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
基本信息
- 批准号:10356857
- 负责人:
- 金额:$ 54.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdultAffectAgeAgricultureAmericanAndrogen ReceptorAnimalsAttentionBiological MarkersBreast Cancer Risk FactorC57BL/6 MouseCell Culture TechniquesCellsChemicalsChildCountryDNADataDefectDeveloping CountriesDevelopmentDiabetes MellitusDiseaseDoseEZH2 geneEmbryoEndocrine DisruptorsEnvironmentEnvironmental ExposureEnvironmental PollutantsEnzymesEpididymisEpigenetic ProcessEpithelialEpithelial CellsEuropeExposure toFathersFertilizationFetal DevelopmentFetal GrowthFetal Growth RetardationFetal TissuesFoodGene ExpressionGenerationsGenetic TranscriptionGenomic SegmentGoalsGrowthHalf-LifeHealthHistologyImmigrantImpairmentIn VitroInjectionsInsectaLeadLinkLiteratureLow Birth Weight InfantMalariaMalignant NeoplasmsMemoryMetabolic DiseasesMetabolic dysfunctionMicroRNAsMicroinjectionsMinorityMolecularMorphologyMouse Cell LineMusNational Institute of Environmental Health SciencesNutrientPaternal ExposurePesticidesPhenotypePlacentaPopulationPreventiveProteinsPublic HealthPublishingRNARecommendationRoleSignal TransductionSmall RNASourceStrategic PlanningTestingTestisToxic Environmental SubstancesTranscriptional RegulationUnited StatesUntranslated RNAVascularizationbasebiomarker identificationblastocystcell typechromatin remodelingcombatdichlorodiphenyltrichloroethanedisorder riskearly life exposureeggenvironmental chemicalepidemiology studyexperimental studyextracellular vesiclesfetalin vivomalemenmouse modelnext generationnon-geneticoffspringpregnantprogramsreproductivesensorsperm cellstem cell fate specificationtooltoxicanttranscriptome sequencingtrophoblast
项目摘要
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
项目成果
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{{ truncateString('Sonia de Assis', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 54.43万 - 项目类别:
Parental Exposure to High Fats Diets and Risk of Pancreatic Cancer in the Offspri
父母高脂肪饮食与后代患胰腺癌的风险
- 批准号:
9319232 - 财政年份:2015
- 资助金额:
$ 54.43万 - 项目类别:
In utero estrogenic exposures and transgenerational risk for breast cancer
子宫内雌激素暴露和乳腺癌的跨代风险
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7896278 - 财政年份:2010
- 资助金额:
$ 54.43万 - 项目类别:
In utero estrogenic exposures and transgenerational risk for breast cancer
子宫内雌激素暴露和乳腺癌的跨代风险
- 批准号:
8043496 - 财政年份:2010
- 资助金额:
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