Neurobehavioral anomalies in zebrafish after sequential exposures to DDT and chlorpyrifos in adulthood: Do multiple exposures interact?
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2021-09
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A sequence of different classes of synthetic insecticides have been used over the past 70 years. Over this period, the widely-used organochlorines were eventually replaced by organophosphates, with dichlorodiphenyltrichloroethane (DDT) and chlorpyrifos (CPF) as the principal prototypes. Considerable research has characterized the risks of DDT and CPF individually, but little is known about the toxicology of transitioning from one class of insecticides to another, as has been commonplace for agricultural and pest control workers. This study used adult zebrafish to investigate neurobehavioral toxicity following 5-week chronic exposure to either DDT or CPF, to or their sequential exposure (DDT for 5 weeks followed by CPF for 5 weeks). At the end of the exposure period, a subset of fish were analyzed for brain cholinesterase activity. Behavioral effects were initially assessed one week following the end of the CPF exposure and again at 14 months of age using a behavioral test battery covering sensorimotor responses, anxiety-like functions, predator avoidance and social attraction. Adult insecticide exposures, individually or sequentially, were found to modulate multiple behavioral features, including startle responsivity, social approach, predator avoidance, locomotor activity and novel location recognition and avoidance. Locomotor activity and startle responsivity were each impacted to a greater degree by the sequential exposures than by individual compounds, with the latter being pronounced at the early (1-week post exposure) time point, but not 3-4 months later in aging. Social approach responses were similarly impaired by the sequential exposure as by CPF-alone at the aging time point. Fleeing responses in the predator test showed flee-enhancing effects of both compounds individually versus controls, and no additive impact of the two following sequential exposure. Each compound was also associated with changes in recognition or avoidance patterns in a novel place recognition task in late adulthood, but sequential exposures did not enhance these phenotypes. The potential for chemical x chemical interactions did not appear related to changes in CPF metabolism to the active oxon, as prior DDT exposure did not affect the cholinesterase inhibition resulting from CPF. This study shows that the effects of chronic adult insecticide exposures may be relevant to behavioral health initially and much later in life, and that the effects of sequential exposures may be unpredictable based on their constituent exposures.
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Hawkey, Andrew B, Zade Holloway, Cassandra Dean, Reese Koburov, Theodore A Slotkin, Frederic J Seidler and Edward D Levin (2021). Neurobehavioral anomalies in zebrafish after sequential exposures to DDT and chlorpyrifos in adulthood: Do multiple exposures interact?. Neurotoxicology and teratology, 87. p. 106985. 10.1016/j.ntt.2021.106985 Retrieved from https://hdl.handle.net/10161/29490.
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Scholars@Duke
Theodore Alan Slotkin
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.
Frederic J. Seidler
We study the effect of drugs, hormones and environmental factors on the intracellular and extracellular biochemical signals that govern the development of mammalian neural tissues, with particular emphasis on the biochemistry and molecular biology underlying control of replication, differentiation, synaptogenesis and onset of synaptic function. Ongoing projects comprise the following areas: (1) the role of endocrine and neurotrophic factors in transmitter and receptor choice by developing neurons; (2) effects of drugs of abuse, hormonal imbalances, environmental contaminants and fetal/neonatal hypoxia, on nervous system development; (3) control of fetal/neonatal cardiovascular and respiratory function by the immature nervous system, with particular emphasis on parturition and Sudden Infant Death Syndrome; (4) molecular mechanisms of brain dysfunction in the elderly (Alzheimer's Disease and Depression); (5) control of gene expression in developing cells by trophic factors that operate through defined second messenger systems and protooncogenes.
Research is directed toward understanding the interaction of drugs, hormones and environmental factors with the developing nervous system. The role of these factors in mediating development of nerve cells is a major effort as they influence the subsequent structural and functional state of nervous system and its targets. The approach is multidisciplinary. Ongoing projects involve three areas:
1. Mechanisms regulating the development of synapses and the role of endocrine and other trophic factors (i.e. neurotransmitters) in this regulation. Long-term structural and functional consequences of altered development are evaluated.
2. Adverse effects of exogenous agents on nervous system development, emphasizing the identification of mechanisms by which behavioral or physiological injury occurs. Under investigation are: Drugs of abuse (especially cocaine and nicotine), hormonal imbalances, environmental contaminants (pesticides, flame retardants, etc.), food additives, stress, intrauterine growth retardation and hypoxia.
3. Molecular mechanisms of human brain dysfunction in the elderly, specifically Alzheimer's disease and depression.
New directions are concentrating on neurotransmitter and hormonal regulation of cell differentiation and gene expression:
1. Neurotransmitter control of cell differentiation in the central nervous system. The role of transient receptor expression and transduction in effecting the switch from replication to differentiation and the molecular (epigenetic) mechanism underlying control of early immediate genes.
2. Consequence of early life exposures on subsequent development of adult decease. Altered vulnerabilities resulting from multiple exposure events (i.e. fetal nicotine x neonatal pesticide).
3. Establishing in vitro models to explore the mechanisms abnormalities.
Edward Daniel Levin
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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