Perinatal diazinon exposure compromises the development of acetylcholine and serotonin systems.

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2019-08

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Abstract

Organophosphate pesticides are developmental neurotoxicants. We gave diazinon via osmotic minipumps implanted into dams prior to conception, with exposure continued into the second postnatal week, at doses (0.5 or 1 mg/kg/day) that did not produce detectable brain cholinesterase inhibition. We evaluated the impact on acetylcholine (ACh) and serotonin (5-hydroxytryptamine, 5HT) systems in brain regions from adolescence through full adulthood. Diazinon produced deficits in presynaptic ACh activity with regional and sex selectivity: cerebrocortical regions and the hippocampus were affected to a greater extent than were the striatum, midbrain or brainstem, and females were more sensitive than males. Diazinon also reduced nicotinic ACh receptors and 5HT1A receptors, with the same regional and sex preferences. These patterns were similar to those of diazinon given in a much more restricted period (postnatal day 1-4) but were of greater magnitude and consistency; this suggests that the brain is vulnerable to diazinon over a wide developmental window. Diazinon's effects differed from those of the related organophosphate, chlorpyrifos, with regard to regional and sex selectivity, and more importantly, to the effects on receptors: chlorpyrifos upregulates nicotinic ACh receptors and 5HT receptors, effects that compensate for the presynaptic ACh deficits. Diazinon can thus be expected to have worse neurodevelopmental outcomes than chlorpyrifos. Further, the disparities between diazinon and chlorpyrifos indicate the problems of predicting the developmental neurotoxicity of organophosphates based on a single compound, and emphasize the inadequacy of cholinesterase inhibition as an index of safety.

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10.1016/j.tox.2019.152240

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Slotkin, Theodore A, Samantha Skavicus, Ashley Ko, Edward D Levin and Frederic J Seidler (2019). Perinatal diazinon exposure compromises the development of acetylcholine and serotonin systems. Toxicology, 424. p. 152240. 10.1016/j.tox.2019.152240 Retrieved from https://hdl.handle.net/10161/29510.

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Scholars@Duke

Slotkin

Theodore Alan Slotkin

Professor of Pharmacology and Cancer Biology

We study the interaction of drugs, hormones and environmental factors with the developing organism, with particular emphasis on the fetal and neonatal nervous system. The role of biochemical factors mediating development of nerve cells and other types of tissue is a major thrust, since they influence the subsequent structural and physiological status of critical organ systems. Ongoing projects comprise five areas: (1) Mechanisms regulating development of synapses - role of endocrine and other trophic factors, intracellular messengers in developing cells, control of target organ differentiation by neural input; (2) Adverse effects of exogenous agents on development, with an emphasis on identification of mechanisms by which behavioral or physiological damage occurs - drugs of abuse (especially nicotine), hormonal imbalances, environmental contaminants (especially pesticides), food additives, intrauterine growth retardation, fetal and neonatal hypoxia; (3) Control of fetal and neonatal cardiovascular and respiratory function by the immature nervous system - normal physiological mechanisms, responses to stress, factors mediating the transition from fetal to neonatal function, reactivity during delivery, Sudden Infant Death Syndrome; (4) Breast cancer cell growth regulation - role of hormone and neurotransmitter receptors converging on common cell signaling mechanisms, and targeting of these receptors for cancer therapeutics.

Levin

Edward Daniel Levin

Professor in Psychiatry and Behavioral Sciences

Dr. Levin is Chief of the Neurobehavioral Research Lab in the Psychiatry Department of Duke University Medical Center. His primary academic appointment is as Professor in the Department of Psychiatry and Behavioral Sciences. He also has secondary appointments in the Department Pharmacology and Cancer Biology, the Department of Psychological and Brain Sciences and the Nicholas School of the Environment at Duke. His primary research effort is to understand basic neural interactions underlying cognitive function and addiction and to apply this knowledge to better understand cognitive dysfunction and addiction disorders and to develop novel therapeutic treatments.

The three main research components of his laboratory are focused on the themes of the basic neurobiology of cognition and addiction, neurobehavioral toxicology and the development of novel therapeutic treatments for cognitive dysfunction and substance abuse. Currently, our principal research focus concerns nicotine. We have documented the basic effects of nicotine on learning memory and attention as well as nicotine self-administration. We are continuing with more mechanistic studies in rat models using selective lesions, local infusions and neurotransmitter interaction studies. We have found that nicotine improves memory performance not only in normal rats, but also in rats with lesions of hippocampal and basal forebrain connections. We are concentrating on alpha7 and alpha4beta2 nicotinic receptor subtypes in the hippocampus, amygdala , thalamus and frontal cortex and how they interact with dopamine D1 and D2 and glutamate NMDA systems with regard to memory and addiction. I am also conducting studies on human cognitive behavior. We have current studies to assess nicotine effects on attention, memory and mental processing speed in schizophrenia, Alzheimer's Disease and Attention Deficit Hyperactivity Disorder. In the area of neurobehavioral toxicology, I have continuing projects to characterize the adverse effects of prenatal and adolescent nicotine exposure. Our primary project in neurobehavioral toxicology focuses on the cognitive deficits caused by the marine toxins. The basic and applied aims of our research complement each other nicely. The findings concerning neural mechanisms underlying cognitive function help direct the behavioral toxicology and therapeutic development studies, while the applied studies provide important functional information concerning the importance of the basic mechanisms under investigation.


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