Di (2-ethyl hexyl) phthalate and its metabolite-induced metabolic syndrome: a review of molecular mechanisms

Objectives: Metabolic disorders, as multifactorial disorders, are induced by genetic susceptibility and exposure to environmental chemicals. Di (2-ethyl hexyl) phthalate (DEHP), a ubiquitous plasticizer, is well known as an endocrine-disrupting chemical in living organisms. In recent decades, researchers have focused on the potential of DEHP and its main metabolite (Mono (2-ethylhexyl) phthalate) (MEHP) to induce metabolic disorders. In the present review, we aimed to summarize studies regarding DEHP and MEHP-induced Metabolic syndrome (MetS) as well as address the involved mechanisms. Methods: A search has been carried out in Google Scholar, PubMed, Scopus, and Web of Science databases using appropriate keywords including ‘Metabolic syndrome’ or ‘Metabolic disorder’ or ‘Obesity’ or ‘Hyperglycemia’ or ‘Hyperlipidemia’ or ‘Hypertension’ or ‘Non-alcoholic fatty liver disease’ and ‘DEHP’ or ‘Di (2-ethyl hexyl) phthalate’ or ‘Bis(2-ethylhexyl) phthalate’ or ‘MEHP’ or ‘Mono (2-ethylhexyl) phthalate’. Studies were chosen based on inclusion and exclusion criteria. Inclusion criteria are in vitro, in vivo, epidemiological studies, and English-written studies. Exclusion criteria are lack of access to the full text of studies, editorial articles, review articles, and conference articles. Results: Animal studies indicate that DEHP and MEHP disrupt insulin hemostasis, increase glucose content, and induce hyperlipidemia and hypertension as well as obesity, which could lead to type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). DEHP and its metabolite induce such effects directly through influence on nuclear receptors such as peroxisome proliferator-activated receptors (PPARs) or indirectly through reactive oxygen species (ROS) production. Both events led to the disruption of several molecular signaling pathways and subsequently metabolic syndrome (MetS). Furthermore, epidemiological studies showed that there was a correlation between DEHP metabolites levels and obesity, hyperglycemia, and hypertension. Conclusions: According to studies, DEHP and its main metabolite have the potential to induce MetS by involving various molecular mechanisms. Epidemiological studies concerning the association of DEHP and MetS in humans are not sufficient. Therefore, more studies are needed in this regard.