Investigating the Developmental Mechanisms of TCDD-Induced Reproductive Dysregulation

TCDD 引起的生殖失调的发育机制研究

• 批准号: 10063524
• 负责人: Danielle Meyer
• 金额: $ 4.36万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2021-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063524
• 关键词: Address; Adolescent; Adult; Affect; Age; Agonist; Animal Model; Behavior; Behavioral Genetics; Binding; Brain; Chemicals; Clinical; Clinical Research; DNA Methylation; Data; Developed Countries; Development; Disease; Disease Outcome; Dose; Elderly; Endocrine; Endocrine Disruptors; Endocrine disruption; Endocrine system; Environmental Exposure; Epigenetic Process; Etiology; Excision; Exposure to; Familiarity; Female; Fertility; Fishes; Functional disorder; Gene Expression; Generations; Genes; Genetic; Goals; Gonadal structure; Health; Histologic; Histology; Human; Impairment; Incidence; Individual; Industrialization; Infertility; Infertility study; Inherited; Intervention; Investigation; Link; Longevity; Mediating; Methods; Modeling; Mutation; Organism; Outcome; Outcome Study; Ovary; Pathway interactions; Physiological; Prevention; Process; Regulation; Reporter; Reporting; Reproductive Periods; Reproductive system; Research; Research Priority; Sex Differentiation; Sex Ratio; Spermatogenesis; System; Systems Development; Techniques; Testicular Tissue; Testing; Testis; Tetrachlorodibenzodioxin; Therapeutic Intervention; Time; Tissues; Toxicant exposure; Toxicology; Transgenic Organisms; United States National Institutes of Health; Work; Zebrafish; aryl hydrocarbons; brain tissue; clinical development; critical period; environmental chemical; hormone regulation; insight; interest; male; novel; reproductive; reproductive development; reproductive function; reproductive outcome; reproductive system disorder; screening; sex; sperm viability; success; tool; toxicant; transcriptomics; transgenerational epigenetic inheritance; transmission process

PROJECT SUMMARY: Environmental exposure to endocrine-disrupting chemicals is heavily implicated in the increasing incidence of infertility and adverse reproductive outcomes across industrialized countries. As early critical periods are highly susceptible to endocrine system disruption, even very low-doses of these chemicals can shift developmental trajectories, leading to lifelong and/or multigenerational disease consequences. Therefore, the long-term goal of our work is to investigate both the specific genetic and epigenetic mechanisms through which toxicant exposures induce later-life reproductive effects and the windows during which this disruption occurs, in order to inform the development of clinical and therapeutic interventions. To address this goal, our lab has previously used zebrafish (Danio rerio), an NIH-validated model organism allowing easy developmental access to toxicological endpoints, to study the effects of early toxicant exposures on adult disease outcomes. Findings of skewed sex ratios and male-mediated transgenerational infertility guided us to further discover specific histologic and transcriptomic changes in the testes of adult male fish, all of which were heavily implicated in infertility. These outcomes told a compelling story of genetic and epigenetic changes in reproductive tissues persisting across the lifespan and inherited to the unexposed F2 generation. However, as everything to this point was assessed in adults, the developmental mechanisms behind these outcomes remain to be determined. The aims of this project propose, initially, the creation of a sex-specific transgenic fish line using well-established methods, in order to gain early developmental access to reproductive tissues and track their development over time. Creation of this line will not only be invaluable to this project, but will also provide a beneficial tool widely applicable to the field of developmental and reproductive toxicology. Using this line, the remaining aims propose to use a variety of physiological, behavioral, genetic, and epigenetic techniques to longitudinally investigate the developmental mechanisms of toxicant-induced infertility. This work promises to provide novel insights into pathways of reproductive development, closely linking adult and multigenerational disease with corresponding developmental origins.

项目总结:

项目成果

Developmental phenotypic and transcriptomic effects of exposure to nanomolar levels of metformin in zebrafish.

斑马鱼暴露于纳摩尔水平的二甲双胍对发育表型和转录组的影响。

• DOI: 10.1016/j.etap.2021.103716
• 发表时间: 2021-10
• 期刊: Environmental toxicology and pharmacology
• 影响因子: 4.3
• 作者: Phillips J;Akemann C;Shields JN;Wu CC;Meyer DN;Baker BB;Pitts DK;Baker TR
• 通讯作者: Baker TR

Nanoplastics impact the zebrafish (Danio rerio) transcriptome: Associated developmental and neurobehavioral consequences.

• DOI: 10.1016/j.envpol.2020.115090
• 发表时间: 2020-07
• 期刊: Environmental pollution
• 影响因子: 8.9
• 作者: A. F. Pedersen;Danielle N. Meyer;A. Petriv;Abraham L Soto;Jeremiah N. Shields;Camille Akemann

The phenotypic and transcriptomic effects of developmental exposure to nanomolar levels of estrone and bisphenol A in zebrafish.

• DOI: 10.1016/j.scitotenv.2020.143736
• 发表时间: 2021-02-25
• 期刊: The Science of the total environment
• 作者: Wu CC;Shields JN;Akemann C;Meyer DN;Connell M;Baker BB;Pitts DK;Baker TR
• 通讯作者: Baker TR

Comparative Toxicotranscriptomics of Single Cell RNA-Seq and Conventional RNA-Seq in TCDD-Exposed Testicular Tissue.

• DOI: 10.3389/ftox.2022.821116
• 发表时间: 2022
• 期刊: FRONTIERS IN TOXICOLOGY
• 作者: Haimbaugh, Alex;Meyer, Danielle;Akemann, Camille;Gurdziel, Katherine;Baker, Tracie R.
• 通讯作者: Baker, Tracie R.

Insight into 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced disruption of zebrafish spermatogenesis via single cell RNA-seq.

• DOI: 10.1093/pnasnexus/pgac060
• 发表时间: 2022-07
• 期刊: PNAS NEXUS
• 作者: Haimbaugh, Alex;Akemann, Camille;Meyer, Danielle;Gurdziel, Katherine;Baker, Tracie R.
• 通讯作者: Baker, Tracie R.