Organophosphate based pesticides and ADHD

Abstract

Attention-Deficit Hyperactivity Disorder (ADHD) is a neurobehavioural and neurodevelopmental disorder that is caused by a dopamine deficiency in the prefrontal cortex and an overall incomplete dopaminergic functioning. 3 to 5% of U.S. and Dutch children are affected by ADHD. Most children are diagnosed with ADHD by the time they go to school. During their childhood and also throughout adulthood they can suffer from ADHD, which is characterised by social, emotional and cognitive dysfunctioning. Inherited genetic variation of genes that involve the dopaminergic system result in an increased risk of developing ADHD. These genes encode for dopamine receptors 2 to 4 (DRD2-4), dopamine transporter (DAT), norepinephrine transporter (NET), monoamine oxidase-A (MAO-A) and catechol-O-methyltransferase (COMT). The environment can also lead to an increased risk of developing ADHD. Studies showed that exposure to organophosphate based pesticides (OPs) is associated with the incidence of ADHD. OPs have a high affinity to acetylcholinesterase (AChE), nicotinic acetylcholine receptor (nAChR) and adenylyl cyclase (AC). AChE and nAChR are involved in the cholinergic transmission leading to regulating dopamine neuronal activity. AC is located in the postsynaptic neuron that is stimulated by dopamine neurons. Inhibition of AChE and nAChR result in disrupted cellular response of the dopamine neurons. When OP is bound to AC in the postsynaptic neuron, AC regulation by G-protein coupled DRDs result in disrupted cellular responses of the postsynaptic neuron. Neuropathy target esterase (NTE) is an enzyme that regulates intracellular membrane trafficking in neurons. During neurodevelopment it is a key component in regulating migration and differentiation of neurons. During adulthood, NTE is critical in axonal maintenance. NTE is also inhibited by OPs. OP exposure is associated with ADHD because OPs disrupt key components considering dopaminergic cell signalling and neurodevelopment possibly leading to behavioural disorders such as ADHD. The aim of this paper is to clarify the exact link between OP exposure during the sensitive phase of neurodevelopment, disorders in neurodevelopment and the incidence of ADHD. It appears that the risk of the occurrence of ADHD can be due to genetic variation leading to a dysfunctional dopaminergic system or to early exposure to OP that causes deregulated cell signalling during the sensitive neurodevelopment phase. This also leads to a dysfunctional dopaminergic system. There were no publications available indicating a relation between NTE inhibition and ADHD. Furthermore, considering that NTE inhibition can lead to Creutzfeldt-Jakob like symptoms and the fact that NTE is located in long axons it appears very unlikely that OP causes ADHD via NTE inhibition. Due to the lack of relevant publications, it can be considered less likely that OP exposure results in ADHD via AC reprogramming. A model is provided showing the possible pathways towards development of ADHD. Pathways that need more investigation are also pointed out. Based on current available publications it can be concluded that it is very likely that exposure to OP increases the risk of developing ADHD. Inhibition of AChE and nAChR by OPs is the most likely pathway leading to ADHD symptoms.