Maternal diethylhexyl phthalate exposure affects adiposity and insulin tolerance in offspring in a PCNA-dependent manner

Abstract

The ubiquitous plasticizer, diethylhexyl phthalate (DEHP), is a known endocrine disruptor. However, DEHP exposure effects are not well understood. Changes in industrial and agricultural practices have resulted in increased prevalence of DEHP exposure and has coincided with the heightened occurrence of metabolic syndrome and obesity. DEHP and its metabolites are detected in the umbilical cord blood of newborns; however, the prenatal and perinatal effects of DEHP exposure have not been intensively studied. Previously, we discovered that phosphorylation (p) of proliferating cell nuclear antigen (PCNA) at tyrosine 114 (Y114) is required for adipogenesis and diet-induced obesity in mice. Here, we show the unique ability of DEHP to induce p-Y114 in PCNA in vitro. We also show that while DEHP promotes adipogenesis of wild type (WT) murine embryonic fibroblasts, mutation of Y114 to phenylalanine (Y114F) in PCNA blocked adipocyte differentiation. Given the induction of p-Y114 in PCNA by DEHP and the relationship to obesity, WT and Y114F PCNA mice were exposed to DEHP during gestation or lactation, followed by high fat diet feeding. Paradoxically, in utero exposure of Y114F PCNA females to DEHP led to a significant increase in body mass and was associated with augmented expression of PPARγ, a critical regulator of obesity, compared to WT controls. In utero exposure of WT mice to DEHP led to insulin sensitivity while Y114F mutation ablated this phenotype, indicating that PCNA is an important regulator of early DEHP exposure and ensuing metabolic phenotypes.

Analysis of Lipid Metabolism, Immune Function, and Neurobehavior in Adult C57BL/6JxFVB Mice After Developmental Exposure to di (2-ethylhexyl) Phthalate

“…We observed transient increases in body weight in females and transient decreases in body weight in males in a few weeks, but taking the entire follow up period into account, no clear impact on body weight was observed. In line with our findings, recent studies report a lack of effects on body weight after developmental exposure to DEHP ( 34 , 36 , 37 ). After 27 weeks of age, we continued with the body weight measurements, performed a locomotion test and studied the glucose homeostasis via glucose and insulin tolerance tests.…”

“…The studies above report alteration in serum lipids under a normal diet. In our experimental setting, we studied for the first time the effect of developmental exposure to DEHP in combination with a HFD challenge as calorie-rich diets are tightly linked to the pandemic of metabolic disorders ( 37 ). We pinpoint here increases in 2 parameters out of 4 related to lipid metabolism studied (TG's, FFA, CHOL, HDL-C).…”

Perinatal phthalate and high-fat diet exposure induce sex-specific changes in adipocyte size and DNA methylation

“…PND 90 females showed no differences in either body weight or body composition. This is consistent with findings from our group and others [26,[33][34][35]. In PND 90 males, on the other hand, HF diet alone as well as 200 μg/kg/day phthalates increased body weight.…”

Developmental programming of offspring adipose tissue biology and obesity risk

“…In humans, maternal urinary BPA has been associated with increased hip to waist ratios in the offspring, an affect that was more severe in females [109]. Animal studies of BPA and phalate exposure in utero have consistently shown to increase offspring adiposity in later life (Table 5 and [106,[110][111][112]). In part, these changes are associated with enhanced adipocyte size, infiltration of inflammatory leukocytes, and elevated expression of lipogenic markers, like PPAR-γ and SREBP [113].…”