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Environ Res. 2017 Nov;159:588-594. doi: 10.1016/j.envres.2017.09.004. Epub 2017 Sep 12.

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

Author information

1
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA.
2
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan.
3
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA; Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan; College of Medicine, Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: wangsc@mail.cmuh.org.tw.
4
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA; Research Service, Cincinnati Veteran's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: susan.waltz@uc.edu.

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.

KEYWORDS:

Obesity; PCNA; Phthalate exposure; Prenatal exposure; Proliferating cell nuclear antigen

PMID:
28915506
PMCID:
PMC5653374
DOI:
10.1016/j.envres.2017.09.004
[Indexed for MEDLINE]
Free PMC Article

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