Francisco Inesta-Vaquera , Wenduo Qi , Silviya Dimova-Vasileva , G. Jean Campbell , Febe Ferro , Richard Meehan , Sari Pennings , C. Roland Wolf
{"title":"整合体内应激报告与转录谱来定义化学混合物的毒性机制,包括跨代效应。","authors":"Francisco Inesta-Vaquera , Wenduo Qi , Silviya Dimova-Vasileva , G. Jean Campbell , Febe Ferro , Richard Meehan , Sari Pennings , C. Roland Wolf","doi":"10.1016/j.cbi.2025.111699","DOIUrl":null,"url":null,"abstract":"<div><div>Humans are exposed to mixtures of chemical pollutants from various environmental sources at all stages of life. Understanding how these compounds are causally linked to population health effects is challenging because of the ethical limitations on studying controlled human exposures and the complexity of the many potential molecular mechanisms involved. We hypothesized that studies using a combination of <em>in vivo</em> murine stress reporter models together with non-targeted global transcriptome analysis will define the toxic mechanisms of complex chemical mixtures in a physiological context. To test this hypothesis, a panel of stress reporter mice were subjected to a mixture of polychlorinated biphenyls (PCBs), persistent environmental pollutants typified by Aroclor 1254 (A1254). In time-dependent and <em>trans</em>-lactational exposure studies we observed activation of stress responses in liver using reporters for <em>Cyp1a1</em> (aryl hydrocarbons receptor, AHR pathway) and <em>Hmox1</em> (oxidative stress and inflammation). Whole liver transcriptional analysis revealed distinct Aroclor 1254-linked signatures including xenobiotic metabolism (AHR, CAR/PXR), oxidative stress (Nrf2), cell proliferation, and carcinogenesis. A combination of genetic and biochemical approaches revealed that NRF2 does not mediate <em>Hmox1</em> activation following A1254 exposure but plays a major role in regulating the expression of genes involved in mitosis. We further demonstrate the utility of our reporter approach to detect the activation of stress responses in mouse neonates exposed to A1254 by lactational transfer. Intriguingly, we observed robust <em>Hmox1</em> reporter activation in neonate livers for up to two generations following initial maternal exposure. Thus, we exemplify how a combination of <em>in vivo</em> reporter and transcriptional analysis captures novel mechanistic insights into the effects of chemical mixtures of persistent organic pollutants in a relevant physiological context and with cellular resolution, after both primary exposure and in a transgenerational manner. This approach may be applied to understand the full spectrum of mechanisms of toxicity of other chemical mixtures of concern in the physiological context.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111699"},"PeriodicalIF":5.4000,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Integration of in vivo stress reporters with transcription profiling to define chemical mixtures mechanisms of toxicity, including trans-generational effects\",\"authors\":\"Francisco Inesta-Vaquera , Wenduo Qi , Silviya Dimova-Vasileva , G. Jean Campbell , Febe Ferro , Richard Meehan , Sari Pennings , C. Roland Wolf\",\"doi\":\"10.1016/j.cbi.2025.111699\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Humans are exposed to mixtures of chemical pollutants from various environmental sources at all stages of life. Understanding how these compounds are causally linked to population health effects is challenging because of the ethical limitations on studying controlled human exposures and the complexity of the many potential molecular mechanisms involved. We hypothesized that studies using a combination of <em>in vivo</em> murine stress reporter models together with non-targeted global transcriptome analysis will define the toxic mechanisms of complex chemical mixtures in a physiological context. To test this hypothesis, a panel of stress reporter mice were subjected to a mixture of polychlorinated biphenyls (PCBs), persistent environmental pollutants typified by Aroclor 1254 (A1254). In time-dependent and <em>trans</em>-lactational exposure studies we observed activation of stress responses in liver using reporters for <em>Cyp1a1</em> (aryl hydrocarbons receptor, AHR pathway) and <em>Hmox1</em> (oxidative stress and inflammation). Whole liver transcriptional analysis revealed distinct Aroclor 1254-linked signatures including xenobiotic metabolism (AHR, CAR/PXR), oxidative stress (Nrf2), cell proliferation, and carcinogenesis. A combination of genetic and biochemical approaches revealed that NRF2 does not mediate <em>Hmox1</em> activation following A1254 exposure but plays a major role in regulating the expression of genes involved in mitosis. We further demonstrate the utility of our reporter approach to detect the activation of stress responses in mouse neonates exposed to A1254 by lactational transfer. Intriguingly, we observed robust <em>Hmox1</em> reporter activation in neonate livers for up to two generations following initial maternal exposure. Thus, we exemplify how a combination of <em>in vivo</em> reporter and transcriptional analysis captures novel mechanistic insights into the effects of chemical mixtures of persistent organic pollutants in a relevant physiological context and with cellular resolution, after both primary exposure and in a transgenerational manner. This approach may be applied to understand the full spectrum of mechanisms of toxicity of other chemical mixtures of concern in the physiological context.</div></div>\",\"PeriodicalId\":274,\"journal\":{\"name\":\"Chemico-Biological Interactions\",\"volume\":\"421 \",\"pages\":\"Article 111699\"},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2025-09-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemico-Biological Interactions\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0009279725003291\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-Biological Interactions","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009279725003291","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Integration of in vivo stress reporters with transcription profiling to define chemical mixtures mechanisms of toxicity, including trans-generational effects
Humans are exposed to mixtures of chemical pollutants from various environmental sources at all stages of life. Understanding how these compounds are causally linked to population health effects is challenging because of the ethical limitations on studying controlled human exposures and the complexity of the many potential molecular mechanisms involved. We hypothesized that studies using a combination of in vivo murine stress reporter models together with non-targeted global transcriptome analysis will define the toxic mechanisms of complex chemical mixtures in a physiological context. To test this hypothesis, a panel of stress reporter mice were subjected to a mixture of polychlorinated biphenyls (PCBs), persistent environmental pollutants typified by Aroclor 1254 (A1254). In time-dependent and trans-lactational exposure studies we observed activation of stress responses in liver using reporters for Cyp1a1 (aryl hydrocarbons receptor, AHR pathway) and Hmox1 (oxidative stress and inflammation). Whole liver transcriptional analysis revealed distinct Aroclor 1254-linked signatures including xenobiotic metabolism (AHR, CAR/PXR), oxidative stress (Nrf2), cell proliferation, and carcinogenesis. A combination of genetic and biochemical approaches revealed that NRF2 does not mediate Hmox1 activation following A1254 exposure but plays a major role in regulating the expression of genes involved in mitosis. We further demonstrate the utility of our reporter approach to detect the activation of stress responses in mouse neonates exposed to A1254 by lactational transfer. Intriguingly, we observed robust Hmox1 reporter activation in neonate livers for up to two generations following initial maternal exposure. Thus, we exemplify how a combination of in vivo reporter and transcriptional analysis captures novel mechanistic insights into the effects of chemical mixtures of persistent organic pollutants in a relevant physiological context and with cellular resolution, after both primary exposure and in a transgenerational manner. This approach may be applied to understand the full spectrum of mechanisms of toxicity of other chemical mixtures of concern in the physiological context.
期刊介绍:
Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.