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Interaction of fetal growth and bisphenol A in obesity

胎儿生长与双酚 A 在肥胖中的相互作用

基本信息

批准号：
9023544
负责人：
SUSAN C NAGEL
金额：
$ 51.94万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-25 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9023544
关键词：
Abdomen Acceleration Adipocytes Adult Animals Barker Hypothesis Biological Models Birth Blood flow Body Weight Cell physiology Childhood Consumption Crowding DNA Methylation Data Deposition Development Diet Dose Eating Endocrine Disruptors Epidemiology Epigenetic Process Estrogens Etiology Exposure to Fatty acid glycerol esters Feeds Female Fetal Growth Fetal Growth Retardation Fetus Food Packaging Gene Expression Genes Genotype Glucose Intolerance Growth Horns Human Hypertrophy Insulin Lead Life Location Metabolic Metabolic Diseases Modeling Molecular Profiling Mothers Mouse Strains Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Oral Administration Overweight Perinatal Perinatal Exposure Phenotype Population Rattus Regulation Reporting Sex Characteristics Siblings Testing Uterus Weaning Weight abdominal fat adipocyte differentiation base bisphenol A blood glucose regulation critical period differential expression environmental chemical estrogenic exercise intervention experience feeding fetal food consumption food restriction genetic strain high risk lipid biosynthesis male methylation pattern mouse model next generation sequencing novel nutrition obesogen obesogenic offspring postnatal pregnant prenatal rapid growth response sex

项目摘要

DESCRIPTION (provided by applicant): There continues to be controversy concerning the "obesogen" hypothesis, which proposes that exposure to certain environmental chemicals during critical periods in development is contributing to the dramatic increase in obesity that has occurred over the last two decades. We have developed a novel mouse model that results in siblings produced by hemiovariectomized mothers that range from intrauterine growth restricted (IUGR) to macrosomic based on location in one crowded uterine horn. The IUGR mice experience a dramatic 90% increase in body weight, while macrosomic males only experience a 30% increase in body weight, during the first week after weaning, after which IUGR and macrosomic males remain significantly heavier than males with a median body weight at birth. Adult IUGR mice show marked similarities to IUGR humans in terms of glucose intolerance, elevated insulin as well as an increase in total abdominal fat weight, but have markedly fewer gonadal fat pad adipocytes and markedly different gene expression profiles relative to equally obese macrosomic mice. Perinatal exposure to very low doses of BPA results in a significant increase in body weight in adulthood but a decrease in adult gonadal fat pad adipocyte and glucose intolerance, similar to untreated IUGR males, but very different from untreated macrosomic males. We propose to use our novel model in two strains of mice with different sensitivities to estrogen to examine the interaction between genotype, rate of fetal growth, postnatal nutrition (by using high and low energy feeds), and BPA exposure at human relevant doses during the critical period of adipocyte differentiation in causing different trajectories to adult obesity. We will examine effects of different doses of BPA during development in C57 and CD-1 males and females on growth, fat deposition, insulin and glucose homeostasis, adipocyte number and size, gene expression by qPCR and Next Generation sequencing and DNA methylation in adulthood and on PND 21-28. Our overarching hypothesis is that mouse fetuses with IUGR, macrosomia and normal fetal growth will show differences in the methylation pattern and expression of genes involved in the differentiation, proliferation and regulation of lipogenesis in abdominal adipocytes. In addition, a low maternal oral dose of BPA is predicted to exacerbate obesity in IUGR offspring due to acceleration of postnatal growth. We predict the effects of BPA will be related to differential DNA methylation as well as differential expression of estrogen-responsive genes in adipocytes, and that BPA will lead to a decrease in the number of adipocytes that are functionally altered and prone to hypertrophy. Perinatal exposure to BPA is predicted to interact synergistically with IUGR via additional epigenetic changes in adipocytes that alter the expression of estrogen-responsive genes and further accelerate postnatal growth.

描述（由申请人提供）：关于“肥胖原”假说的争议一直存在，该假说认为，在发育的关键时期接触某些环境化学物质会导致肥胖的急剧增加

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Obesity III: Obesogen assays: Limitations, strengths, and new directions.

DOI：
10.1016/j.bcp.2022.115014
发表时间：
2022-05
期刊：
BIOCHEMICAL PHARMACOLOGY
影响因子：
5.8
作者：
Kassotis, Christopher D.;Saal, Frederick S. vom;Babin, Patrick J.;Lagadic-Gossmann, Dominique;Le Mentec, Helene;Blumberg, Bruce;Mohajer, Nicole;Legrand, Antoine;Kos, Vesna Munic;Martin-Chouly, Corinne;Podechard, Normand;Langoue, Sophie;Touma, Charbel;Barouki, Robert;Kim, Min Ji;Audouze, Karine;Choudhury, Mahua;Shree, Nitya;Bansal, Amita;Howard, Sarah;Heindel, Jerrold J.
通讯作者：
Heindel, Jerrold J.

Prenatal Exposure to Unconventional Oil and Gas Operation Chemical Mixtures Altered Mammary Gland Development in Adult Female Mice.

产前接触非常规石油和天然气作业化学混合物会改变成年雌性小鼠的乳腺发育。

DOI：
10.1210/en.2017-00866
发表时间：
2018
期刊：
Endocrinology
影响因子：
4.8
作者：
Sapouckey,SarahA;Kassotis,ChristopherD;Nagel,SusanC;Vandenberg,LauraN
通讯作者：
Vandenberg,LauraN

Perinatal exposure to endocrine disruptors: sex, timing and behavioral endpoints.

DOI：
10.1016/j.cobeha.2015.11.017
发表时间：
2016-02
期刊：
Current opinion in behavioral sciences
影响因子：
5
作者：
Palanza P;Nagel SC;Parmigiani S;Vom Saal FS
通讯作者：
Vom Saal FS

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.

DOI：
10.1016/j.reprotox.2013.07.017
发表时间：
2013-12
期刊：
Reproductive toxicology (Elmsford, N.Y.)
影响因子：
0
作者：
Angle BM;Do RP;Ponzi D;Stahlhut RW;Drury BE;Nagel SC;Welshons WV;Besch-Williford CL;Palanza P;Parmigiani S;vom Saal FS;Taylor JA
通讯作者：
Taylor JA

Risk Evaluation of Endocrine-Disrupting Chemicals: Effects of Developmental Exposure to Low Doses of Bisphenol A on Behavior and Physiology in Mice (Mus musculus).