Biomedical subjects

Theodore A Slotkin

Publications and source records attributed to Theodore A Slotkin.

At least 19 recordsLinked to original sources

PubMed2006

Permanent, sex-selective effects of prenatal or adolescent nicotine exposure, separately or sequentially, in rat brain regions: indices of cholinergic and serotonergic synaptic function, cell signaling, and neural cell number and size at 6 months of age.

Nicotine is a neuroteratogen that disrupts neurodevelopment and synaptic function, with vulnerability extending into adolescence. We assessed the permanence of effects in rats on indices of neural cell number and size, and on acetylcholine and serotonin (5HT) systems, conducting assessments at 6 months of age, after prenatal nicotine exposure, adolescent exposure, or sequential exposure in both periods. For prenatal nicotine, indices of cell number and size showed few abnormalities by 6 months, but there were persistent deficits in cerebrocortical choline acetyltransferase activity and hemicholinium-3 binding to the presynaptic choline transporter, a pattern consistent with cholinergic hypoactivity; these effects were more prominent in males than females. The expression of 5HT receptors also showed permanent effects in males, with suppression of the 5HT(1A) subtype and upregulation of 5HT(2) receptors. In addition, cell signaling through adenylyl cyclase showed heterologous uncoupling of neurotransmitter responses. Nicotine exposure in adolescence produced lasting effects that were similar to those of prenatal nicotine. However, when animals were exposed to prenatal nicotine and received nicotine subsequently in adolescence, the adverse effects then extended to females, whereas the net effect in males was similar to that of prenatal nicotine by itself. Our results indicate that prenatal or adolescent nicotine exposure evoke permanent changes in synaptic function that transcend the recovery of less-sensitive indices of structural damage; further, prenatal exposure sensitizes females to the subsequent adverse effects of adolescent nicotine, thus creating a population that may be especially vulnerable to the lasting behavioral consequences of nicotine intake in adolescence.

Acetylcholine↗

PubMed2006

Alterations of serotonin synaptic proteins in brain regions of neonatal Rhesus monkeys exposed to perinatal environmental tobacco smoke.

Serotonin (5HT) systems play important roles in brain development, and early perturbations of 5HT receptor expression produce permanent changes in 5HT synaptic function and associated behaviors. We exposed pregnant Rhesus monkeys to environmental tobacco smoke (ETS) during gestation and for up to 3 months postnatally and examined the expression of 5HT(1A) and 5HT(2) receptors, and of the presynaptic 5HT transporter in brain regions containing 5HT projections (frontal, temporal and occipital cortex) and cell bodies (midbrain). Perinatal ETS exposure elicited upregulation of 5HT(1A) receptor expression without parallel changes in the other two proteins, a pattern consistent with specific 5HT receptor dysregulation, rather than universal disruption of 5HT synaptic development. The effects seen here for ETS in a primate model are virtually identical in direction, magnitude and regional selectivity to those obtained previously for prenatal nicotine administration in rats. Specifically, early 5HT(1A) overexpression alters the program for future synaptic and behavioral 5HT responses, thus providing a mechanistic link for the shared effects of ETS and nicotine on a specific pathway responsible for behavioral anomalies associated with perinatal tobacco exposure. These results reinforce the need to reduce ETS exposure of pregnant women and young children.

Animals↗

PubMed2006

A unique role for striatal serotonergic systems in the withdrawal from adolescent nicotine administration.

