Theodore Slotkin

..The present findings reinforce the concept of biologically distinct effects of nicotine in the adolescent brain and provide evidence for a mechanistic involvement of alpha 7 nAChRs in its unique effects during this developmental period...

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..Our studies suggest that identifying the initial mechanism of action of a developmental neurotoxicant may be strategically less important than focusing on the pathways that converge on common final outcomes such as cell loss...

..Equally important, these effects do not reflect actions on cholinesterase and operate at exposures below the threshold for any detectable inhibition of this enzyme...

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..The fact that the combined treatment produced greater effects points to potentially worsened neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers...

..In light of the large number of chemicals that are potential developmental neurotoxicants, there is a need to develop rapid screening techniques...

..The approach used here demonstrates how planned comparisons with microarrays can be used to screen for developmental neurotoxicity...

..These effects may contribute to lifelong vulnerability to readdiction...

..Equally importantly, the interaction between terbutaline and chlorpyrifos suggests that tocolytic therapy may alter the subsequent susceptibility to common environmental toxicants...

..These effects may contribute to lifelong vulnerability to readdiction...

..Organophosphate developmental neurotoxicity involves multiple mechanisms converging on neural cell replication and differentiation...

..The effects on 5HT circuits expand the scope of behavioral endpoints that need to be considered in evaluating the developmental neurotoxicity of organophosphates...

..This review considers the ramifications of the basic science findings of nicotine's effects on brain development for NRT in these populations...

..Similar, but lesser effects were seen for dopamine turnover in the same regions. These results indicate that, in a critical developmental period, apparently subtoxic exposures to CPF produce long-term activation of 5HT systems...

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..Our findings at 5 months of age replicate those seen in young adulthood and strongly suggest that the effects of neonatal CPF exposure on 5HT systems are permanent...

..Accordingly, adverse neurobehavioral consequences may be inescapable in glucocorticoid therapy of preterm infants...

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..These effects are likely responsible for the maintenance of betaAR activity associated with neurotrophic input during synaptogenesis but may also contribute to adverse effects of betaAR agonists used in preterm labor...

..For parathion, the threshold for lethality lies below that necessary for adverse effects on brain development, whereas the opposite is true for chlorpyrifos and diazinon...

..These results reinforce the need to reduce ETS exposure of pregnant women and young children...

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..These effects in the chick model recapitulate many of the actions of early gestational CPF exposure in rats, and thus suggest that CPF exerts direct actions on the immature brain to compromise the development of ACh and 5HT pathways...

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..We are seeking interventions that can ameliorate or reverse the effects later in life...

..Thus, dietary factors may produce similar synaptic changes as do developmental neurotoxicants, potentially contributing to the increasing incidence of neurodevelopmental disorders...

..Our results thus point to potentially worse neurobehavioral outcomes of the pharmacotherapy of preterm labor in the offspring of smokers...

..Instead, additional mechanisms for each agent may provide alternative routes to neurotoxicity, or may be additive or synergistic with oxidative stress...

..Organophosphates elicit developmental neurotoxicity through multiple mechanisms other than their shared property as cholinesterase inhibitors. Accordingly, these agents may differ in their effects on specific brain circuits...

..The fact that the combined treatment produced greater effects for many parameters points to potentially worse neurobehavioral outcomes after pharmacotherapy of preterm labor in the offspring of smokers...

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..BaP thus has direct actions on developing neuronal cells that could contribute to the adverse neurodevelopmental effects seen with in vivo exposures...

..Further, the results for choline acetyltransferase indicate that early depletion of norepinephrine compromises development of acetylcholine systems, consistent with a trophic role for this neurotransmitter...

..Since this developmental phase in the rat corresponds to the critical period in which glucocorticoids are used in preterm infants, adverse effects on brain development may be inescapable...

..The widespread detection of perfluoroalkyl acids and their derivatives in wildlife and humans, and their entry into the immature brain, raise increasing concern about whether these agents might be developmental neurotoxicants...

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..Our results thus provide mechanistic evidence that nicotine exposure, during the period in which nearly all smokers begin to use tobacco, reprograms the future response of 5-HT systems to nicotine...

..Oxidative stress and excitotoxicity underlie the developmental neurotoxicity of numerous chemicals...

..These studies show how common insecticides may contribute to the increased worldwide incidence of obesity and diabetes...

..These results may explain why apparently unrelated developmental neurotoxicants may ultimately produce a common set of neurochemical and behavioral anomalies...

..These data indicate that perinatal ETS exposure evokes changes in cells signaling that they are selective for the lung and that may ultimately reflect adverse effects at the level of physiological function...

