Gene-pesticide interactions and ADHD

基因-农药相互作用和多动症

• 批准号: 10264050
• 负责人: Charles V Vorhees
• 金额: $ 43.39万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264050
• 关键词: Acoustics; Adhesions; Adult; Affect; Age; Amygdaloid structure; Apoptosis; Attention deficit hyperactivity disorder; Behavioral; Binding; Biochemical; Biological; Biological Models; Brain region; Cell Adhesion; Centers for Disease Control and Prevention (U.S.); Cerebellum; Child; Corpus striatum structure; Data; Development; Disease; Dopamine; Dose; Electrophysiology (science); Environment; Environmental Risk Factor; Exposure to; Extracellular Domain; FLRT3 gene; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Hippocampus (Brain); Home; Human; Hyperactivity; Impaired cognition; Insecticides; Knock-out; Learning; Light; Memory; Mental disorders; Modeling; N-Methylaspartate; Names; National Institute of Mental Health; Neurotoxins; Occupational Exposure; Odds Ratio; Online Mendelian Inheritance In Man; Outcome; Permethrin; Pesticides; Phenotype; Population; Prefrontal Cortex; Prevalence; Radial; Rattus; Risk Assessment; Risk Factors; Rodent; Short-Term Memory; Stimulus; Susceptibility Gene; Symptoms; Tactile; Testing; Variant; Weaning; alpha-latrotoxin receptor; base; cost; decamethrin; environmental agent; gene environment interaction; genetic risk factor; morris water maze; neurobehavioral; neurochemistry; neuropsychiatric disorder; novel; novel strategies; null mutation; pesticide exposure; pesticide interaction; postnatal; prepulse inhibition; pyrethroid; risk variant; water maze

Attention Deficit Hyperactivity Disorder (ADHD) is the most prevalent neurodevelopmental psychiatric disorder (9.4% prevalence in children; 4.4% in adults) and is polygenic. A novel gene associated with ADHD is Latrophilin-3 found in striatum, hippocampus, cerebellum, prefrontal cortex (PFC), and amygdala. In humans, there are 21 variants of LPHN3 associated with ADHD. Some pesticides may interact with ADHD genetic risk factors to trigger or exacerbate the symptoms. We found that the common pyrethroid, deltamethrin (DLM), administered prior to weaning in rats causes long-term behavioral, neurochemical, and electrophysiological effects. We developed the first KO rats of Lphn3. Lphn3 KO rats are hyperactive, hyper-reactive to startle stimuli, and cognitively impaired. This PAR-19-386 “Environmental Risks for Psychiatric Disorders: Biological Basis of Pathophysiology” seeks models that will elucidate Gene x Environment interactions related to neuropsychiatric disorders, such as ADHD. We hypothesize that Lphn3-/- and Lphn3+/- rats will interact with DLM (Type II pyrethroid) or permethrin (PRM, Type I pyrethroid) to exacerbate an ADHD-like phenotype. Specific Aim 1: Determine the effects of DLM in Lphn3-/-, Lphn3+/-, and wildtype (WT) rats on activity, reactivity, learning and memory (L&M), dopamine (DA) and NMDA markers, and apoptosis. Aim-1a: Compare WT rats with Lphn3-/- and Lphn3+/- rats administered 0, 0.5, or 2.0 mg/kg DLM from P3-20 for changes in activity, acoustic and tactile startle (including prepulse inhibition (PPI)) egocentric, allocentric, and working L&M, and for changes in DA and NMDA-R markers in various brain regions, including markers for programmed cell death. Aim-1b, neurochemical outcomes in rats not behaviorally tested. Specific Aim 2: Determine the effects of PRM in Lphn3-/-, Lphn3+/- rats vs. WT rats on the outcomes used in Aim-1. Aim-2a: Same as Aim-1a with PRM. Aim-2b: Same as Aim-1b with PRM. Specific Aim 3: Determine the effects of DLM in adult Lphn3- /-, Lphn3+/- rats vs. WT rats. Aim-3a: same outcomes as in Aim-1a. Adults with ADHD are an understudied and a population susceptible for higher exposure to pyrethroids from occupational exposure, making Aims 3 and 4 important. Aim-3b: Same as Aim-1b in adult rats. Specific Aim 4: Determine the effects of PRM in adult Lphn3-/-, Lphn3+/- rats vs. WT rats. Aim-4a: Same outcomes used in Aim-1a. Aim-4b: Same as Aim-1b in adult rats not behaviorally tested. Impact: ADHD interferes with normal development, costs billions to treat and manage, yet we know little about environmental contributions to those with ADHD. Insecticides are suspected in ADHD but such interactions between gene and environment are not established. Lphn3-/- and Lphn3+/- rats represent a novel approach to probing the effects of exposure to pyrethroids using a known ADHD genetic susceptibility. The model will shed new light on how a gene known to be associated with ADHD affects the behavioral and biochemical effects of prototypical pyrethroids. Interaction data can be used for risk assessment and help provide safeguards against pyrethroid exposure for those with ADHD.