Adolescent smokers experience more severe withdrawal symptoms upon smoking cessation than do adults, even when daily smoking has occurred for only a short period or with low levels of consumption. Animal models of nicotine withdrawal indicate involvement of striatal serotonin (5-HT) systems in nicotine reward, withdrawal and craving. We evaluated indices of striatal 5-HT and dopamine (DA) synaptic activity, neurotransmitter levels and turnover (metabolite/transmitter ratio), after continuous nicotine infusions to adolescent rats from postnatal days 30 to 47, using a dose rate (6 mg/kg/day) that produces plasma levels typical of smokers. Withdrawal was accompanied by a significant and persistent loss of striatal 5-HT synaptic activity, evidenced by an initial decline in turnover followed by a reduction in 5-HT content without a compensatory increase in turnover. Similar effects were seen for striatal DA activity. These effects were superimposed on a loss of stimulatory 5-HT cellular responses and promotion of inhibitory responses as identified in an earlier work with this model. None of these alterations was seen during withdrawal in adult rats given the same regimen. The unique adolescent withdrawal effects were not seen when the adolescent nicotine treatment period was shortened to early adolescence (days 30-37), even if the administration paradigm was changed to twice-daily injections to maximize withdrawal stress. Our results are consistent with unique effects of adolescent nicotine withdrawal on striatal 5-HT and DA systems, and point to a potential for serotonin-specific reuptake inhibitors as alternatives to nicotine replacement therapy for smoking cessation in adolescents.

Age Factors↗

PubMed2006

Anomalous regulation of beta-adrenoceptor signaling in brain regions of the newborn rat.

Desensitization, an essential homeostatic response to excessive or continued beta-adrenoceptor (betaAR) stimulation, is deficient in immature cells. To determine the mechanisms underlying anomalous betaAR responses in newborn rats, we administered terbutaline, a beta2AR agonist, on postnatal day 2 and evaluated signaling through adenylyl cyclase (AC) in cell membrane preparations 4 h later. Although a small decrement in isoproterenol-stimulated AC was obtained in the forebrain, robust sensitization was seen in the brainstem and cerebellum, in association with heterologous increases in AC catalytic activity: increased basal, dopamine-stimulated and forskolin-stimulated AC. Superimposed on this global increase, there was a small degree of betaAR and dopamine receptor desensitization, characterized by decreases in the isoproterenol/forskolin and dopamine/forskolin AC activity ratios. Our results indicate that, in some immature brain regions, betaAR desensitization is masked by more substantial increases in the activity of signaling elements downstream from the receptors, resulting in sustained responses in the face of continued receptor stimulation. 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.

Adenylyl Cyclases↗

PubMed2006

Lasting effects of developmental dexamethasone treatment on neural cell number and size, synaptic activity, and cell signaling: critical periods of vulnerability, dose-effect relationships, regional targets, and sex selectivity.

Glucocorticoids administered to prevent respiratory distress in preterm infants are associated with neurodevelopmental disorders. To evaluate the long-term effects on forebrain development, we treated developing rats with dexamethasone (Dex) at 0.05, 0.2, or 0.8 mg/kg, doses below or spanning the range in clinical use, testing the effects of administration during three different stages: gestational days 17-19, postnatal days 1-3, or postnatal days 7-9. In adulthood, we assessed biomarkers of neural cell number and size, cholinergic presynaptic activity, neurotransmitter receptor expression, and synaptic signaling mediated through adenylyl cyclase (AC), in the cerebral cortex, hippocampus, and striatum. Even at doses that were devoid of lasting effects on somatic growth, Dex elicited deficits in the number and size of neural cells, with the largest effect in the cerebral cortex. Indices of cholinergic synaptic function (choline acetyltransferase, hemicholinium-3 binding) indicated substantial hyperactivity in males, especially in the hippocampus, effectively eliminating the normal sex differences for these parameters. However, the largest effects were seen for cerebrocortical cell signaling mediated by AC, where Dex treatment markedly elevated overall activity while obtunding the function of G-protein-coupled catecholaminergic or cholinergic receptors that stimulate or inhibit AC; uncoupling was noted despite receptor upregulation. Again, the effects on signaling were larger in males and offset the normal sex differences in AC. 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.

Adenylyl Cyclases↗

PubMed2006

Critical prenatal and postnatal periods for persistent effects of dexamethasone on serotonergic and dopaminergic systems.

