Parental Co-Exposure to Methylmercury and Inorganic Arsenic in Zebrafish (Danio rerio): Metabolism and Offspring Behavior

斑马鱼（斑马鱼）父母同时接触甲基汞和无机砷：代谢和后代行为

• 批准号: 10352116
• 负责人: Sarah E Rothenberg
• 金额: $ 39.27万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352116
• 关键词: Ablation; Adolescent; Adult; Age; Arsenic; Attention; Behavior; Biological; Biological Models; Blood Pressure; Brain; Carcinogens; Chemicals; Child; Development; Diet; Embryo; Environment; Enzymes; Exposure to; Eye; Female; Fertilization; Fetal Growth; Frequencies; Gills; Health; Heavy Metals; Homologous Gene; Hour; Human; Inductively Coupled Plasma Mass Spectrometry; Intestines; Joints; Kidney; Lasers; Link; Liver; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mercury; Metabolic syndrome; Metabolism; Metals; Methionine; Methylation; Methylmercury Compounds; Methyltransferase; Modeling; Molecular; Morphology; Motor; Muscle; Muscle Tonus; Natural regeneration; Neuraxis; Neurocognitive Deficit; Neurotoxins; Organ; Outcome; Performance; Poison; Process; Rattus; Renal carcinoma; Research Personnel; S-Adenosylmethionine; Sex Differences; Signal Pathway; Site; Skin; Skin Cancer; Statistical Methods; Tissues; Toxic effect; Visuospatial; Water; Zebrafish; base; cytotoxic; disease registry; epidemiology study; exposed human population; fetal; genome-wide; genotoxicity; in vitro Model; male; methylmercury exposure; neurobehavioral; neurodevelopment; neurotoxic; neurotoxicity; offspring; postnatal; prenatal; sex; sodium arsenite; synergism; transcriptome sequencing; transcriptomics; treatment group; uptake

Summary Methylmercury (MeHg) is a potent neurotoxin, and recent studies indicate that inorganic arsenic(III) (iAs) is also neurotoxic. Although chemicals co-occur in the environment, the study of chemical mixtures is more recent. Heavy metals target the central nervous system, and co-exposure may result in synergistic neurotoxic impacts. However, the biological and molecular mechanisms underlying these joint effects are uncertain. The aim of our study is to investigate synergism between iAs and MeHg, using the zebrafish (Danio rerio) model system. Aim 1. Investigate the uptake and metabolism of iAs and MeHg in zebrafish. We anticipate that co-exposure to both chemicals will alter the proportion of arsenic species in the liver, compared to controls. Adult zebrafish will be exposed to environmentally relevant levels of MeHg (through diet) and sodium arsenite (through water) (six treatment groups). In the liver, mercury species and arsenic species will be compared between treatment groups, and sex-specific differences will be investigated. Accumulation of mercury and arsenic in adult tissues and organs will be visualized using laser ablation-ICP-MS. Aim 2. Determine the impacts of MeHg and iAs exposure in progeny, including neurobehavioral outcomes, and mechanisms of toxicity. Mercury and arsenic species will be determined in whole embryos [120 hours post fertilization (hpf)], exposed to both neurotoxicants through maternal transfer. In embryos (6-120 hpf) and adults [90 days post fertilization (dpf)], morphological and neurobehavioral endpoints will be assessed. Using RNA sequencing, we will conduct genome-wide transcriptomics of offspring brains (90 dpf), and identify signaling pathways, which are enriched or depleted due to co-exposure. Transcriptomic results will be compared between treatment groups and males/females. This study will advance our understanding of the mechanisms by which co-exposure to two chemicals, which frequently co-occur in the environment, contribute synergistically to offspring neurotoxicity.

总结 甲基汞（MeHg）是一种强有力的神经毒素，最近的研究表明，无机砷（III） (iAs)也有神经毒性虽然化学品在环境中共存，但对化学混合物的研究 最近的。重金属靶向中枢神经系统，共同暴露可能导致协同作用 神经毒性影响。然而，这些联合效应背后的生物学和分子机制是 不确定本研究的目的是探讨iAs和甲基汞之间的协同作用，利用斑马鱼（Danio Rerio）模型系统。目标1.研究了斑马鱼对iAs和MeHg的吸收和代谢。我们 预计同时接触这两种化学物质将改变肝脏中砷物种的比例， 控制。成年斑马鱼将（通过饮食）暴露于环境相关水平的甲基汞， 亚砷酸钠（通过水）（6个处理组）。在肝脏中，汞物种和砷物种将 将在治疗组之间进行比较，并研究性别特异性差异。积累 成人组织和器官中的汞和砷将使用激光烧蚀-ICP-MS可视化。 确定甲基汞和iAs暴露对后代的影响，包括神经行为结果，以及 毒性机制。汞和砷的种类将在整个胚胎中测定[120小时后 受精（hpf）]，通过母体转移暴露于两种神经毒物。在胚胎（6-120 hpf）和成人中 [90受精后天数（DPF）]，将评估形态学和神经行为终点。使用RNA 测序，我们将进行后代大脑的全基因组转录组学（90 dpf），并确定信号转导 途径，这是丰富或耗尽，由于共同曝光。将比较转录组学结果 给药组和雄性/雌性之间的差异。这项研究将促进我们对机制的理解 同时接触两种经常在环境中共存的化学品， 与后代神经毒性协同作用。