Intrauterine exposure to low-dose DBP in the mice induces obesity in offspring via suppression of UCP1 mediated ER stress

Huan Li,Zhenting Qu,Xiaolei Xu,Jianqiao Li,Jing Zhang,Shengyuan Liu,Honghao Qian,Hongyan Wang

doi:10.1038/s41598-020-73477-3

Huan Li, Zhenting Qu + Show 6 more

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https://doi.org/10.1038/s41598-020-73477-3

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Abstract

Dibutyl phthalate (DBP) is recognized as an environmental endocrine disruptor that has been detected in fetal and postnatal samples. Recent evidence found that in utero DBP exposure was associated with an increase of adipose tissue weight and serum lipids in offspring, but the precise mechanism is unknown. Here we aimed to study the effects of in utero DBP exposure on obesity in offspring and examine possible mechanisms. SPF C57BL/6J pregnant mice were gavaged with either DBP (5 mg /kg/day) or corn oil, from gestational day 12 until postnatal day 7. After the offspring were weaned, the mice were fed a standard diet for 21 weeks, and in the last 2 weeks 20 mice were selected for TUDCA treatment. Intrauterine exposure to low-dose DBP promoted obesity in offspring, with evidence of glucose and lipid metabolic disorders and a decreased metabolic rate. Compared to controls, the DBP exposed mice had lower expression of UCP1 and significantly higher expression of Bip and Chop, known markers of endoplasmic reticulum (ER) stress. However, TUDCA treatment of DBP exposed mice returned these parameters nearly to the levels of the controls, with increased expression of UCP1, lower expression of Bip and Chop and ameliorated obesity. Intrauterine exposure of mice to low-dose DBP appears to promote obesity in offspring by inhibiting UCP1 via ER stress, a process that was largely reversed by treatment with TUDCA.

Highlights

Obesity is a metabolic disorder disease characterized by energy imbalance and excessive accumulation of fat
The growth and development of all mice were normal throughout the experimental period, but the body weights in the dibutyl phthalate (DBP) group were significantly higher than those in the Ctrl group from 15 to 21 weeks (Fig. 1A)
H&E staining showed that the volume of the adipocytes that constitute the epididymal white adipose tissue (eWAT) in the DBP group was significantly larger than in the Ctrl group (Fig. 1E)

Summary

Introduction

Obesity is a metabolic disorder disease characterized by energy imbalance and excessive accumulation of fat. The obesogens hypothesis suggests that endocrine disrupting chemicals (EDCs) in the environment are the main cause of o besity[1,2]. Phthalate esters (PAEs), which are widely used in the manufacturing of plastics have been implicated as EDCs, and studies have suggested that low-dose PAEs exposure may be associated with obesity. There is evidence that Mono(2-ethylhexyl) phthalate (MEHP) interferes with the biological transformation of adipose tissue, disrupts the endocrine hormone system and causes the dysregulation of the hypothalamic–pituitary–adrenal control system to promote the formation of fat through a variety of biological pathways, including interference with steroid or thyroid hormones and activation of P PARs5. Similar observations were made by Maresca et al in an urban population cohort, suggesting that pre-natal DEHP exposure is associated with increases in early childhood BMI, waist circumference and body fat content[8]. Intrauterine DBP exposure was used to study its effect on offspring obesity

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