Abstract
The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental ‘window’ contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.
References
54
Referenced
178
10.1002/bdra.20140
/ Birth Defects Res. A Clin. Mol. Teratol. / Overview of clinical perspectives and mechanisms of obesity by Collins (2005)10.1001/jama.289.1.76
/ JAMA, J. Am. Med. Assoc. / Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001 by Mokdad (2003)10.1001/jama.282.16.1519
/ JAMA, J. Am. Med. Assoc. / The spread of the obesity epidemic in the United States, 1991–1998 by Mokdad (1999)10.1001/jama.288.14.1728
/ JAMA, J. Am. Med. Assoc. / Prevalence and trends in overweight among US children and adolescents, 1999–2000 by Ogden (2002)10.1016/j.mce.2009.02.017
/ Cell. Endocrinol. / PPAR-mediated activity of phthalates: a link to the obesity epidemic? Mol by Desvergne (2009)10.1016/j.envres.2007.10.006
/ Environ. Res. / High serum PCBs are associated with elevation of serum lipids and cardiovascular disease in a Native American population by Goncharov (2008)10.1016/S0022-3476(00)90012-X
/ J. Pediatr. / Pubertal growth and development and prenatal and lactational exposure to polychlorinated biphenyls and dichlorodiphenyl dichloroethene by Gladen (2000)10.1097/01.ede.0000220553.84350.c5
/ Epidemiology / Polybrominated biphenyls, polychlorinated biphenyls, body weight, and incidence of adult-onset diabetes mellitus by Vasiliu (2006)10.2337/dc06-2190
/ Diabetes Care / Association between serum concentrations of persistent organic pollutants and insulin resistance among non-diabetic adults: results from the National Health and Nutrition Examination Survey 1999–2002 by Lee (2007)10.1007/s00125-007-0896-5
/ Diabetologia / Can persistent organic pollutants explain the association between serum γ-glutamyltransferase and type 2 diabetes? by Lee (2008)10.1093/toxsci/67.1.46
/ Toxicol. Sci. / Associations between weight loss-induced changes in plasma organochlorine concentrations, serum T3 concentration, and resting metabolic rate by Pelletier (2002)10.1111/j.1651-2227.2008.00937.x
/ Acta Paediatr. / Exposure to hexachlorobenzene during pregnancy increases the risk of overweight in children aged 6 years by Smink (2008)10.1289/ehp.9882
/ Environ. Health Perspect. / Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males by Stahlhut (2007)10.1186/1476-069X-7-27
/ Environ. Health / Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999–2002 by Hatch (2008)10.1507/endocrj.51.165
/ Endocr. J. / Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction by Takeuchi (2004)10.1210/en.2005-1129
/ Endocrinology / Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling by Grün (2006)10.1016/0048-9697(87)90072-6
/ Sci. Total Environ. / Diethylhexylphthalate as an environmental contaminant – a review by Wams (1987)10.1136/oem.2004.017590
/ Occup. Environ. Med. / Phthalates and human health by Hauser (2005)10.1007/s00204-003-0522-3
/ Arch. Toxicol. / Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP by Koch (2004)10.1080/10408440600779065
/ Crit. Rev. Toxicol. / Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver by Rusyn (2006)10.1016/S0278-6915(98)00065-9
/ Food Chem. Toxicol. / Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat by Arcadi (1998)10.1006/taap.1998.8550
/ Toxicol. Appl. Pharmacol. / Effects of relatively low levels of mono-(2-ethylhexyl) phthalate on cocultured Sertoli cells and gonocytes from neonatal rats by Li (1998)10.1093/toxsci/kfj128
/ Toxicol. Sci. / A dose–response study following in utero and lactational exposure to di(2-ethylhexyl)phthalate: effects on female rat reproductive development by Grande (2006)10.1074/jbc.M702724200
/ J. Biol. Chem. / The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor γ modulator that promotes adipogenesis by Feige (2007)10.1146/annurev.biochem.77.061307.091829
/ Annu. Rev. Biochem. / Fat and beyond: the diverse biology of PPARγ by Tontonoz (2008)10.1016/S0041-008X(03)00083-8
/ Toxicol. Appl. Pharmacol. / AhR- and ERK-dependent pathways function synergistically to mediate 2,3,7,8-tetrachlorodibenzo-p-dioxin suppression of peroxisome proliferator-activated receptor-γ 1 expression and subsequent adipocyte differentiation by Hanlon (2003)10.1016/S0021-9258(17)37913-9
/ J. Biol. Chem. / Participation of one isozyme of cytosolic glycerophosphate dehydrogenase in the adipose conversion of 3T3 cells by Wise (1979)10.1006/bbrc.1999.1885
/ Biochem. Biophys. Res. Commun. / Role of the CCAAT enhancer binding proteins (C/EBPs) in adipocyte differentiation by Lane (1999)10.1073/pnas.0337434100
/ Proc. Natl. Acad. Sci. U.S.A. / CCAAT/enhancer binding protein beta is required for mitotic clonal expansion during adipogenesis by Tang (2003)10.1101/gad.13.17.2231
