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可能会引起父系的表观遗传变化 精子并影响后代患病的风险，这种对过去暴露的分子记忆可能是存在的。 通过精子非编码 RNA（例如 miRNA）在代际间传播。 了解父母的环境暴露如何使儿童容易患上诸如此类的疾病 因为糖尿病和癌症与 NIEHS 战略规划的目标一致。 DDT（二氯二苯基三氯乙烷）是一种具有内分泌干扰物的环境毒物 (EDC) 活动虽然在西方国家已被禁止 30 多年，但滴滴涕却是一种持久存在的物质。 在美国人口中，特别是少数族裔中，仍然发现了环境污染物 目前，美国这种农药的主要来源是进口食品。 我们在小鼠模型中生成的初步数据表明，使用 DDT 的区域。 受孕前接触 DDT 会改变父亲精子中的 miRNA，更重要的是，会改变父亲精子中的 miRNA。 滴滴涕会导致低出生体重，这是一种与胎盘和胎儿体积缩小有关的表型。 DDT 父亲的后代表现出代谢功能障碍并加速癌症生长。 通过受孕前父亲接触 DDT 来促进后代疾病的编程 我们还通过精子 miRNA 改变胎盘发育和胎儿生长。 DDT 暴露信号通过分泌的细胞外囊泡传递给精子 我们的假设将在小鼠模型和细胞培养物中进行检验。 重点关注以下目标： 1) 研究与环境相关的机制 DDT 及其代谢物 DDE 的剂量会改变 miRNA（和其他小 RNA）的含量 父本精子；2) 表征胎盘改变的机制 父系 DDT 暴露导致的发育和功能；3) 评估 miRNA 是否 接触 DDT 的男性精子中的（可能还有其他小 RNA）与 胎盘和胎儿发育的改变，而证据表明父系的。 暴露计划对后代的疾病影响很大，我们对潜在疾病的了解 仍然缺乏确定父亲接触滴滴涕的机制。 其他 EDC 可以促进胎儿和胎盘发育的变化，这对于识别至关重要 这项研究也将有助于预防糖尿病和癌症等疾病。 对环境引起的非基因遗传的一般理解，并可能导致 最后，我们的研究结果可能会导致育龄男性的公共卫生建议。 父母暴露的潜在胎盘生物标志物。