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: 10529335
• 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/10529335
• 关键词: Acceleration; Adult; Affect; Age; Agriculture; American; Androgen Receptor; Animals; Attention; Biological Markers; Breast Cancer Risk Factor; C57BL/6 Mouse; Cell Culture Techniques; Cells; Chemicals; Child; Conceptions; 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 Cells; Epithelium; Europe; Euthanasia; Exposure to; Fathers; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Reduction; Fetal Tissues; Food; Gene Expression; Generations; Genetic Transcription; Genomic Segment; Goals; Growth; Half-Life; Health; Histology; Immigrant; Impairment; In Vitro; Injections; Insecta; 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; blastocyst; cell type; chromatin remodeling; combat; dichlorodiphenyltrichloroethane; disorder risk; early life exposure; 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; transmission process; trophoblast; zygote

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可诱导父体的表观遗传变化。 影响后代患病风险。这种对过去暴露的分子记忆可以 通过精子非编码RNA如miRNA在世代之间传递。我们的长期目标 了解父母的环境暴露如何使儿童易患疾病， 因为糖尿病和癌症与NIEHS战略规划的目标一致。农药 DDT（二氯二苯三氯乙烷）是一种具有内分泌干扰作用的环境毒物 (EDC)活动虽然DDT在西方国家已经被禁止了30多年，但它仍然是一种持久的杀虫剂。 环境污染物仍然在美国人口中检测到，特别是在少数民族中 最近的移民。目前，该农药在美国的主要来源是进口食品 从使用滴滴涕的地区。我们在小鼠模型中生成的初步数据表明， 怀孕前暴露于DDT会改变父亲精子中的miRNAs。更重要的是， DDT导致低出生体重，这是一种与胎盘减少和胎儿大小有关的表型。 DDT父亲的后代表现出代谢功能障碍和加速癌症生长。我们 父亲DDT暴露对子代疾病影响 通过精子miRNA发生，改变胎盘发育和胎儿生长。我们也 假设DDT暴露信号通过分泌的细胞外囊泡传递给精子， 由附睾细胞产生。我们的假设将在小鼠模型和细胞培养中进行测试， （1）审查与环境有关的 剂量的DDT及其代谢物DDE改变了细胞中的miRNA（和其他小RNA）含量， 2）探讨胎盘结构改变的机制 3）评估miRNAs是否与DDT暴露有关， (and可能是其他小RNA）在DDT暴露的男性精子中， 胎盘和胎儿发育的改变。虽然证据显示父亲 暴露程序疾病的后代是强大的，我们的理解的基础 机制仍然缺乏。确定父亲接触滴滴涕和 其他内分泌干扰物可以促进胎儿和胎盘发育的变化， 糖尿病和癌症等疾病的预防工具。这项研究也将有助于 对环境引起的非遗传性遗传的一般理解，并可能导致 对育龄男性的公共卫生建议。最后，我们的发现可能会导致 母体暴露的潜在胎盘生物标志物。