Paternal DDT exposure and programming of metabolic dysfunction and cancer in offspring: Understanding the role of sperm mirnas and placenta development

父系 DDT 暴露以及后代代谢功能障碍和癌症的规划：了解精子 mirnas 和胎盘发育的作用

• 批准号: 10356857
• 负责人: Sonia de Assis
• 金额: $ 54.43万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-20 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356857
• 关键词: Adult; Affect; Age; Agriculture; American; Androgen Receptor; Animals; Attention; Biological Markers; Breast Cancer Risk Factor; C57BL/6 Mouse; Cell Culture Techniques; Cells; Chemicals; Child; Country; DNA; Data; Defect; Developing Countries; Development; Diabetes Mellitus; Disease; Dose; EZH2 gene; Embryo; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Pollutants; Enzymes; Epididymis; Epigenetic Process; Epithelial; Epithelial Cells; Europe; Exposure to; Fathers; Fertilization; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Food; Gene Expression; Generations; Genetic Transcription; Genomic Segment; Goals; Growth; Half-Life; Health; Histology; Immigrant; Impairment; In Vitro; Injections; Insecta; Lead; Link; Literature; Low Birth Weight Infant; Malaria; Malignant Neoplasms; Memory; Metabolic Diseases; Metabolic dysfunction; MicroRNAs; Microinjections; Minority; Molecular; Morphology; Mouse Cell Line; Mus; National Institute of Environmental Health Sciences; Nutrient; Paternal Exposure; Pesticides; Phenotype; Placenta; Population; Preventive; Proteins; Public Health; Publishing; RNA; Recommendation; Role; Signal Transduction; Small RNA; Source; Strategic Planning; Testing; Testis; Toxic Environmental Substances; Transcriptional Regulation; United States; Untranslated RNA; Vascularization; base; biomarker identification; blastocyst; cell type; chromatin remodeling; combat; dichlorodiphenyltrichloroethane; disorder risk; early life exposure; egg; environmental chemical; epidemiology study; experimental study; extracellular vesicles; fetal; in vivo; male; men; mouse model; next generation; non-genetic; offspring; pregnant; programs; reproductive; sensor; sperm cell; stem cell fate specification; tool; toxicant; transcriptome sequencing; trophoblast

Exposure to chemicals present in the environment can induce epigenetic changes in paternal sperm and affect risk of disease in offspring. This molecular memory of past exposures can be transmitted between generations via sperm non-coding RNAs such miRNAs. Our long-term goals to understand how parental environmental exposures can predispose children to diseases such as diabetes and cancer aligns with aims in the NIEHS’ strategic planning. The pesticide DDT(dichlorodiphenyltrichloroethane) is an environmental toxicant with endocrine disruptor (EDC) activity. While banned from Western countries for over 30 years, DDT is a persistent environmental pollutant that is still is detected in the American population, particularly in minorities and recent immigrants. Currently, the major of source of this pesticide in the U.S. is food imported from regions where DDT is used. Our preliminary data, generated in a mouse model, show that pre-conception exposure to DDT alters miRNAs in paternal sperm. More importantly, paternal DDT leads to low birth weight, a phenotype associated with reduced placenta and fetal size. Offspring of DDT fathers show metabolic dysfunction and accelerated cancer growth. We hypothesize that programming of offspring’s disease by pre-conception paternal DDT exposure occurs via sperm miRNA which alters placenta development and fetal growth. We also hypothesize that DDT exposure signals are relayed to sperm via extracellular vesicles secreted by epididymal cells. Our hypothesis will be tested in a mouse model and in cell cultures by focusing on the following aims: 1) To examine the mechanisms by which environmentally relevant doses of DDT and its metabolite, DDE, alter the miRNA (and other small RNAs) content in paternal sperm; 2) To characterize the mechanisms underlying alterations in placenta development and function resulting from paternal DDT exposure; 3) To evaluate whether miRNAs (and possibly other small RNAs) in sperm of DDT exposed males are mechanistically linked to alterations in placenta and fetal development. While the evidence showing that paternal exposures programs disease in offspring is robust, our understanding of the underlying mechanisms is still lacking. Defining the mechanisms by which paternal exposure to DDT and other EDCs can promote changes in fetal and placenta development is critical to identifying preventive tools for disease such as diabetes and cancer. This study will also contribute the general understanding of environmentally-induced non-genetic inheritance and could lead to public health recommendations to men of reproductive age. Finally, our findings could lead to potential placental biomarkers of parental exposure.

暴露于环境中存在的化学物质会引起父系基因的表观遗传变化