Novel fluorescent and secreted transcriptional reporters for quantifying activity of the xenobiotic sensor aryl hydrocarbon receptor (AHR)

Degrelle, Séverine; Ferecatu, Ioana; Fournier, Thierry

doi:10.1016/j.envint.2022.107545

Cited by 8 publications

(6 citation statements)

References 30 publications

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“…While the discovery of the labile NFK as a potential AhR-activating metabolite demonstrates the implementation of our bioactivity-guided, fractionation-empowered metabolomics profiling workflow, additional biological validation, which controls the in-cell conversion of NFK to KYN, is essential to unambiguously confirm NFK as a novel AhR activator. Furthermore, binding competition assays, , and chemical proteomics methods like photoaffinity-based protein profiling, can further support the AhR engagement by novel activators.…”

Section: Resultsmentioning

confidence: 99%

“…Given these factors, cell-based screening becomes crucial to determine AhR activities. Conventional methods involve measuring the expression of AhR target genes, such as CYP1A1, at the mRNA, protein, and catalytic activity levels. , As AhR signaling regulates the expression of a myriad of genes, including the AHR repressor (AHRR), detoxifying monooxygenases (CYP1A1 and CYP1B1), and cytokines, these methods have found more applications in studying mechanisms of the AhR-CYP1A1 signaling rather than rapidly and robustly assessing the AhR activation by small molecules. Gene reporter assays are functional analysis techniques.…”

Section: Introductionmentioning

confidence: 99%

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Bioassay-Driven, Fractionation-Empowered, Focused Metabolomics for Discovering Bacterial Activators of Aryl Hydrocarbon Receptor

Tian,

Wang,

Hardy

et al. 2024

J. Am. Soc. Mass Spectrom.

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Aryl hydrocarbon receptor (AhR) is a transcription factor that regulates gene expression upon ligand activation, enabling microbiota-dependent induction, training, and function of the host immune system. A spectrum of metabolites, encompassing indole and tryptophan derivatives, have been recognized as activators. This work introduces an integrated, mass spectrometry-centric workflow that employs a bioassay-guided, fractionation-based methodology for the identification of AhR activators derived from human bacterial isolates. By leveraging the workflow efficiency, the complexities inherent in metabolomics profiling are significantly reduced, paving the way for an in-depth and focused mass spectrometry analysis of bioactive fractions isolated from bacterial culture supernatants. Validation of AhR activator candidates used multiple criteria�MS/MS of the synthetic reference compound, bioassay of AhR activity, and elution time confirmation using a C-13 isotopic reference�and was demonstrated for N-formylkynurenine (NFK). The workflow reported provides a roadmap update for improved efficiency of identifying bioactive metabolites using mass spectrometry-based metabolomics. Mass spectrometry datasets are accessible at the National Metabolomics Data Repository (PR001479, Project

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bioassay-Driven, Fractionation-Empowered, Focused Metabolomics for Discovering Bacterial Activators of Aryl Hydrocarbon Receptor

Tian,

Wang,

Hardy

et al. 2024

J. Am. Soc. Mass Spectrom.

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“…We then assessed the transcriptional activity of the CYP1A1 promoter using a dual luciferase reporter assay and found enhanced transcriptional activity of CYP1A1 in the PM2.5 exposed cells compared with the control cells ( Figure 9B ). Previous studies have shown that the expression of some cytochrome P450 family genes are regulated by transcription factors (TFs) ( Degrelle et al, 2022 ; Liu et al, 2022 ; Rannug, 2022 ; Shivaram et al, 2023 ). Thus, whether PM2.5 modified CYP1A1 expression via TFs in trophoblast cells was assessed.…”

Section: Resultsmentioning

confidence: 99%

PM2.5 leads to adverse pregnancy outcomes by inducing trophoblast oxidative stress and mitochondrial apoptosis via KLF9/CYP1A1 transcriptional axis

Li,

Zhang

et al. 2023

eLife

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Epidemiological studies have demonstrated that fine particulate matter (PM2.5) is associated with adverse obstetric and postnatal metabolic health outcomes, but the mechanism remains unclear. This study aimed to investigate the toxicological pathways by which PM2.5 damaged placental trophoblasts in vivo and in vitro. We confirmed that PM2.5 induced adverse gestational outcomes such as increased fetal mortality rates, decreased fetal number and weight, damaged placental structure, and increased apoptosis of trophoblasts. Additionally, PM2.5 induced dysfunction of the trophoblast cell line HTR8/SVneo, including in its proliferation, apoptosis, invasion, migration and angiogenesis. Moreover, we comprehensively analyzed the transcriptional landscape of HTR8/SVneo cells exposed to PM2.5 through RNA-Seq and observed that PM2.5 triggered overexpression of pathways involved in oxidative stress and mitochondrial apoptosis to damage HTR8/SVneo cell biological functions through CYP1A1. Mechanistically, PM2.5 stimulated KLF9, a transcription factor identified as binding to CYP1A1 promoter region, which further modulated the CYP1A1-driven downstream phenotypes. Together, this study demonstrated that the KLF9/CYP1A1 axis played a crucial role in the toxic progression of PM2.5 induced adverse pregnancy outcomes, suggesting adverse effects of environmental pollution on pregnant females and putative targeted therapeutic strategies.

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“…Once bound to PAHs, AHR moves into the cell nucleus to form a heterodimer with the aryl hydrocarbon nuclear translocator (ARNT) protein. The AHR/ARNT complex binds in turn to xenobiotic response element (XRE), a specific DNA sequence located in the promoters of target genes, and activates the transcription of a number of genes, including members of cytochrome P450 family 1 (CYP1A1, CYP1A2, CYP1B1) [ 2 , 19 ].…”

Section: Toxicants Exposure and Human Biodiversitymentioning

confidence: 99%

Evolutionary Implications of Environmental Toxicant Exposure

et al. 2022

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Homo sapiens have been exposed to various toxins and harmful compounds that change according to various phases of human evolution. Population genetics studies showed that such exposures lead to adaptive genetic changes; while observing present exposures to different toxicants, the first molecular mechanism that confers plasticity is epigenetic remodeling and, in particular, DNA methylation variation, a molecular mechanism proposed for medium-term adaptation. A large amount of scientific literature from clinical and medical studies revealed the high impact of such exposure on human biology; thus, in this review, we examine and infer the impact that different environmental toxicants may have in shaping human evolution. We first describe how environmental toxicants shape natural human variation in terms of genetic and epigenetic diversity, and then we describe how DNA methylation may influence mutation rate and, thus, genetic variability. We describe the impact of these substances on biological fitness in terms of reproduction and survival, and in conclusion, we focus on their effect on brain evolution and physiology.

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Novel fluorescent and secreted transcriptional reporters for quantifying activity of the xenobiotic sensor aryl hydrocarbon receptor (AHR)

Cited by 8 publications

References 30 publications

Bioassay-Driven, Fractionation-Empowered, Focused Metabolomics for Discovering Bacterial Activators of Aryl Hydrocarbon Receptor

Bioassay-Driven, Fractionation-Empowered, Focused Metabolomics for Discovering Bacterial Activators of Aryl Hydrocarbon Receptor

PM2.5 leads to adverse pregnancy outcomes by inducing trophoblast oxidative stress and mitochondrial apoptosis via KLF9/CYP1A1 transcriptional axis

Evolutionary Implications of Environmental Toxicant Exposure

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