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Cited by 21Effects and risks of endocrine disrupting chemicalsPeroxisome Proliferator-Activated ReceptorsToxic Organic Pollutants Impact

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

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Hunt, Brian G., Wang, Yuan-Liang, Chen, Min-Shan, Wang, Shao-Chun, Waltz, Susan E.·2017·Environmental Research
DOI 10.1016/j.envres.2017.09.004PMC PMC5653374
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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.

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  • Animal studies of BPA and phalate exposure in utero have consistently shown increased offspring adiposity in later life.

    “Animal studies of BPA and phalate exposure in utero have consistently shown to increase offspring adiposity in later life (Table 5 and [106, 110–112]).”

    From Developmental programming of offspring adipose tissue biology and obesity risk (2021) · cites this paper as [112]

    The Results (no page available) report increased fat-pad mass after high-dose maternal DEHP exposure, but only in female offspring with the PCNA mutation; wild-type offspring did not show increased weight gain. This supports a conditional finding for one phthalate, not the claim that animal studies of BPA and phthalates have consistently found increased offspring adiposity. (LLM, conf=0.90)

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Cited by

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Authors
Hunt, B. G., Wang, Y.-L., Chen, M.-S., Wang, S.-C., & Waltz, S. E.
Affiliations
  • University of Cincinnati (US)
  • Asia University (TW)
  • Cincinnati VA Medical Center (US)
Corresponding author
  • Wang, Shao-Chun
  • Waltz, Susan E.
ORCID
Venue
Environmental Research
Publisher
Elsevier BV
Published
2017-11
Volume
159
Pages
588-594
ISSN
0013-9351 (ISSN-L)
DOI
10.1016/j.envres.2017.09.004
PMC
PMC5653374
OpenAlex
W2754864922
Cited by
21
References
1
Citations by year
2024: 3 · 2023: 1 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 1 · 2018: 3
FWCI
1.18
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Environmental Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (ES023942)
Topics
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Keywords
DEHP, plasticizers, endocrine disruptors, adipogenesis, diet-induced obesity, insulin sensitivity, PPARγ, maternal exposure, prenatal exposure, perinatal exposure, high-fat diet, adiposity
MeSH terms
Animals, Diethylhexyl Phthalate, Environmental Pollutants, Female, Insulin Resistance, Male, Obesity, Phosphorylation, Pregnancy, Prenatal Exposure Delayed Effects, Proliferating Cell Nuclear Antigen, Maternal Exposure, Adiposity, Mice

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