/ Genes Dev. / Activation and centromeric localization of CCAAT/enhancer-binding proteins during the mitotic clonal expansion of adipocyte differentiation by Tang (1999)10.1093/jn/130.12.3122S
/ J. Nutr. / Adipocyte differentiation and gene expression by Ntambi (2000)10.1016/j.tem.2008.11.005
/ Trends Endocrinol. Metab. / New developments in adipogenesis by Lefterova (2009)10.1016/j.cmet.2006.07.001
/ Cell Metab. / Transcriptional control of adipocyte formation by Farmer (2006)10.14310/horm.2002.1271
/ Hormones (Athens) / Impact of environmental endocrine disrupting chemicals on the development of obesity by Newbold (2010)10.1093/toxsci/kfh253
/ Toxicol. Sci. / Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters by Bility (2004)10.1093/toxsci/kfg145
/ Toxicol. Sci. / Activation of PPARα and PPARγ by environmental phthalate monoesters by Hurst (2003)10.1210/me.2005-0367
/ Mol. Endocrinol. / Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates by Grün (2006)10.1289/ehp.10554
/ Environ. Health Perspect. / Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis by Arsenescu (2008)10.1289/ehp.11342
/ Environ. Health Perspect. / Perinatal exposure to bisphenol a alters early adipogenesis in the rat by Somm (2009)10.5551/jat.E486
/ J. Atheroscler. Thromb. / Perinatal and postnatal exposure to bisphenol a increases adipose tissue mass and serum cholesterol level in mice by Miyawaki (2007)10.1002/bdra.20147
/ Birth Defects Res. A Clin. Mol. Teratol. / Developmental exposure to estrogenic compounds and obesity by Newbold (2005)10.1016/j.reprotox.2007.07.005
/ Reprod. Toxicol. / Chapel Hill Bisphenol A Expert Panel Consensus Statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure by vom Saal (2007)10.1093/toxsci/68.1.121
/ Toxicol. Sci. / Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague–Dawley rats by Tyl (2002)10.1093/toxsci/kfn084
/ Toxicol. Sci. / Two-generation reproductive toxicity study of dietary bisphenol A in CD-1 (Swiss) mice by Tyl (2008)10.1210/en.2006-0365
/ Endocrinology / Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner by Penza (2006)10.1289/ehp.0901217
/ Environ. Health Perspect. / The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms by Feige (2010)10.1016/j.tox.2011.02.007
/ Toxicology / Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)-phthalate on offspring of mice by Hayashi (2011)10.1006/taap.1999.8809
/ Toxicol. Appl. Pharmacol. / trans-Activation of PPARα and PPARγ by structurally diverse environmental chemicals by Maloney (1999){'key': '2021111618135276700_B49', 'first-page': '31', 'article-title': 'Two generation reproductive and developmental toxicity following subchronic exposure of pubescent male mice to di(2-ethylhexyl)phthalate', 'volume': '19', 'author': 'Dobrzyńska', 'year': '2012', 'journal-title': 'Ann. Agric. Environ. Med.'}
/ Ann. Agric. Environ. Med. / Two generation reproductive and developmental toxicity following subchronic exposure of pubescent male mice to di(2-ethylhexyl)phthalate by Dobrzyńska (2012)10.1021/pr200765v
/ J. Proteome Res. / Combined transcriptomic-1H NMR metabonomic study reveals that mono-ethylhexyl-phthalate stimulates adipogenesis and glyceroneogenesis in human adipocytes by Ellero-Simatos (2011)10.1016/S0092-8674(00)81654-2
/ Cell / PPARγ: an essential regulator of adipogenesis and modulator of fat cell function by Lowell (1999)10.1371/journal.pone.0030983
/ PLoS ONE / Mammalian ste20-like kinase and SAV1 promote 3T3-L1 adipocyte differentiation by activation of PPARγ by Park (2012)10.1023/B:PHAM.0000041444.06122.8d
/ Pharm. Res. / Peroxisome proliferator-activated receptor (PPAR)-α: a pharmacological target with a promising future by van Raalte (2004)10.1074/jbc.M210062200
/ J. Biol. Chem. / Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor γ1 (PPARγ1) overexpression by Yu (2003)
Dates
Type | When |
---|---|
Created | 12 years, 11 months ago (Sept. 7, 2012, 7:49 a.m.) |
Deposited | 3 years, 9 months ago (Nov. 16, 2021, 1:41 p.m.) |
Indexed | 2 days, 9 hours ago (Aug. 31, 2025, 7:16 p.m.) |
Issued | 12 years, 10 months ago (Oct. 19, 2012) |
Published | 12 years, 10 months ago (Oct. 19, 2012) |
Published Online | 12 years, 10 months ago (Oct. 19, 2012) |
Published Print | 12 years, 9 months ago (Dec. 1, 2012) |
@article{Hao_2012, title={The endocrine disruptor mono-(2-ethylhexyl)phthalate promotes adipocyte differentiation and induces obesity in mice}, volume={32}, ISSN={1573-4935}, url={http://dx.doi.org/10.1042/bsr20120042}, DOI={10.1042/bsr20120042}, number={6}, journal={Bioscience Reports}, publisher={Portland Press Ltd.}, author={Hao, Chanjuan and Cheng, Xuejia and Xia, Hongfei and Ma, Xu}, year={2012}, month=oct, pages={619–629} }