Investigating the hepatic toxicity of 3,3â-dichlorobiphenyl (PCB-11) in zebrafish (Danio rerio)

研究 3,3-二氯联苯 (PCB-11) 对斑马鱼 (Danio rerio) 的肝毒性

• 批准号: 10058206
• 负责人: Monika Roy
• 金额: $ 3.21万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-06-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058206
• 关键词: Acute; Adolescent; Affect; Agonist; Aryl Hydrocarbon Receptor; Benzo(a)pyrene; Biochemistry; Biological Assay; Biological Sciences; CYP11A1 gene; Cell Culture Techniques; Cells; Child; Chronic; Cytochromes; Data; Deformity; Deposition; Development; Disease Progression; Dose; Economic Burden; Embryo; Environment; Environmental Pollution; Equipment; Etiology; Exposure to; Faculty; Fatty Acids; Fertilization; Fishes; Fluorescence Microscopy; Fluorescence-Activated Cell Sorting; Funding; Genes; Goals; Government; Growth; Growth and Development function; Half-Life; Hepatic; Hepatocyte; Hepatotoxicity; Histopathology; Hour; Human; Individual; Infant; Institutes; Institution; Learning; Life; Lipids; Liver; Liver diseases; Measures; Mentors; Mentorship; Methods; Microscopy; Modeling; Molecular; Molecular Biology; Morphology; Obesity; Oils; Organ; Outcome; Parents; Pathway interactions; Pharmacologic Substance; Phenols; Phenotype; Pigments; Polychlorinated Biphenyls; Population; Postdoctoral Fellow; Pregnant Women; Process; Public Health; Research; Resources; Rodent; Sampling; Scientist; Serum; Stains; Sulfate; Techniques; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Training; Transgenic Organisms; United States National Institutes of Health; Universities; Vacuole; Work; Zebrafish; career preparation; enzyme activity; experience; in vivo; lipid metabolism; liver development; longitudinal analysis; member; non-alcoholic fatty liver disease; prevent; transcriptome sequencing; translational impact; urban area

! PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) affects 30-40% of the U.S. population and has an estimated U.S. economic burden of $103 billion per year. NAFLD is also prevalent in children and adolescents, affecting 34.2% of obese individuals and 7.6% of this population overall. Higher-chlorinated polychlorinated biphenyls (PCBs) are implicated in the etiology of NAFLD, however, little is known about the hepatic toxicity potential of lower-chlorinated PCBs, including 3,3’-dichlorobiphenyl (PCB-11), widely detected in environmental and human samples, including in pregnant women. Preliminary research shows that acute developmental exposures to PCB-11 alone do not result in overt toxicological outcomes in zebrafish (Danio rerio), however, it misregulates hepatic-associated genes, stunts liver development, and increases vacuolization in liver tissue. Further, in combination with Aryl hydrocarbon receptor (Ahr) agonists, PCB-11 can either inhibit Cytochrome p4501a (Cyp1a) enzyme activity induced by a model PAH, exacerbating toxicity, or prevent toxicity induced by PCB-126, highlighting the importance of using a mixtures approach. The objective of this proposed study is to investigate the hepatic toxicity of PCB-11 metabolites, which have longer half-lives in vivo for rodents, and in preliminary data of low-dose exposures show increased hepatic lipid deposition in 15-day fish. The central hypothesis of this proposed study is that PCB-11 induced hepatic toxicity is attributed to its metabolites and is associated with a NAFLD liver phenotype during juvenile development. Aim 1 will determine the toxicity contribution of phenolic and sulfate PCB-11 metabolites in 4-day old fish. Aim 2 will assess PCB-11 and PCB-11-Sulfate toxicity in 30-day juvenile stage fish after low-dose chronic single and mixture exposures. The proposed training plan to execute these aims includes learning and/or performing methods such as EROD assays to measure Cyp1a activity, fluorescence microscopy to assess liver development, histopathology, Oil- Red-O staining to assess lipid deposition, and Fluorescence-Activated Cell Sorting (FACS) for fatty acid composition analysis of hepatocytes. In addition, chronic exposures will be carried out using the OECD Fish, Early-Life Stage (FELS) toxicity test (OECD TG 210) to gain practical experience in regulatory toxicity approaches and to increase preparation for the career goal of working as a government scientist to assess the public health impacts of contaminant exposures. This project will yield in vivo mechanistic toxicity data on PCB-11 and its metabolites at several developmental stages to be of use for public health regulators. The sponsor, Dr. Alicia Timme-Laragy, has a record of NIH funding, is a recent mentor of an NIH F32 Postdoctoral Fellow (now a faculty member at San Diego State University), has numerous equipment for fluorescence microscopy, molecular biology and biochemistry work, and is capable of providing the mentorship and guidance needed to accomplish the goals of the proposed project. Further, UMass Amherst is a large R1 research institution and houses several resources, including the Institute for Applied Life Sciences (IALS). !

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