Sex- and Dose-Specific Effects of Maternal Bisphenol A Exposure on Pancreatic Islets of First- and Second-Generation Adult Mice Offspring

被引:89
作者
Bansal, Amita [1 ,2 ,3 ]
Rashid, Cetewayo [1 ,2 ,3 ]
Xin, Frances [2 ,4 ]
Li, Changhong [5 ]
Polyak, Erzsebet [6 ]
Duemler, Anna [1 ,7 ]
van der Meer, Tom [1 ,8 ]
Stefaniak, Martha [4 ]
Wajid, Sana [9 ]
Doliba, Nicolai [10 ]
Bartolomei, Marisa S. [1 ,2 ,4 ]
Simmons, Rebecca A. [1 ,2 ,3 ]
机构
[1] Univ Penn, Ctr Res Reprod & Womens Hlth, Perelman Sch Med, 1308 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA
[2] Univ Penn, Ctr Excellence Environm Toxicol, Perelman Sch Med, Philadelphia, PA 19104 USA
[3] Childrens Hosp Philadelphia, Div Neonatol, Philadelphia, PA 19104 USA
[4] Univ Penn, Epigenet Inst, Dept Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA
[5] Childrens Hosp Philadelphia, Dept Pediat, Div Endocrinol & Diabet, Philadelphia, PA 19104 USA
[6] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA
[7] Penn State Univ, Eberly Coll Sci, University Pk, PA 16802 USA
[8] Univ Groningen, Dept Pediat, Groningen, Netherlands
[9] Univ Penn, Perelman Sch Med, Exposure Biol Informat Core, Philadelphia, PA 19104 USA
[10] Univ Penn, Dept Biochem & Biophys, Perelman Sch Med, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
ESTROGEN-RECEPTOR-ALPHA; BETA-CELL MASS; GROWTH-FACTOR-II; MESSENGER-RIBONUCLEIC-ACID; MITOCHONDRIAL DYSFUNCTION; DEVELOPMENTAL EXPOSURE; EPIGENETIC DISRUPTION; GLUCOSE-HOMEOSTASIS; PERINATAL EXPOSURE; INSULIN-SECRETION;
D O I
10.1289/EHP1674
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
摘要
BACKGROUND: Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring. OBJECTIVE: We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets. METHODS: Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10 mu g/kg/d-LowerB and 10 mg/kg/d-UpperB). RESULTS: Both doses of BM significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and-UpperB induced islet inflammation in male 1 offspring that persisted into the next generation. We also observed close-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced beta-cell mass and increased beta-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important beta-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation. CONCLUSION: These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications.
引用
收藏
页数:18
相关论文
共 111 条
[1]   Relationship of serum bisphenol A with diabetes in the Thai population, National Health Examination Survey IV, 2009 [J].
Aekplakorn, Wichai ;
Chailurkit, La-or ;
Ongphiphadhanakul, Boonsong .
JOURNAL OF DIABETES, 2015, 7 (02) :240-249
[2]   Association of urinary bisphenol a concentration with type-2 diabetes mellitus [J].
Ahmadkhaniha, Reza ;
Mansouri, Masoumeh ;
Yunesian, Masud ;
Omidfar, Kobra ;
Jeddi, Maryam Zare ;
Larijani, Bagher ;
Mesdaghinia, Alireza ;
Rastkari, Noushin .
JOURNAL OF ENVIRONMENTAL HEALTH SCIENCE AND ENGINEERING, 2014, 12
[3]   Screening and testing for endocrine disruption in fish - Biomarkers as "signposts," not "traffic lights," in risk assessment [J].
Hutchinson, Thomas H. ;
Ankley, Gerald T. ;
Segner, Helmut ;
Tyler, Charles R. .
ENVIRONMENTAL HEALTH PERSPECTIVES, 2006, 114 :106-114
[4]   Prenatal Exposure to BPA and Offspring Outcomes: The Diabesogenic Behavior of BPA [J].
Alonso-Magdalena, Paloma ;
Quesada, Ivan ;
Nadal, Angel .
DOSE-RESPONSE, 2015, 13 (02)
[5]   Bisphenol-A Treatment During Pregnancy in Mice: A New Window of Susceptibility for the Development of Diabetes in Mothers Later in Life [J].
Alonso-Magdalena, Paloma ;
Garcia-Arevalo, Marta ;
Quesada, Ivan ;
Nadal, Angel .
ENDOCRINOLOGY, 2015, 156 (05) :1659-1670
[6]   Bisphenol A Exposure during Pregnancy Disrupts Glucose Homeostasis in Mothers and Adult Male Offspring [J].
Alonso-Magdalena, Paloma ;
Vieira, Elaine ;
Soriano, Sergi ;
Menes, Lorena ;
Burks, Deborah ;
Quesada, Ivan ;
Nadal, Angel .
ENVIRONMENTAL HEALTH PERSPECTIVES, 2010, 118 (09) :1243-1250
[7]   Economic Costs of Diabetes in the U.S. in 2012 [J].
Yang W. ;
Dall T.M. ;
Halder P. ;
Gallo P. ;
Kowal S.L. ;
Hogan P.F. ;
Petersen M. .
DIABETES CARE, 2013, 36 (04) :1033-1046
[8]   Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation [J].
Angle, Brittany M. ;
Do, Rylee Phuong ;
Ponzi, Davide ;
Stahlhut, Richard W. ;
Drury, Bertram E. ;
Nagel, Susan C. ;
Welshons, Wade V. ;
Besch-Williford, Cynthia L. ;
Palanza, Paola ;
Parmigiani, Stefano ;
vom Saal, Frederick S. ;
Taylor, Julia A. .
REPRODUCTIVE TOXICOLOGY, 2013, 42 :256-268
[9]   Mitochondrial metabolism sets the maximal limit of fuel-stimulated insulin secretion in a model pancreatic beta cell - A survey of four fuel secretagogues [J].
Antinozzi, PA ;
Ishihara, H ;
Newgard, CB ;
Wollheim, CB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (14) :11746-11755
[10]   Glucocorticoid-Induced Preterm Birth and Neonatal Hyperglycemia Alter Ovine β-Cell Development [J].
Bansal, Amita ;
Bloomfield, Frank H. ;
Connor, Kristin L. ;
Dragunow, Mike ;
Thorstensen, Eric B. ;
Oliver, Mark H. ;
Sloboda, Deborah M. ;
Harding, Jane E. ;
Alsweiler, Jane M. .
ENDOCRINOLOGY, 2015, 156 (10) :3763-3776