Impacts of parental benzo[a]pyrene exposure on offspring’s bone development

父母接触苯并[a]芘对后代骨骼发育的影响

• 批准号: 10203208
• 负责人: Frauke Seemann
• 金额: $ 40.52万
• 依托单位: TEXAS A&M UNIVERSITY-CORPUS CHRISTI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10203208
• 关键词: Address; Adult; Adverse effects; Affect; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Bone Density; Bone Development; Cardiovascular system; Cell Differentiation process; Cells; Chemical Exposure; DNA Methylation; DNA Sequence; Data; Data Analyses; Defect; Deformity; Development; Diabetes Mellitus; Diagnostic; Disease; Disease susceptibility; Dose; Elderly; Environment; Environmental Exposure; Environmental Health; Environmental Pollutants; Environmental Risk Factor; Epidemic; Epigenetic Process; Exposure to; Fishes; Future Generations; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Goals; Health; Heritability; Histones; Impairment; Japanese Killifish; Knowledge; Life; Long-Term Effects; Malignant Neoplasms; MicroRNAs; Minority-Serving Institution; Mitotic; Modeling; Modification; Molecular; National Institute of Environmental Health Sciences; Oryziinae; Osteoblasts; Osteoporosis; Osteoporotic; Pathology; Pathway interactions; Pattern; Phenotype; Physiologic calcification; Pollution; Population; Prevention strategy; Preventive; Public Health; Regulation; Reporter; Research; Research Methodology; Risk; Risk Factors; Role; Science; Sclerotome; Small RNA; Testing; Therapeutic; Therapeutic Intervention; Toxicology; Transgenic Organisms; Underrepresented Students; Vertebral Bone; Work; bone; bone fragility; bone health; bone loss; career; design; disorder risk; environmental stressor; experience; exposed human population; fracture risk; human disease; improved; in utero; methylation pattern; methylome; next generation; offspring; osteoblast differentiation; osteoporosis with pathological fracture; premature; progenitor; prognostic; programs; response; skeletal; tool; tool development; toxicant; transcriptome; transcriptome sequencing; transcriptomics; undergraduate student

Project Summary The universally present environmental pollutant benzo[a]pyrene (BaP) has been recently described as transgenerational bone toxicant. Average human exposure doses induced skeletal and cardiovascular defects in the ancestrally exposed offspring in fish models. Cross-generational inheritance of disease susceptibilities in response to environmental stressors is of current concern and needs to be addressed to re-assess the population risk for various diseases, such as cancer, diabetes, osteoporosis or cardiovascular impairments. However, the understanding of the underlying mechanisms, affected molecular pathways and their subsequent impacts on the offspring is not yet conclusive. Deciphering the role of DNA methylation and histone marks in phenotype inheritance is imperative to address the next generations’ health. The long-term goal is preventive and therapeutic tool development to better assess, avert, and mitigate osteoporotic fracture risks, eventually reducing human disease susceptibilities due to parental exposures to environmental pollutants. This project is designed to address the central hypothesis that parental BaP-exposure deregulates osteoblast gene expression during critical windows of cell differentiation through a modified DNA methylation profile. To test this hypothesis, parental BaP- exposure induced methylation pattern (SA2) and miRNA level changes (SA1), and the developmental onset of adult bone impairment (SA1) will be studied in three different osteoblast subpopulations. The characterization of the genetic and epigenetic profile of the osteoblast cells at different maturation stages will allow to pinpoint critical windows for later bone mineral density impairment employing the unique medaka fish bone model. This study aligns closely with NIEHS mandate to advance environmental health sciences through enhanced understanding of molecular pathways targeted by environmental pollutants. Discriminating epigenetic marks and genes associated with cross-generational toxicology, the proposed research provides a platform for the development of prognostic/diagnostic tools to identify the risks of adverse effects of parental chemical exposure. Further, this study, in alignment with the goal of the AREA program, provides a unique opportunity for undergraduate students of a minority serving institution to gain research experience in the field of biomedical sciences.

项目摘要 目前普遍存在的环境污染物苯并[a]芘(Bap)是近年来才出现的。 被描述为跨代骨骼毒剂。人体暴露致骨骼的平均剂量 在鱼类模型中，祖先暴露的后代中存在心血管缺陷。跨代 对环境应激源的疾病易感性的遗传是目前关注的问题 并需要解决，以重新评估人口对各种疾病的风险，如癌症， 糖尿病、骨质疏松症或心血管疾病。然而，对 潜在的机制，受影响的分子途径及其对后续的影响 后代还没有定论。破译DNA甲基化和组蛋白标记在 为了下一代的健康，表型遗传势在必行。长期目标 是否开发预防和治疗工具以更好地评估、避免和缓解骨质疏松 骨折风险，最终降低由于父母暴露于 环境污染物。该项目旨在解决以下中心假设 亲代BaP暴露对成骨细胞基因表达的影响 通过修改的DNA甲基化图谱进行分化。为了验证这一假设，父母巴普- 暴露诱导甲基化模式(SA2)和miRNA水平变化(SA1)，以及 将在三种不同的成骨细胞中研究成人骨损伤(SA1)的发育性发病 亚群。成骨细胞遗传学和表观遗传学特征的研究 在不同的成熟阶段将允许精确的关键窗口为以后的骨密度 使用独特的青竹鱼骨模型的损伤。这项研究与NIEHS密切相关 通过加强对环境健康科学的理解来促进环境健康科学的任务 作为环境污染物靶标的分子途径。辨别表观遗传标记和 与跨代毒理学相关的基因，拟议的研究提供了一个平台 用于开发预测/诊断工具，以确定以下疾病不良影响的风险 父母接触化学物质。此外，这项研究与地区方案的目标相一致， 为少数族裔服务机构的本科生提供了一个独特的机会 在生物医学领域的研究经验。