注意缺陷多动障碍(ADHD)是最常见的神经发育精神障碍 (儿童患病率为9.4%；成人患病率为4.4%)，是多基因的。一种与ADHD相关的新基因是 LatroPhilin-3存在于纹状体、海马体、小脑、前额叶皮质(PFC)和杏仁核。在人类身上， 有21种LPHN3的变种与ADHD有关。一些杀虫剂可能与ADHD遗传风险相互作用 触发或加重症状的因素。我们发现，常见的拟除虫菊酯，溴氰菊酯(DLM)， 在大鼠断奶前给药会导致长期的行为、神经化学和电生理 效果。我们培育了第一只Lphn3的KO大鼠。Lphn3KO大鼠对惊吓反应过度活跃 刺激和认知障碍。本PAR-19-386《精神疾病的环境风险：生物学》 《病理生理学基础》寻求能够解释基因与环境相互作用的模型 神经精神障碍，如ADHD。我们假设Lphn3-/-和Lphn3+/-大鼠将与 DLm(II型拟除虫菊酯)或氯菊酯(PRM，I型拟除虫菊酯)可加重ADHD样表型。 具体目标1：确定DLM对Lphn3-/-、Lphn3+/-和野生型(WT)大鼠活动的影响 反应性、学习记忆(L&M)、多巴胺(DA)和N-甲基-D-天冬氨酸(N-甲基-D-天冬氨酸)标志物，以及细胞凋亡。AIM-1a：比较 WT大鼠与Lphn3-/-和Lphn3+/-大鼠从P3-20开始给予0，0.5或2.0 mg/kg DLm，以改变 活动、声音和触觉惊吓(包括脉冲前抑制(PPI))以自我为中心、以分配为中心和工作 L和M，以及不同脑区DA和NMDA-R标记物的变化，包括程序化标记物 细胞死亡。Aim-1b，未进行行为测试的大鼠的神经化学结果。具体目标2：确定 Lphn3-/-、Lphn3+/-大鼠与WT大鼠的PRM对用于AIM-1的结果的影响。AIM-2a：与AIM-1a相同 使用PRM。AIM-2b：与使用PRM的AIM-1b相同。具体目标3：确定DLM对成人Lphn3-的影响 /-、Lphn3+/-大鼠与WT大鼠比较。AIM-3a：结果与AIM-1a相同。患有ADHD的成年人是一个被忽视的研究对象 以及职业暴露对拟除虫菊酯暴露程度较高的人群，使AIMS 3 四是重要。Aim-3b：与成年大鼠Aim-1b相同。具体目标4：确定PRM在以下方面的影响 成年Lphn3-/-、Lphn3+/-大鼠与WT大鼠比较。AIM-4a：与AIM-1a相同的结果。AIM-4b：与AIM-1b相同 在没有进行行为测试的成年大鼠身上。影响：ADHD干扰正常发育，治疗费用数十亿美元 和管理，但我们对环境对ADHD患者的贡献知之甚少。杀虫剂有 怀疑患有ADHD，但基因和环境之间的这种相互作用尚未建立。Lphn3-/-和 Lphn3+/-大鼠代表了一种新的方法来探索接触拟除虫菊酯的影响 多动症遗传易感性。该模型将为已知的与ADHD相关的基因提供新的线索 影响典型拟除虫菊酯的行为和生化效应。交互数据可用于风险 评估并帮助为ADHD患者提供防止拟除虫菊酯暴露的保护措施。