New insights into the regulation of cyp3a65 expression in transgenic tg(cyp3a65:GFP) zebrafish embryos.

Facing the need for alternative models allowing assessment of metabolic-endocrine disrupting chemicals (MDCs), especially in poorly investigated tissues such as the intestine, we recently developed a transgenic zebrafish embryo in vivo model, tg(cyp3a65:GFP), expressing the Green Fluorescent Protein (GFP) under the control of the zebrafish cyp3a65 promoter, ortholog of human cyp3a4, a gene coding for a key enzyme of intestinal xenobiotic and endobiotic metabolism. In this study, we aimed to better understand the regulation of cyp3a65 expression by zfPXR, zfAhR2, and zfGR zebrafish orthologs of well-known human xenosensors PXR and AhR, and steroid nuclear receptor GR. For this purpose, we performed zebrafish embryo tg(cyp3a65:GFP) (co)exposures to a variety of agonists (clotrimazole, TCDD, fluticasone propionate) and antagonists (econazole nitrate, CH223181, RU486), which were characterized using in vitro zebrafish reporter gene assays.

Metabolic disrupting chemicals in the intestine: the need for biologically relevant models: Zebrafish: what can we learn from this small environment-sensitive fish?

Although the concept of endocrine disruptors first appeared almost 30 years ago, the relatively recent involvement of these substances in the etiology of metabolic pathologies (obesity, diabetes, hepatic steatosis, etc.) has given rise to the concept of Metabolic Disrupting Chemicals (MDCs). Organs such as the liver and adipose tissue have been well studied in the context of metabolic disruption by these substances.

Per- and polyfluoroalkyl substances as persistent pollutants with metabolic and endocrine-disrupting impacts.

The widespread use of per- and polyfluoroalkyl substances (PFASs), and their resistance to degradation, renders human exposure to them inevitable. PFAS exposure disturbs endocrine function, potentially affecting cognitive development in newborns through thyroid dysfunction during pregnancy. Recent studies reveal varying male and female reproductive toxicity across PFAS classes, with alternative analogs affecting sperm parameters and legacy PFASs correlating with conditions like endometriosis.

Assessing the contribution of the chemical exposome to neurodegenerative disease.

Over the past few decades, numerous environmental chemicals from solvents to pesticides have been suggested to be involved in the development and progression of neurodegenerative diseases. Most of the evidence has accumulated from occupational or cohort studies in humans or laboratory research in animal models, with a range of chemicals being implicated. What has been missing is a systematic approach analogous to genome-wide association studies, which have identified dozens of genes involved in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.

Food additive emulsifiers and the risk of type 2 diabetes: analysis of data from the NutriNet-Santé prospective cohort study.

Background: Experimental studies have suggested potential detrimental effects of emulsifiers on gut microbiota, inflammation, and metabolic perturbations. We aimed to investigate the associations between exposures to food additive emulsifiers and the risk of type 2 diabetes in a large prospective cohort of French adults.

Methods: We analysed data from 104 139 adults enrolled in the French NutriNet-Santé prospective cohort study from May 1, 2009, to April 26, 2023; 82 456 (79·2%) were female and the mean age was 42·7 years (SD 14·5).

Digital Futures of Learning Pharmacology and Medicinal and Organic Chemistry.

Traditional pharmacology and medicinal and organic chemistry teaching often rely on the trusted textbook visuals. However, students may struggle to grasp mechanisms that appear too complex. Because the pandemic has mandated the majority of educators to use new techniques and innovative technology in their communication approaches with students, we offer several digital strategies for educators to explore and/or to enhance student learning.

Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps.

The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they are referenced in the AOP-Wiki database, which is supported by the OECD. Here, we present a study that aims at identifying well-defined biological areas, as well as gaps within the AOP-Wiki for future research needs.

Food additive emulsifiers and cancer risk: Results from the French prospective NutriNet-Santé cohort.

Background: Emulsifiers are widely used food additives in industrially processed foods to improve texture and enhance shelf-life. Experimental research suggests deleterious effects of emulsifiers on the intestinal microbiota and the metabolome, leading to chronic inflammation and increasing susceptibility to carcinogenesis. However, human epidemiological evidence investigating their association with cancer is nonexistent.

Costs of molecular adaptation to the chemical exposome: a focus on xenobiotic metabolism pathways.

Organisms adapt to their environment through different pathways. In vertebrates, xenobiotics are detected, metabolized and eliminated through the inducible xenobiotic-metabolizing pathways (XMP) which can also generate reactive toxic intermediates. In this review, we will discuss the impacts of the chemical exposome complexity on the balance between detoxication and side effects.

Assessment of endocrine disruptor impacts on lipid metabolism in a fatty acid-supplemented HepaRG human hepatic cell line.

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. This disease encompasses several stages, from steatosis to steatohepatitis and, eventually, to fibrosis and cirrhosis. Exposure to environmental contaminants is one of the risk factors and an increasing amount of evidence points to a role for endocrine disrupting compounds (EDCs).

Editorial trend: adverse outcome pathway (AOP) and computational strategy - towards new perspectives in ecotoxicology.

