Chronic exposure to a pollutant mixture at low doses led to tissue-specific metabolic alterations in male mice fed standard and high-fat high-sucrose diet

Abstract

Excessive consumption of industrialized food and beverages is a major etiologic factor in the epidemics of obesity and associated metabolic diseases because these products are rich in fat and sugar. In addition, they contain food contact materials and environmental pollutants identified as metabolism disrupting chemicals. To evaluate the metabolic impact of these dietary threats (individually or combined), we used a male mouse model of chronic exposure to a mixture of low-dose archetypal food-contaminating chemicals that was added in standard or high-fat, high-sucrose (HFHS) diet. Specifically, the mixture contained bisphenol A, diethylhexylphthalate, 2,3,7,8-tetrachlorodibenzo-p-dioxine and polychlorinated biphenyl 153. Exposure lasted from 5 to 20 weeks of age. Metabolic exploration was conducted setting the basis of candidate gene expression mRNA analyses in liver, jejunum and adipose tissue depots from 20 week-old mice. Strong metabolic deleterious effects of the HFHS diet were demonstrated in line with obesity-associated metabolic features and insulin resistance. Pollutant exposure resulted in significant changes on plasma triglyceride levels and on the expression levels of genes mainly encoding xenobiotic processing in jejunum; estrogen receptors, regulators of lipoprotein lipase and inflammatory markers in jejunum and adipose tissues as well as adipogenesis markers. Importantly, the impact of pollutants was principally evidenced under standard diet. In addition, depending on nutritional conditions and on the metabolic tissue considered, the impact of pollutants could mimic or oppose the HFHS effects. Collectively, the present study extends the cocktail effect concept of a low-dosed pollutant mixture and originally points to tissue-specificity responsiveness especially in jejunum and adipose tissues. 3 Highlights: Low-dosed pollutants trigger metabolic disturbances in postnatally exposed male mice The mixture of pollutants induced metabolic alterations in a tissue-specific manner Jejunum is highly sensitive with regards to xenobiotic receptors and lipolysis Pollutants have a greatest metabolic impact in standard nutritional conditions Differences in the response to the pollutant mixture were seen between the 2 fat pads

Estrogen withdrawal and replacement differentially target liver and adipose tissues in female mice fed a high-fat high-sucrose diet: impact of a chronic exposure to a low-dose pollutant mixture☆

“…Importantly, we observed that the response to the mixture of pollutants was highly tissue-dependent extending our previous data [26,50]. While we did not identify estrogenomimetic activities of the pollutant mixture in the liver, the situation was clearly distinct in SAT.…”

“…We expected these genes to exhibit changes in mRNA levels in response to chronic exposure to a mixture of archetypal endocrine disruptors previously identified as bearing some estrogeno-mimetic activities as well as metabolic disrupting effects [25,27,50]. Specifically, the protocol used herein was adapted from the published previous model [25,26] except that female mice were not exposed to the [25,27,50], the mixture did not impact body weight. No changes were observed in glucose tolerance or insulin resistance in the mice exposed compared to those not exposed to the pollutant mixture.…”

“…For example, it was demonstrated that hepatic metabolic gene expression in adult mice including Esr1 was strongly impacted in mice exposed in utero to BPA as compared to control mice [59]. In addition, the vulnerability of the fetal period towards exposure to the presently used mixture of pollutants has been evidenced in male mice [50].…”

Exposure to pollutants altered glucocorticoid signaling and clock gene expression in female mice. Evidence of tissue- and sex-specificity

“…The purpose of the current study was to address the implication of glucocorticoid signaling in mediating the effects of the pollutants in female mice. We also looked for sexual dimorphism benefiting from male samples taken in a previous study (Naville et al, 2019).…”

The EDCMET Project: Metabolic Effects of Endocrine Disruptors

“…Indeed, epidemiological data from humans and experimental data from rodents indicate that exposure to certain EDs, the so-called metabolism disrupting chemicals (MDCs), may predispose patients to different components of metabolic syndrome, T2D, and NAFLD (for reviews, see [15][16][17][18][19][20]). The main targets for MDCs are liver and adipose tissue, where they can provoke, e.g., adipogenesis and fat accumulation [21], insulin resistance [22], and changes in cholesterol and bile acid metabolism [18][19][20]. MDCs have also been shown to regulate nutrient ingestion and metabolism by altering the composition of gut microbiota and intestinal transport.…”