Abstract
Triclosan (TCS), as a broad spectrum antibacterial agent, is commonly utilized in personal care and household products. Maternal urinary TCS level has been associated with changes in birth weight of infants. We in the present study investigated whether exposure of mice to 8 mg/kg TCS from gestational day (GD) 6 to GD14 alters prenatal and postnatal growth and development, and metabolic phenotypes in male and female offspring (TCS-offspring). Compared with control offspring, body weight in postnatal day (PND) 1 male or female TCS-offspring was reduced, but body weight gain was faster within postnatal 5 days. PND30 and PND60 TCS-offspring showed overweight with increases in visceral fat and adipocyte size. PND60 TCS-offspring displayed delayed glucose clearance and insulin resistance. PND30 TCS-offspring showed an increase in food intake without the changes in the oxygen consumption and respiratory exchange ratio (RER). The expression levels of proopiomelanocortin (POMC), α-melanocyte-stimulating hormone (α-MSH) and single-minded 1 (SIM1) in hypothalamus arcuate nucleus (ARC) and paraventricular nucleus (PVN), respectively, were significantly reduced in PND30 TCS-offspring compared to controls. The hypermethylation of CpG sites at the POMC promoter was observed in PND30 TCS-offspring, while the concentration of serum leptin was elevated and the level of STAT3 phosphorylation in ARC had no significant difference from control. This study demonstrates that TCS exposure during early/mid-gestation through the hypermethylation of the POMC promoter reduces the expression of anorexigenic neuropeptides to cause the postnatal hyperphagic obesity, leading to metabolic syndrome in adulthood.
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Acknowledgements
This work was supported by Grants for National Natural Science Foundation of China (81671253; 81471157); National 973 Basic Research Program of China (2014CB943303); Jiangsu provincial Natural Science Foundation of China (BE2016765); Science and Technology Development Foundation of Nanjing Medical University (2017NJMU006).
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Xu Hua and Ya-Jie Zhang performed the animal care, drug administration, measurements of food intake and energy expenditure, measurement of plasma glucose and insulin, and DNA methylation analysis. Jian-Wei Xiong participated in the histological examinations and western blot analysis. Xin-Yuan Cao contributed to statistical analyses. Peng Sun participated in for the experimental design. Ling Chen and Jie Wu are responsible for the experimental design and finished the manuscript.
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Hua, X., Xiong, JW., Zhang, YJ. et al. Exposure of pregnant mice to triclosan causes hyperphagic obesity of offspring via the hypermethylation of proopiomelanocortin promoter. Arch Toxicol 93, 547–558 (2019). https://doi.org/10.1007/s00204-018-2338-1
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DOI: https://doi.org/10.1007/s00204-018-2338-1