In utero exposure to the endocrine disruptor di-(2-ethylhexyl) phthalate promotes local adipose and systemic inflammation in adult male offspring

Abstract

Background:Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer used to increase the flexibility of polyvinyl chloride. DEHP and its active metabolite mono-(2-ethylhexyl) phthalate are detected in many biological fluids during fetal and postnatal life. In rodent models, in utero DEHP exposure has been shown to alter sexual organ development, decrease testosterone and aldosterone production, increase body and epididymal adipose tissue weight, and raise serum lipids and glucose levels in male offspring.Objectives:The objective of this study is to characterize the effects of in utero DEHP exposure on adipose tissue development and function in male offspring.Methods:Sprague–Dawley pregnant dams were gavaged 1, 20, 50 or 300 mg DEHP per kg per day from gestational day 14 until birth.Results:Global gene expression analyses of postnatal day 60 male offspring that were exposed in utero to 300 mg DEHP per kg per day revealed increased expression of immune response and inflammation markers, and increased expression of differentiation pathway genes in the epididymal whole-adipose tissue and isolated stromal vascular fraction. C-reactive protein and tumor necrosis factor (TNF) serum levels were increased in the 300 mg DEHP in utero-exposed offspring. TNF levels in adipose tissue homogenates were increased in the 50 and 300 mg DEHP in utero-exposed offspring. Immunofluorescence studies revealed focal macrophage infiltration in whole-adipose tissue confirmed by increased CD163 tissue content.Conclusions:In utero DEHP exposure promotes local adipose tissue inflammation and chronic low-grade systemic inflammation. Moreover, evidence is presented, suggesting that DEHP increases the differentiation capacity of the pre-adipocytes of male offspring without affecting total body weight.

Adipose Tissue as a Site of Toxin Accumulation

“…Moreover, di(2-ethylhexyl) phthalate (DEHP) or its metabolite mono-(2-ethylhexyl) phthalate (MEHP) increased adipocyte differentiation in 3T3-L1 cells, (142) (115), murine mesenchymal stem cells (44), and in vivo (142) (62). Few human studies have addressed effects of BFRs on obesity and metabolic syndrome; however, adipocyte differentiation was increased by the BFRs PDBE (397) and BDE-47 (185).…”

Effects of Endocrine Disrupters on Immune Function and Inflammation

“…Campioli et al [83] found that in utero exposure of Sprague Dawley rats to DEHP resulted in increased adipose tissue inflammatory markers (e.g., TNF-α) across several doses, and this association was also reflected in the serum of offspring at the highest exposure dose. In addition, gene expression analysis showed alteration in both immune response and inflammatory-associated genes.…”

Environmental chemical risk factors for Type 2 diabetes: an update

“…One possible mechanism by which prenatal environmental exposures may influence childhood or adult disease risk is through epigenetic modifications [189], mitotically heritable changes to DNA that affect subsequent gene expression. Another possible mechanism is through the promotion of adipocyte differentiation or proliferation at critical periods of development [196]. More research is needed to elucidate the role of in utero exposure to environmental chemicals in altering adult s usceptibility to chronic disease.…”