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.

项目概要 普遍存在的环境污染物苯并[a]芘（BaP）最近被 被描述为跨代骨毒物，人类平均暴露剂量会引起骨骼损伤。 鱼类模型中祖先暴露的后代的心血管缺陷。 对环境压力因素的疾病易感性遗传是当前关注的问题 并需要重新评估人口罹患各种疾病的风险，例如癌症、 糖尿病、骨质疏松症或心血管疾病。 潜在的机制、受影响的分子途径及其对 后代中 DNA 甲基化和组蛋白标记的作用尚未定论。 非凡的传承对于解决下一代的健康问题至关重要。 是预防和治疗工具的开发，以更好地评估、避免和减轻骨质疏松症 骨折风险，最终降低由于父母接触而导致的人类疾病易感性 该项目旨在解决以下中心假设： 亲代 BaP 暴露会在细胞关键窗口期解除成骨细胞基因表达的调节 通过修改 DNA 甲基化谱进行分化 为了检验这一假设，亲代 BaP-。 暴露诱导的甲基化模式 (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）的发育起始 成骨细胞的遗传和表观遗传特征的表征。 在不同的成熟阶段将能够确定后期骨矿物质密度的关键窗口 这项研究与 NIEHS 密切相关。 任务是通过加深对环境健康科学的了解来推进环境健康科学 环境污染物靶向的分子途径和识别表观遗传标记。 与跨代毒理学相关的基因，拟议的研究提供了一个平台 开发预测/诊断工具来识别不良影响的风险 此外，本研究与 AREA 计划的目标一致， 为少数族裔服务机构的本科生提供了获得知识的独特机会 生物医学科学领域的研究经验。