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）是最普遍的神经发育精神疾病 （儿童患病率为9.4％；成人4.4％），是多基因的。与多动症相关的新型基因是 在纹状体，海马，小脑，前额叶皮层（PFC）和杏仁核中发现的Latrophilin-3。在人类中 与ADHD相关的LPHN3有21种变体。一些农药可能与多动症遗传风险相互作用 触发或加剧症状的因素。我们发现普通的拟除虫菊酯，deltamethrin（DLM）， 在大鼠洗涤之前进行给药会导致长期行为，神经化学和电生理学 效果。我们开发了lphn3的第一批KO大鼠。 lphn3 ko大鼠过度活跃，过度反应与惊吓 刺激和认知受损。这款第19款 - 386年“精神疾病的环境风险：生物学 病理生理学的基础”寻求将阐明与基因x环境相互作用相关的模型 神经精神疾病，例如ADHD。我们假设LPHN3 - / - 和LPHN3 +/-大鼠将与 DLM（II型拟除虫菊酯）或苄氯菊酯（PRM，I型拟甲虫素）加剧ADHD样表型。 具体目标1：确定DLM在LPHN3 - / - ，LPHN3 +/-和WildType（WT）大鼠中的影响， 反应性，学习和记忆（L＆M），多巴胺（DA）和NMDA标记以及凋亡。 AIM-1A：比较 wt大鼠lphn3 - / - 和lphn3 +/-大鼠从p3-20施用0、0.5或2.0 mg/kg DLM，以改变 活动，声学和触觉惊吓（包括抑制前（PPI）），以中心为中心和工作 L＆M，以及在各个大脑区域的DA和NMDA-R标记的变化，包括编程的标记 细胞死亡。 AIM-1B，未经行为测试的大鼠的神经化学结果。特定目标2：确定 PRM在LPHN3 - / - ，LPHN3 +/-大鼠与WT大鼠对AIM-1中使用的结果的影响。 AIM-2A：与AIM-1A相同 与PRM。 AIM-2B：与PRM的AIM-1B相同。特定目标3：确定DLM在成年LPHN3-的影响 / - ，LPHN3 +/-大鼠与WT大鼠。 AIM-3A：与AIM-1A相同的结果。患有多动症的成年人是一个理解的 以及容易受到职业暴露拟甲虫素的更高接触的人群，AIMS 3 4重要。 AIM-3B：与成年大鼠的AIM-1B相同。特定目标4：确定PRM在 成人lphn3 - / - ，lphn3 +/-大鼠与WT大鼠。 AIM-4A：AIM-1A中使用的相同结果。 AIM-4B：与AIM-1B相同 在不受行为测试的成年大鼠中。影响：多动症干扰正常发展，需要数十亿的治疗 并管理，但是我们对多动症患者的环境贡献知之甚少。杀虫剂是 在ADHD中涉嫌，但尚未建立基因与环境之间的这种相互作用。 lphn3 - / - 和 LPHN3 +/-大鼠代表了一种新的方法，用于探测使用已知的拟除虫菊酯的影响 ADHD遗传敏感性。该模型将为如何与ADHD相关的基因开发新的启示 影响典型拟除虫菊酯的行为和生化作用。交互数据可用于风险 评估并帮助为患有多动症患者提供防止拟除虫菊酯暴露的保障措施。