Steatosis and Metabolic Disorders Associated with Synergistic Activation of the CAR/RXR Heterodimer by Pesticides.

The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation results in metabolic disorders, including non-alcoholic fatty liver disease, by activating lipogenesis in the liver. Our objective was to determine whether synergistic activations of the CAR/RXR heterodimer could occur in vivo as described in vitro by other authors, and to assess the metabolic consequences. For this purpose, six pesticides, ligands of CAR, were selected, and Tri-butyl-tin (TBT) was used as an RXR agonist. In mice, CAR's synergic activation was induced by dieldrin associated with TBT, and combined effects were induced by propiconazole, bifenox, boscalid, and bupirimate. Moreover, a steatosis, characterized by increased triglycerides, was observed when TBT was combined with dieldrin, propiconazole, bifenox, boscalid, and bupirimate. Metabolic disruption appeared in the form of increased cholesterol and lowered free fatty acid plasma levels. An in-depth analysis revealed increased expression of genes involved in lipid synthesis and lipid import. These results contribute to the growing understanding of how environmental contaminants can influence nuclear receptor activity and associated health risks.

Are BPA Substitutes as Obesogenic as BPA?

Metabolic diseases, such as obesity, Type II diabetes and hepatic steatosis, are a significant public health concern affecting more than half a billion people worldwide. The prevalence of these diseases is constantly increasing in developed countries, affecting all age groups. The pathogenesis of metabolic diseases is complex and multifactorial. Inducer factors can either be genetic or linked to a sedentary lifestyle and/or consumption of high-fat and sugar diets. In 2002, a new concept of "environmental obesogens" emerged, suggesting that environmental chemicals could play an active role in the etiology of obesity. Bisphenol A (BPA), a xenoestrogen widely used in the plastic food packaging industry has been shown to affect many physiological functions and has been linked to reproductive, endocrine and metabolic disorders and cancer. Therefore, the widespread use of BPA during the last 30 years could have contributed to the increased incidence of metabolic diseases. BPA was banned in baby bottles in Canada in 2008 and in all food-oriented packaging in France from 1 January 2015. Since the BPA ban, substitutes with a similar structure and properties have been used by industrials even though their toxic potential is unknown. Bisphenol S has mainly replaced BPA in consumer products as reflected by the almost ubiquitous human exposure to this contaminant. This review focuses on the metabolic effects and targets of BPA and recent data, which suggest comparable effects of the structural analogs used as substitutes.

[Oral cavity as a target and a marker of environmental exposures: developmental dental defects]. / La sphère orale, cible et marqueur de l'exposition environnementale - I. Défauts du développement dentaire.

The oral cavity is one of the main route for environmental contaminations associated to many chronic diseases (cancers, fertility and behavior disorders for example) via alimentation, medications and respiration. These environmental factors including, among others, endocrine disruptors and excessive fluoride can disrupt dental development and thus generate irreversible enamel defects. These defects are then treated with materials that may release molecules capable of generating these defects, leading to a vicious circle, particularly in pregnant women and young children. The present paper aims to review the state of knowledge, questions and controversies on common environmental factors in contact with the oral cavity. It also reviews their mechanisms of action and the mediators involved in enamel pathologies associated with environmental conditions. Dental tissues can not only be targeted by environmental factors but can also serve as early and easily accessible markers of exposure to these agents. Understanding and characterizing the environmental impact in the oral cavity will help to prevent multiple diseases, oral and distant, whose link with oral homeostasis is just being explored.

