Persistent neurobehavioral and neurochemical anomalies in middle-aged rats after maternal diazinon exposure.
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2022-04
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Abstract
Diazinon is an organophosphate pesticide that has a history of wide use. Developmental exposures to organophosphates lead to neurobehavioral changes that emerge early in life and can persist into adulthood. However, preclinical studies have generally evaluated changes through young adulthood, whereas the persistence or progression of deficits into middle age remain poorly understood. The current study evaluated the effects of maternal diazinon exposure on behavior and neurochemistry in middle age, at 1 year postpartum, comparing the results to our previous studies of outcomes at adolescence and in young adulthood (4 months of age) (Hawkey 2020). Female rats received 0, 0.5 or 1.0 mg/kg/day of diazinon via osmotic minipump throughout gestation and into the postpartum period. The offspring were tested on a battery of locomotor, affective, and cognitive tests at young adulthood and during middle age. Some of the neurobehavioral consequences of developmental DZN seen during adolescence and young adulthood faded with continued aging, whereas other neurobehavioral effects emerged with aging. At middle age, the rats showed few locomotor effects, in contrast to the locomotor hyperactivity that had been observed in adolescence. Notably, though, DZN exposure during development impaired reference memory performance in middle-aged males, an effect that had not been seen in the younger animals. Likewise, middle-aged females exposed to DZN showed deficient attentional accuracy, an effect not seen in young adults. Across adulthood, the continued potential for behavioral defects was associated with altered dopaminergic function, characterized by enhanced dopamine utilization that was regionally-selective (striatum but not frontal/parietal cortex). This study shows that the neurobehavioral impairments from maternal low dose exposure to diazinon not only persist, but may continue to evolve as animals enter middle age.
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Hawkey, Andrew B, Erica Pippen, Bruny Kenou, Zade Holloway, Theodore A Slotkin, Frederic J Seidler and Edward D Levin (2022). Persistent neurobehavioral and neurochemical anomalies in middle-aged rats after maternal diazinon exposure. Toxicology, 472. p. 153189. 10.1016/j.tox.2022.153189 Retrieved from https://hdl.handle.net/10161/29478.
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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.
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