","url":null,"abstract":"<p><p>Volatile organic compounds (VOCs) produced by the lung in response to exposure to environmental pollutants can be utilized to study their impact on lung health and function. Previously, we developed a method to measure VOCs emitted from well-differentiated tracheobronchial epithelial cells in vitro. Using this method, we exposed well-differentiated proximal (PECs) and distal airway epithelial cells (DECs) to varying doses of traffic-related air pollutants (TRAP) and wildfire particulates to determine specific VOC signatures after exposure. We utilized PM2.5 TRAP collected from the Caldecott tunnel in Oakland, CA and the 2018 Camp Fire to model \"real-life\" exposures. The VOCs were collected and extracted from Twisters and analyzed using gas chromatography-mass spectrometry (GC-MS). Exposure to both types of particulate matter (PM) resulted in specific VOC responses grouped by individual subjects with little overlap. Interestingly the VOCs produced by the PECs and DECs were also differentiated from each other. Our studies suggest that PM exposure induces a specific compartmentalized cellular response that can be exploited for future studies. This response is cell-type specific and potentially related to a phenotype we have yet to uncover.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547643","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}