TITLE: La sphère orale, cible et marqueur de l'exposition environnementale - I. Défauts du développement dentaire. ABSTRACT: La cavité buccale est l'une des voies majeures des contaminations environnementales connues pour être impliquées dans de nombreuses pathologies chroniques (cancers, troubles de la fertilité et du comportement) via l'alimentation, les médications ou même la respiration. Ces facteurs environnementaux incluant, entre autres, des perturbateurs endocriniens et le fluor en excès, peuvent perturber le développement dentaire et ainsi générer des défauts irréversibles de l'émail. Ces défauts sont alors traités avec des matériaux dont certains libèrent des molécules capables à leur tour de générer ces défauts, conduisant à un cercle vicieux, notamment chez la femme enceinte et le jeune enfant. Cette synthèse fait le point sur l'état des connaissances, les questions et controverses sur les facteurs environnementaux courants susceptibles d'entrer en contact avec la sphère orale, leurs mécanismes d'actions et les médiateurs impliqués dans les pathologies de l'émail associées aux conditions environnementales.

Environmental pollutants, a possible etiology for premature ovarian insufficiency: a narrative review of animal and human data.

BACKGROUND: Because only 25% of cases of premature ovarian insufficiency (POI) have a known etiology, the aim of this review was to summarize the associations and mechanisms of the impact of the environment on this pathology. Eligible studies were selected from an electronic literature search from the PUBMED database from January 2000 to February 2016 and associated references in published studies. Search terms included ovary, follicle, oocyte, endocrine disruptor, environmental exposure, occupational exposure, environmental contaminant, pesticide, polyaromatic hydrocarbon, polychlorinated biphenyl PCB, phenol, bisphenol, flame retardant, phthalate, dioxin, phytoestrogen, tobacco, smoke, cigarette, cosmetic, xenobiotic. The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We have included the human and animal studies corresponding to the terms and published in English. We have excluded articles that included results that did not concern ovarian pathology and those focused on ovarian cancer, polycystic ovary syndrome, endometriosis or precocious puberty. We have also excluded genetic, auto-immune or iatrogenic causes from our analysis. Finally, we have excluded animal data that does not concern mammals and studies based on results from in vitro culture. Data have been grouped according to the studied pollutants in order to synthetize their impact on follicular development and follicular atresia and the molecular pathways involved. Ninety-seven studies appeared to be eligible and were included in the present study, even though few directly address POI. Phthalates, bisphenol A, pesticides and tobacco were the most reported substances having a negative impact on ovarian function with an increased follicular depletion leading to an earlier age of menopause onset. These effects were found when exposure occured at different times throughout the lifetime from the prenatal to the adult period, possibly due to different mechanisms. The main mechanism seemed to be an increase in atresia of pre-antral follicles. CONCLUSION: Environmental pollutants are probably a cause of POI. Health officials and the general public must be aware of this environmental effect in order to implement individual and global preventive actions.

A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie.

Quinacrine was reported to have a marked in vitro antiprion action in mouse neuroblastoma cells. On compassionate grounds, quinacrine was administered to Creutzfeldt-Jakob disease patients, despite the absence of preclinical in vivo studies to evaluate efficacy. Quinacrine failed to provide therapeutic benefit. The aim of the study was to investigate possible pharmacokinetic and/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine in vitro and its lack of clinical efficacy. We conducted in vitro experiments reproducing the culture conditions in which antiprion effects had been previously observed and recalculated the EC(50) by determining the actual extracellular (120 nM) and intracellular (6713 nM) quinacrine neuroblastoma concentrations with the reported quinacrine EC(50) (300 nM). A randomized clinical trial in scrapie-affected ewes confirmed the absence of therapeutic benefit of quinacrine. The in vivo quinacrine exposure was evaluated in a pharmacokinetic investigation in healthy ewes. Cerebrospinal fluid concentrations (<10.6 and 55 nM after administration of therapeutic and toxic quinacrine doses, respectively) were much lower than the quinacrine extracellular neuroblastoma concentrations corresponding to the reported EC(50). The total brain tissue concentrations (3556 nM) obtained after a repeated therapeutic dosage regimen were within the range of the intracellular neuroblastoma quinacrine concentrations. In conclusion, in order to avoid in vivo trials for which failure can be predicted, the measurement in vitro of the antiprion EC(50) in both intra- and extracellular biophases should be determined. It can then be established if these in vitro antiprion concentrations are achievable in vivo.