Early exposure to endocrine disruptors and the metabolic syndrome: a review of animal studies.

ABSTRACT Background. The prevalence of non communicable diseases, such as cardiovascular (hypertension) and metabolic (obesity, type 2 diabetes, dyslipidemia) diseases, often clustered under the definition of metabolic syndrome, is remarkably increasing worldwide and is among causes of premature mortality. Numerous studies have shown that part of their origins can be found during development, schematically from peri-conceptional period to the end of the second year of the child’s life. This period represents a vulnerability window during which alterations of fetus’, newborn’s or young child’s environment can imprint durable epigenetics marks, designing life trajectories which may be at risk for chronic diseases during their course. It has been hypothesized that an early exposure to substances altering hormonal homeostasis, namely endocrine disruptors, play a role in the metabolic syndrome manifesting later in life. Objectives. •To identify in scientific literature studies on cardio-metabolic alterations induced by early exposure to endocrine disruptors. • To characterize at best scientific evidence from animal studies, linking early exposure to endocrine disruptors with the metabolic syndrome at adulthood, and its limitations. • To determine the endocrine disruptors shown to be responsible for such alterations, exposition doses and the most sensitive period to their effects. • To describe the main pathogenic mechanisms for every biological system concerned, at cellular and molecular levels, with particular attention to epigenetic alterations (CpG islands promoters methylation of some genes, histones modifications, non coding RNA). • To identify possible preventative interventions aiming to decrease endocrine disruptors influence during the sensitive period and identify early metabolic syndrome biomarkers. Method. This is a narrative and critical review of scientific literature. Bibliographic research of scientific literature was principally realized in PubMed (https://www.ncbi.nlm.nih.gov/pubmed) and Embase (https://www.elsevier.com/solutions/embase-biomedical-research) databases, completed by Google Schoolar (https://scholar.google.ch/). Two librarians from the medicine university library helped us with search strategies. Animal model studies were included. Results. Animals exposed to endocrine disruptors early in their life displayed phenotypes associated with metabolic syndrome features at adulthood. An exposure occurring between the peri- conceptional period and the weaning, mainly to bisphenol A, but also to other plasticizers and industry related compounds such as phthalates, dioxins and flame retardants, has been associated with: body weight increase with adipose tissue accumulation, insulin resistance and glucose intolerance, dyslipidemia and hypertension (these last two conditions have been less but still observed). Concerning underlying mechanisms proposed, lipid metabolism-related pathways such as Peroxisome Proliferator-Activated Receptor-alpha and -gamma, Fatty acid synthase and Carnitine palmitoyltransferase among others have been associated with obesity. In T2DM ones, Glucokinase and Glucose Transporter gene appeared possible involved pathways, while implication of Lipoprotein lipase and RAAS-related genes have been observed in dyslipidemia and HT studies respectively. Also, epigenetic mechanisms such as CpG hypermethylation of key genes promoters have been reported as potential “programming” mechanisms involved in obesity and T2DM