The adverse outcome pathway (AOP) has been conceptualized in 2010 as an analytical construct to describe a sequential chain of causal links between key events, from a molecular initiating event leading to an adverse outcome (AO), considering several levels of biological organization. An AOP aims to identify and organize available knowledge about toxic effects of chemicals and drugs, either in ecotoxicology or toxicology, and it can be helpful in both basic and applied research and serve as a decision-making tool in support of regulatory risk assessment. The AOP concept has evolved since its introduction, and recent research in toxicology, based on integrative systems biology and artificial intelligence, gave it a new dimension.

SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex.

Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in two interconnected metabolic processes for energy production: the transfer of electrons in the mitochondrial respiratory chain and the oxidation of succinate to fumarate in the Krebs cycle.

The Role of the Kynurenine/AhR Pathway in Diseases Related to Metabolism and Cancer.

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand's battery, emphasizing the different responses triggered by these high diverse molecules.

Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study.

Objective: To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD).

Design: Prospective cohort study.

Setting: French NutriNet-Santé study, 2009-21.

The effects of pollutant mixture released from grafted adipose tissues on fatty acid and lipid metabolism in the skeletal muscles, kidney, heart, and lungs of male mice.

Persistent organic pollutants (POPs) accumulated in the adipose tissue can affect the fatty acid and lipid metabolism in the body. Gas chromatography-mass spectrometry (GC-MS) metabolomics analysis was carried out to study the metabolic changes induced by internal exposure to the POPs in mouse skeletal muscle (soleus, plantaris, and gastrocnemius), kidney, heart, and lungs. Male donor mice were injected with a mixture of 10 POPs at concentrations of 0 × and 5 × lowest-observed-adverse-effect level (LOAEL).

NMR metabolomics study of chronic low-dose exposure to a cocktail of persistent organic pollutants.

Nowadays, exposure to endocrine-disrupting chemicals (EDCs), including persistent organic pollutants (POPs), is one of the most critical threats to public health. EDCs are chemicals that mimic, block, or interfere with hormones in the body's endocrine system and have been associated with a wide range of health issues. This innovative, untargeted metabolomics study investigates chronic low-dose internal exposure to a cocktail of POPs on multiple tissues that are known to accumulate these lipophilic compounds.

New approach methodologies to facilitate and improve the hazard assessment of non-genotoxic carcinogens-a PARC project.

Carcinogenic chemicals, or their metabolites, can be classified as genotoxic or non-genotoxic carcinogens (NGTxCs). Genotoxic compounds induce DNA damage, which can be detected by an established and battery of genotoxicity assays. For NGTxCs, DNA is not the primary target, and the possible modes of action (MoA) of NGTxCs are much more diverse than those of genotoxic compounds, and there is no specific assay for detecting NGTxCs.

The Ah Receptor from Toxicity to Therapeutics: Report from the 5th AHR Meeting at Penn State University, USA, June 2022.

The aryl hydrocarbon receptor (AHR) is a sensor of low-molecular-weight molecule signals that originate from environmental exposures, the microbiome, and host metabolism. Building upon initial studies examining anthropogenic chemical exposures, the list of AHR ligands of microbial, diet, and host metabolism origin continues to grow and has provided important clues as to the function of this enigmatic receptor. The AHR has now been shown to be directly involved in numerous biochemical pathways that influence host homeostasis, chronic disease development, and responses to toxic insults.

Benzo(a)pyrene and Cerium Dioxide Nanoparticles in Co-Exposure Impair Human Trophoblast Cell Stress Signaling.

Human placenta is a multifunctional interface between maternal and fetal blood. Studying the impact of pollutants on this organ is crucial because many xenobiotics in maternal blood can accumulate in placental cells or pass into the fetal circulation. Benzo(a)pyrene (BP) and cerium dioxide nanoparticles (CeO NP), which share the same emission sources, are found in ambient air pollution and also in maternal blood.

Nutritional Modulation of Associations between Prenatal Exposure to Persistent Organic Pollutants and Childhood Obesity: A Prospective Cohort Study.

Background: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disorders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations.

Objectives: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on childhood obesity.

The exposome and liver disease - how environmental factors affect liver health.

Since the initial development of the exposome concept, much effort has been devoted to the characterisation of the exposome through analytical, epidemiological, and toxicological/mechanistic studies. There is now an urgent need to link the exposome to human diseases and to include exposomics in the characterisation of environment-linked pathologies together with genomics and other omics. Liver diseases are particularly well suited for such studies since major functions of the liver include the detection, detoxification, and elimination of xenobiotics, as well as inflammatory responses.

Cigarette smoke and tumor microenvironment copromote aggressiveness of human breast cancer cells.

Breast cancer is a major public health issue and the role of pollutants in promoting breast cancer progression has recently been suggested. We aimed to assess if a mixture of pollutants, cigarette smoke, could favor the aggressivity of breast cancer cells. We also evaluated the impact of the tumor microenvironment, largely represented by adipocytes, in mediating this modification of cell phenotype.

Inhibition by pesticides of the DJ-1/Park7 protein related to Parkinson disease.

Parkinson's disease is a severe neurodegenerative disease. Several environmental contaminants such as pesticides have been suspected to favor the appearance of this pathology. The protein DJ-1 (or Park7) protects against the development of Parkinson's disease.