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Gene-pesticide interactions and ADHD

基因-农药相互作用和多动症

基本信息

批准号：
10640880
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
项目类别：
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/10640880
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 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 Heterozygote Hippocampus Home Human Hyperactivity Impaired cognition Insecticides Knock-out Learning Membrane 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 Predisposition Prefrontal Cortex Prevalence Radial Rattus Risk Assessment Risk Factors Rodent Short-Term Memory Stimulus Susceptibility Gene Symptoms Tactile Testing Variant Weaning alpha-latrotoxin receptor 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

项目摘要

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性精神障碍 (9.4儿童患病率为4.4%;成人为4.4%），并且是多基因的。一种与多动症相关的新基因是在纹状体、海马、小脑、前额叶皮质（PFC）和杏仁核中发现的嗜Latrophilin-3。在人类中，有21种LPHN 3变体与ADHD有关。一些杀虫剂可能与ADHD遗传风险相互作用引发或加剧症状的因素。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，导致长期的行为，神经化学和电生理方面的影响.我们开发了Lphn 3的第一个KO大鼠。Lphn 3 KO大鼠是过度活跃的，对惊吓反应过度刺激和认知受损。本PAR-19-386“精神疾病的环境风险：生物学病理生理学的基础”寻求模型，将阐明基因x环境的相互作用，神经精神疾病，如ADHD。我们假设Lphn 3-/-和Lphn 3 +/-大鼠将与 DLM（II型拟除虫菊酯）或氯菊酯（PRM，I型拟除虫菊酯）加重ADHD样表型。具体目的1：确定Lphn 3-/-、Lphn 3 +/-和野生型（WT）大鼠中DLM对活动的影响，反应性、学习和记忆（L&M）、多巴胺（DA）和NMDA标志物以及凋亡。目标-1a：比较从P3-20开始给予0、0.5或2.0 mg/kg DLM的Lphn 3-/-和Lphn 3 +/-大鼠的WT大鼠，活动，听觉和触觉惊吓（包括前脉冲抑制（PPI））自我中心，allocentric，和工作 L&M，以及各种脑区域中DA和NMDA-R标记物的变化，包括程序性脑损伤的标记物。细胞死亡目的-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 Lphn 3-/-、Lphn 3 +/-大鼠与WT大鼠中PRM对Aim-1中使用的结果的影响。Aim-2a：与Aim-1a相同关于PRM Aim-2b：与带有PRM的Aim-1b相同。具体目标3：确定DLM在成人Lphn 3- /-，Lphn 3 +/-大鼠相对于WT大鼠。目标3a：与目标1a相同的结果。患有多动症的成年人是一个未被研究的以及因职业接触而对拟除虫菊酯有较高接触敏感性的人群，四是重要。Aim-3b：与成年大鼠中的Aim-1b相同。具体目标4：确定PRM在成年Lphn 3-/-、Lphn 3 +/-大鼠与WT大鼠。目标-4a：与目标-1a相同的结局。Aim-4 b：与Aim-1b相同在成年大鼠中没有进行行为测试。影响：ADHD干扰正常发育，治疗成本数十亿美元然而，我们对环境对ADHD患者的影响知之甚少。杀虫剂在ADHD中，这种基因和环境之间的相互作用尚未建立。Lphn 3-/-和 Lphn 3 +/-大鼠代表了一种新的方法，使用已知的 ADHD遗传易感性该模型将揭示一种已知与ADHD相关的基因是如何与ADHD相关的影响原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，并帮助提供预防措施，防止拟除虫菊酯暴露于多动症。