..The present findings reinforce the mechanistic involvement of alpha7 nAChRs in the actions of developmental neurotoxicants, and its biomarker potential for neuroteratogens that target neuritic outgrowth...

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..Novel in vitro and in vivo exposure models are being developed to uncover heretofore unsuspected mechanisms and targets for developmental neurotoxicants...

..The multiple pharmacologic properties of theophylline, producing mitotic inhibition, cytotoxicity and altered signaling in MDA-MB-231 cells, may provide insight into novel therapeutic strategies...

..The effects are likely to contribute to gender-selective alterations in behavioral performance that persist or emerge long after the termination of exposure and well after the restoration of cholinesterase activity...

..The inability to desensitize betaAR responses may lead to disruption of neural cell development as a consequence of tocolytic therapy...

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..The effects seen here are likely to contribute to alterations in behavioral performance that persist or emerge long after the termination of CPF exposure...

..These results indicate that perinatal ETS exposes the fetus and neonate to quantities of nicotine that are sufficient to alter brain development...

..Effects of nicotine on critical components of reward pathways and circuits involved in learning, memory and mood are likely to contribute to increased addictive properties and long-term behavioral problems seen in adolescent smokers...

..At the same time, however, the inability to restrict betaAR function may underlie adverse effects of betaAR-agonist tocolytics that are used in the treatment of preterm labor...

..Novel pharmacologic strategies that focus on cell surface receptors operating through adenylyl cyclase may offer opportunities to combat cancers that are unresponsive to hormonal agents, or that have developed multidrug resistance...

..OBX may provide a useful animal model with which to test therapeutic interventions for geriatric depression...

..Given the high incidence of HPA axis dysregulation in the elderly, and particularly in elderly depression, effects of glucocorticoids on cell signaling may contribute to disrupted function and to altered drug reactivity...

..The fibroblast growth factor (FGF) superfamily of neurotrophic factors plays critical roles in neural cell development, brain assembly, and recovery from neuronal injury...

..These results indicate that even a single, low dose of glucocorticoids used in late gestation, can disrupt the transcription factors that regulate brain cell differentiation...

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..These distinctions may influence the etiology and therapy of depression, while at the same time providing potential biomarkers (such as platelet MAO) that may serve to predict successful treatment outcome in patient subpopulations...

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..These results indicate that, during a critical developmental period, Dex administration leads to widespread interference with forebrain development, likely contributing to eventual, adverse neurobehavioral outcomes...

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..These results indicate that, during critical developmental periods, Dex administration evokes lasting alterations in neural cell numbers and synaptic function in forebrain regions, even at doses below those used in preterm infants...

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..At the same time, nicotine promotes trophic actions that protect against neurotoxicants that work through other mechanisms...

..g., differentiation state) in which exposure occurs...

..Our results indicate that 5HT systems represent a target for otherwise unrelated neuroteratogens...

..The resemblance of these findings to those of late gestational or neonatal CPF exposure indicates a prolonged window of vulnerability of brain development to CPF...

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..Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression...

..These effects may contribute to neuropsychiatric, cognitive, cardiovascular, and metabolic abnormalities reported in the offspring of women treated with beta-agonist tocolytics...

..Organophosphorus pesticides (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism...

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..The simultaneous targeting of neurons and glia by CPF is likely to play an important role in its developmental neurotoxicant effects...

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..Exposure to silver is increasing because of silver nanoparticles in consumer products...

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..The balance between neuroprotectant and neurotoxicant actions of nicotine may be particularly important in situations where exposure to tobacco smoke is combined with other prooxidant insults...

..These effects are likely to contribute to neurobehavioral teratology of CPF...

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..Both molecular/neurochemical and behavioral effects of developmental OP exposure have been seen at doses below those which cause appreciable cholinesterase inhibition...

..The rare, read-through isoform, AChE-R, is preferentially induced by injury and appears to promote repair and protect against neurodegeneration. Overexpression of the more abundant, synaptic isoform, AChE-S, enhances neurotoxicity...

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..These results indicate that, in a critical developmental period, apparently nontoxic exposures to CPF produce lasting activation of 5HT systems in association with 5HT-associated behavioral anomalies...

..Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain...

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..These effects are likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity...

..The sea urchin model may thus be useful in high-throughput screening of suspected developmental neurotoxicants...

..Although delayed neurotoxic effects of prenatal CPF may emerge subsequently in development, our results are consistent with the preferential targeting of late developmental events such as gliogenesis, axonogenesis, and synaptogenesis...

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..Molecular mechanisms of developmental neurotoxicity can be determined and linked to eventual alterations in behavioral performance. ..