Glucocorticoid administration to preterm infants is associated with neurodevelopmental disorders. We treated developing rats with dexamethasone (Dex) at 0.05, 0.2, or 0.8 mg/kg, doses below or spanning the range in clinical use, testing the effects of administration during three different stages: gestational days 17-19, postnatal days 1-3 or postnatal days 7-9. In adulthood, we assessed the impact on synaptic biomarkers for serotonin (5-hydroxytryptamine (5HT)) systems. Across all three regimens, Dex administration evoked upregulation of cerebrocortical 5HT1A and 5HT2 receptors and the presynaptic 5HT transporter, greatest for 5HT1A receptors. The effects were fully evident even at the lowest dose. In contrast, 5HT levels in the cerebral cortex and hippocampus showed disparate patterns of temporal sensitivity, with no change after gestational treatment, an increase with the early postnatal regimen, and a decrease with the later postnatal exposure. None of the changes in 5HT concentrations were offset by adaptive changes in the fractional 5HT turnover rate. Furthermore, the critical period of sensitivity seen for 5HT levels differed from that of dopamine even within the same brain region. These findings suggest that developmental exposure to Dex during the critical neurodevelopmental period corresponding to its use in preterm infants, elicits selective changes in 5HT and dopaminergic synaptic function over and above its effects on general aspects of neural cell development, below the threshold for somatic growth impairment, and even at doses below those used clinically. Accordingly, adverse neurobehavioral consequences may be inescapable in glucocorticoid therapy of preterm infants.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Perinatal environmental tobacco smoke exposure in rhesus monkeys: critical periods and regional selectivity for effects on brain cell development and lipid peroxidation.

Perinatal environmental tobacco smoke (ETS) exposure in humans elicits neurobehavioral deficits. We exposed rhesus monkeys to ETS during gestation and through 13 months postnatally, or postnatally only (6-13 months). At the conclusion of exposure, we examined cerebrocortical regions and the midbrain for cell damage markers and lipid peroxidation. For perinatal ETS, two archetypal patterns were seen in the various regions, one characterized by cell loss (reduced DNA concentration) and corresponding increases in cell size (increased protein/DNA ratio), and a second pattern suggesting replacement of larger neuronal cells with smaller and more numerous glia (increased DNA concentration, decreased protein/DNA ratio). The membrane/total protein ratio, a biomarker of neurite formation, also indicated potential damage to neuronal projections, accompanied by reactive sprouting. When ETS exposure was restricted to the postnatal period, the effects were similar in regional selectivity, direction, and magnitude. These patterns resemble the effects of prenatal nicotine exposure in rodent and primate models. Surprisingly, perinatal ETS exposure reduced the level of lipid peroxidation as assessed by the concentration of thiobarbituric acid reactive species, whereas postnatal ETS did not. The heart, a tissue that, like the brain, has high oxygen demand, displayed a similar but earlier decrease (2-3 months) in lipid peroxidation in the perinatal exposure model, whereas values were reduced at 13 months with the postnatal exposure paradigm. Our results provide a mechanistic connection between perinatal ETS exposure and neurobehavioral anomalies, reinforce the role of nicotine in these effects, and buttress the importance of restricting or eliminating ETS exposure in young children.

Animals↗

PubMed2006

Chlorpyrifos affects phenotypic outcomes in a model of mammalian neurodevelopment: critical stages targeting differentiation in PC12 cells.

The organophosphate insecticide chlorpyrifos (CPF) adversely affects mammalian brain development through multiple mechanisms. To determine if CPF directly affects neuronal cell replication and phenotypic fate, and to identify the vulnerable stages of differentiation, we exposed PC12 cells, a model for mammalian neurodevelopment, to CPF concentrations spanning the threshold for cholinesterase inhibition (5-50 microM) and conducted evaluations during mitosis and in early and mid-differentiation. In undifferentiated cells, exposure to 5 microM CPF for 1-3 days reduced DNA synthesis significantly without eliciting cytotoxicity. At the same time, CPF increased the expression of tyrosine hydroxylase (TH), the enzymatic marker for the catecholamine phenotype, without affecting choline acetyltransferase (ChAT), the corresponding marker for the cholinergic phenotype. Upon exposure to nerve growth factor (NGF), PC12 cells developed neuritic projections in association with vastly increased TH and ChAT expression accompanying differentiation into the two phenotypes. CPF exposure begun at the start of differentiation significantly reduced ChAT but not TH activity. In contrast, when CPF was added in mid-differentiation (4 days of NGF pretreatment), ChAT was unaffected and TH was increased slightly. Thus, CPF exerts stage-specific effects, reducing DNA synthesis in the undifferentiated state, impairing development of the cholinergic phenotype at the start of differentiation, and promoting expression of the catecholaminergic phenotype both in undifferentiated and differentiated cells. CPF administration in vivo produces deficits in the number of neurons and cholinergic function, and because we were able to reproduce these effects in vitro, our results suggest that CPF directly influences the phenotypic fate of neuronal precursors.

