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

暴露于环境中存在的化学物质可诱导父亲的表观遗传变化 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以是 通过精子非编码RNA(如miRNAs)在世代之间传播。我们的长期目标 为了了解父母的环境暴露如何使孩子容易患上这样的疾病 因为糖尿病和癌症符合NIEHS战略规划的目标。杀虫剂 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。虽然西方国家30多年来一直禁止滴滴涕，但滴滴涕是一种顽固的 在美国人口中，特别是在少数族裔中仍能检测到的环境污染物 以及最近的移民。目前，该农药在美国的主要来源是进口食品 来自使用滴滴涕的地区。我们在老鼠模型中产生的初步数据表明， 怀孕前接触滴滴涕会改变父亲精子中的miRNAs。更重要的是，父亲般的 滴滴涕导致低出生体重，这是一种与胎盘和胎儿大小减少相关的表型。 DDT父亲的后代表现出代谢障碍和加速癌症生长。我们 假设子代疾病的编程是通过孕前接触父亲的DDT 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胞外小泡传递给精子 由附睾细胞产生。我们的假设将在小鼠模型和细胞培养中得到验证 重点关注以下目标：1)审查与环境有关的机制 DDT及其代谢物DDE的剂量改变了小分子RNA(和其他小RNA)的含量 父系精子；2)研究胎盘改变的机制 父亲DDT暴露导致的发育和功能；3)评估miRNAs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。而有证据表明，父亲 暴露程序在后代中的疾病是健壮的，我们对潜在的 目前仍缺乏相关机制。确定父亲接触滴滴涕和 其他内分泌细胞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 对环境诱导的非遗传遗传的一般理解，并可能导致 对育龄男子的公共卫生建议。最后，我们的发现可能导致 父母接触的潜在胎盘生物标志物。

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.