Project 2: Persisting Neurobehavioral Dysfunction Caused by Interacting Toxicant Exposures During Development: Mechanistic and Treatment Studies with Zebrafish and Rats

项目 2：发育过程中相互作用的有毒物质暴露引起的持续性神经行为功能障碍：斑马鱼和大鼠的机制和治疗研究

• 批准号: 10353152
• 负责人: EDWARD D LEVIN
• 金额: $ 30.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353152
• 关键词: Acetylcholine; Address; Adolescent; Adult; Adverse effects; Analytical Chemistry; Anti-Inflammatory Agents; Antioxidants; Aromatic Polycyclic Hydrocarbons; Attenuated; Back; Behavioral; Benzo(a)pyrene; Biological; Biological Assay; Budgets; Cadmium; Chemicals; Chronic; Cognitive deficits; Communication; Communities; Complex; Complex Mixtures; DNA Methylation; Data; Data Analyses; Development; Developmental Toxicant; Dopamine; Dose; Emotional; Epigenetic Process; Evaluation; Exposure to; Functional disorder; Hazardous Substances; Health; Heavy Metals; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Inflammatory; Inflammatory Response; Interleukin-1 beta; Investigation; Lead; Mammals; Mediating; Metal exposure; Metals; Methods; Mitochondria; Modeling; Molecular; Motor; Motor Activity; Neurotoxins; Neurotransmitters; Outcome; Oxidative Stress; Persons; Pharmaceutical Preparations; Process; Rattus; Research; Risk; Rodent Model; Role; Serotonin; Sex Differences; Societies; Statistical Data Interpretation; Superfund; System; Techniques; Testing; Therapeutic; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Translational Research; Universities; Zebrafish; base; behavioral impairment; biological adaptation to stress; cell motility; cognitive function; community engagement; cytokine; data management; developmental neurotoxicity; efficacy testing; emotional functioning; fluoranthene; improved; mitochondrial dysfunction; neurobehavioral; neurobehavioral test; neurotoxic; neurotoxicity; novel strategies; prevent; relating to nervous system; remediation; response; screening; sex; therapy development; toxicant; toxicant interaction

Abstract Persisting neurobehavioral toxicity has been shown to result from early developmental exposure to many different types of toxicants, including polyaromatic hydrocarbons (PAHs) and heavy metals. While the developmental neurobehavioral toxicity of individual chemicals have been well-studied, their interactions have not, despite the fact that people are most often exposed to toxicant combinations. Project 1 focuses on understanding how developmental PAH exposure impacts neurotoxic effects of heavy metals. We will use an effects-driven mechanistic investigation, working from the persisting neurobehavioral dysfunction caused by developmental toxicant exposures back to determine the critical mechanisms that caused the neurobehavioral toxicity. Interactions of two prototypic PAHs (benzo[a]pyrene and fluoranthene) and two heavy metals (lead and cadmium) producing persisting alterations in locomotor activity, emotional dysfunction and cognitive impairment will be determined. The mechanistic investigations will range from molecular (DNA methylation) to intracellular (oxidative stress related to mitochondrial dysfunction) to intercellular (dopamine, serotonin and acetylcholine neurotransmitter impairments and microglial-mediated changes in inflammatory processes via IL-1β, 6, 10 and related cytokines). At an organismal level, the importance of behavioral stress response potentiating neurobehavioral toxicity to PAHs and heavy metals will be determined. Zebrafish will be used as a front-end model to assess detailed dose-effect interactions of PAH and heavy metal neurotoxicity with isobolographic characterization, charting interacting dose-effect functions. Rats will be used to determine the character and mechanisms of persisting neurobehavioral impairment more directly relevant to humans, including sex-selective effects. Working from this improved mechanistic understanding of the neurobehavioral toxicity, this project will advance to the study of complex environmental mixtures. Project 2 will determine the efficacy of potential rescue treatments using antioxidants, methyl donors and anti-inflammatory cytokines during the toxicant exposure. These will be developed in zebrafish and verified with the rat model. Another important type of toxicant interaction is sequential exposures. In an exploratory aim we will determine how early exposure to one neurotoxicant could cause maladaptive development that would impair response to later exposure to another neurotoxicant. This sequential change in toxicant exposure is important for understanding risks of changing exposures through a lifetime. Project 2 will collaborate with the other projects, particularly regarding epigenetics (Project 3), oxidative stress (Projects 3 and 4), behavioral impairments (Projects 1 and 4), complex environmental mixtures (Projects 1, 4, and 5), neurotransmitter analysis (Analytic Chemistry Core), mixture statistical evaluation (Data Management and Analysis Core), and sharing information with the broader community (Community Engagement Core) to enhance understanding of real world neurotoxic risks to toxicant mixtures and develop treatments to reduce adverse neurobehavioral toxicity.

摘要