Long-term dietary administration of diethyl phthalate triggers loss of insulin sensitivity in two key insulin target tissues of mice

Abstract

Over the past years, a growing body of work has linked numerous pervasive environmental chemicals with a multitude of adverse reproductive, developmental, behavioral, and metabolic changes in humans and animal models. Plasticizers include a wide variety of phthalate esters that are extensively used in a host of personal day care and cosmetic products. Many population-based studies have indicated a close association between diethyl phthalate (DEP) and diabetes albeit the mechanisms remain much unexplored. Presently, we report that long-term dietary administration of DEP to adult male Swiss albino mice at two different concentrations mirroring the recommended tolerable doses, severely impaired insulin signaling in hepatocytes and adipocytes. This was concomitant with sustained oxidative stress from the overactivation of NADPH oxidase 2, a major intracellular source of reactive oxygen species, in both the cell types. The present study provides evidences of the onset of insulin resistance in mice after chronic exposure to DEP in diet even at lower levels. This, in turn, can have serious pathological consequences with ultimate manifestations of type 2 diabetes and metabolic syndrome (MetS). Thus, by disrupting the central metabolic function of liver and adipose tissue, the key insulin target tissues, daily exposure to phthalates in plastics can potentially contribute to the alarming prevalence of MetS in recent times.

Consequences of in vitro benzyl butyl phthalate exposure for blubber gene expression and insulin-induced Akt activation in juvenile grey seals

“…Since insulin typically acts through the activation of Akt (Sutherland et al 2013), we examined BBzP influence on Akt phosphorylation. Overnight and longer exposures to HMW phthalates, including BBzP, alter Akt phosphorylation in other species and tissues (Chen et al, 2013;Rajesh and Balasubramanian, 2014;Deng et al, 2018;Ding et al, 2019b;Mondal and Mukherjee, 2020;Mohammadi and Ashari, 2021;Zhang and Choudhury, 2021). Here, overnight BBzP exposure had no effect on total Akt protein expression or its basal or insulin-induced phosphorylation in grey seal blubber.…”

“…Phthalates can act through phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt), a key effector in the insulin signalling pathway (Pereira-Fernandes et al, 2014;Mohammadi and Ashari, 2021). High doses in rodents can also reduce insulin secretion and exacerbate glucose intolerance and insulin insensitivity mediated by altered signalling through PI3K and Akt (Deng et al, 2018;Ding et al, 2019b;Mondal and Mukherjee, 2020;Mohammadi and Ashari, 2021). BBzP is a particularly obesogenic phthalate (Yin et al, 2016), more so than other, more abundant HMW phthalates, such as di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP) (Pereira-Fernandes et al, 2013.…”

Diethyl phthalate, a plasticizer, induces adipocyte inflammation and apoptosis in mice after long‐term dietary administration

“…This study is an extension of our previous work and is based on the same experimental model. [10,11] In brief, adult male Swiss albino mice 8-week-old weighing 20-25 g were housed in a 12 h light/12 h dark cycle environment at 23 ± 2°C and relative humidity 55 ± 5% along with access to drinking water and a standard diet (Carbohydrate [57.3%]; Protein [18.1%]; Fat [4.1%] with added vitamins and minerals) ad libitum. [23] After acclimatization for 1 week, the mice were randomly divided into three groups of six animals each and treated for 3 months as depicted in the flowchart (Figure 1).…”

Modelling and parameter estimation of diethyl phthalate partitioning behaviour on glass and aluminum surfaces

“…Semi-volatile organic compounds (SVOCs), such as phthalates, can partition between different materials and their surrounding air in indoor environments, affecting levels of human exposure to these compounds, which have been associated with adverse health effects, including endocrine disruption, cancer, birth defects and alteration of insulin signalling molecules which could trigger type 2 diabetes (Miles-Richardson, 2017;Mondal and Mukherjee, 2020). Thus, understanding the distribution of these compounds is fundamental for properly assessing and quantifying levels of human exposure (Cao et al, 2016;Eichler et al, 2018;Xu and Little, 2006).…”

“…For instance, the loss of plasticisers such as DEP from cellulose acetate-based artefacts is known to initiate or promote physical changes, such as warping, crazing, cracking and brittleness, which could ultimately reduce the value of these art objects (Da Ros et al, 2021;Richardson et al, 2014;Shashoua, 2008;Strlič et al, 2013). Furthermore, although the partial substitution of DEP by less volatile phthalates has led to a reduction of its worldwide consumption (IHS Markit, 2018), DEP still finds application in a wide range of consumer products, including orthodontic adhesives and dentures, cosmetic formulations (such as bath oils, tablets and salts; eye shadow, perfumes, hair sprays, nail polish and enamel removers, nail extenders, detergents, aftershave lotions and skin care products), and pharmaceutical products (such as in coatings for drug controlled release) (Mondal and Mukherjee, 2020;Sekizawa et al, 2003;Wypych, 2017). Thus, it is not surprising that DEP is still found as an important constituent of pollutants in indoor (Fromme et al, 2004;Yang et al, 2020) and outdoor (Vasiljevic et al, 2021) environments.…”