Long-term physiological and behavioral outcomes, epigenetic profiles and multigenerational phenotypes in a mouse ART model

小鼠 ART 模型中的长期生理和行为结果、表观遗传特征和多代表型

• 批准号: 9921459
• 负责人: MARISA S. BARTOLOMEI
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921459
• 关键词: ATAC-seq; Abnormal placentation; Accounting; Affect; Angelman Syndrome; Animal Model; Applications Grants; Assisted Reproductive Technology; Basic Science; Beckwith-Wiedemann Syndrome; Behavior; Behavioral; Biological Assay; Biological Models; Birth; Body mass index; Cardiac; Cardiovascular Abnormalities; Cardiovascular Physiology; Cells; Cesarean section; Child; Chromatin Structure; Congenital Abnormality; Country; Couples; DNA Methylation; Diagnosis; Disease; Embryo; Embryonic Development; Environmental Exposure; Epigenetic Process; European; Exhibits; Fertilization in Vitro; Fetal Tissues; Fetal Weight; Fetus; Fostering; Foundations; Frequencies; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Growth; Health; Heart Diseases; Hormonal; Human; Iatrogenesis; Individual; Infertility; Knowledge; Lead; Link; Low Birth Weight Infant; Maternal Age; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modification; Molecular; Mus; Mutation; National Institute of Child Health and Human Development; Outcome; Phenotype; Physiological; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Premature Birth; Procedures; Reporting; Risk; Silver-Russell syndrome; Structure; Superovulation; Systemic blood pressure; Testing; Therapeutic; Tissues; United States; Validation; Variant; Weight; Weight Gain; Work; adverse outcome; behavioral outcome; behavioral phenotyping; design; embryo cryopreservation; embryo culture; epigenomics; experimental study; fetal; genome-wide; high throughput analysis; human data; imprint; improved; infertility treatment; mouse model; next generation; novel strategies; offspring; placental morphology; postnatal; prognostic; stillbirth; transcriptome sequencing; transmission process

Abstract Infertile couples are increasingly turning to Assisted Reproductive Technologies (ART) to treat their infertility. Of growing concern is that ART-conceived children are at increased risk for specific loss-of-imprinting disorders, congenital malformations, growth restriction, preeclampsia as well as postnatal cardiac and metabolic disorders. Given the difficulty of conducting studies using human embryos, a mouse model system, which anticipated some risks associated with ART, will be used to assess the effects of ART on placental morphology, imprinted gene regulation, growth, metabolic, cardiac and behavioral phenotypes of the offspring, and gene expression and chromatin structure genome-wide. Specific Aim 1 will assess the phenotypes, including growth, behavior metabolism and cardiovascular function, of ART-offspring in comparison to naturally-conceived controls. We will also interrogate imprinted gene regulation and gene expression, DNA methylation and chromatin structure using gene-specific and high throughput analyses. Moreover, the design of this aim will enable us to isolate, phenotype and match placenta to offspring to determine whether the placental phenotype can accurately predict health of in vitro fertilization (IVF)-derived offspring. Because we have previously reported a low frequency of epigenetic errors in multiple tissues of IVF-conceived offspring, we hypothesize that the germline cells also harbor epigenetic mutations. In Specific Aim 2, we will test this hypothesis by determining whether aberrant phenotypes observed in IVF offspring are transmitted to subsequent generations and, if so, assess the mechanism of this transmission. The result from these experiments will provide a trove of information regarding the linkage between epigenetic changes and health of offspring conceived by ART and whether placental phenotyping can predict offspring health. Our findings may also suggest experimental modifications to ART procedures that can improve offspring outcomes. !

摘要