Animals↗

PubMed2006

Comparative developmental neurotoxicity of organophosphate insecticides: effects on brain development are separable from systemic toxicity.

A comparative approach to the differences between systemic toxicity and developmental neurotoxicity of organophosphates is critical to determine the degree to which multiple mechanisms of toxicity carry across different members of this class of insecticides. We contrasted neuritic outgrowth and cholinergic synaptic development in neonatal rats given different organophosphates (chlorpyrifos, diazinon, parathion) at doses spanning the threshold for impaired growth and viability. Animals were treated daily on postnatal days 1-4 by subcutaneous injection so as to bypass differences in first-pass activation to the oxon or catabolism to inactive products. Evaluations occurred on day 5. Parathion (maximum tolerated dose, 0.1 mg/kg) was far more systemically toxic than was chlorpyrifos or diazinon (maximum tolerated dose, 1-5 mg/kg). Below the maximum tolerated dose, diazinon impaired neuritic outgrowth in the forebrain and brainstem, evidenced by a deficit in the ratio of membrane protein to total protein. Diazinon also decreased choline acetyltransferase activity, a cholinergic neuronal marker, whereas it did not affect hemicholinium-3 binding to the presynaptic choline transporter, an index of cholinergic neuronal activity. There was no m(subscript)2(/subscript)-muscarinic acetylcholine receptor down-regulation, as would have occurred with chronic cholinergic hyperstimulation. The same pattern was found previously for chlorpyrifos. In contrast, parathion did not elicit any of these changes at its maximum tolerated dose. These results indicate a complete dichotomy between the systemic toxicity of organophosphates and their propensity to elicit developmental neurotoxicity. 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.

Animals↗

PubMed2006

Organophosphate insecticides target the serotonergic system in developing rat brain regions: disparate effects of diazinon and parathion at doses spanning the threshold for cholinesterase inhibition.

BACKGROUND: In the developing brain, serotonin (5HT) systems are among the most sensitive to disruption by organophosphates. OBJECTIVES: We exposed neonatal rats to daily doses of diazinon or parathion on postnatal days (PND)1-4 and evaluated 5HT receptors and the 5HT transporter in brainstem and forebrain on PND5, focusing on doses of each agent below the maximum tolerated dose and spanning the threshold for cholinesterase inhibition: 0.5, 1, or 2 mg/kg for diazinon, and 0.02, 0.05, and 0.1 mg/kg for parathion. RESULTS: Diazinon evoked up-regulation of 5HT1A and 5HT2 receptor expression even at doses devoid of effects on cholinesterase activity, a pattern similar to that seen earlier for another organophosphate, chlorpyrifos. In contrast, parathion decreased 5HT1A receptors, again at doses below those required for effects on cholinesterase. The two agents also differed in their effects on the 5HT transporter. Diazinon evoked a decrease in the brainstem and an increase in the forebrain, again similar to that seen for chlorpyrifos; this pattern is typical of damage of nerve terminals and reactive sprouting. Parathion had smaller, nonsignificant effects. CONCLUSIONS: Our results buttress the idea that, in the developing brain, the various organophosphates target specific neurotransmitter systems differently from each other and without the requirement for cholinesterase inhibition, their supposed common mechanism of action.

Animals↗

PubMed2005

Visuospatial memory deficits emerging during nicotine withdrawal in adolescents with prenatal exposure to active maternal smoking.

Active maternal smoking during pregnancy elevates the risk of cognitive deficits and tobacco smoking among offspring. Preclinical work has shown that combined prenatal and adolescent exposure to nicotine produces more pronounced hippocampal changes and greater deficits in cholinergic activity upon nicotine withdrawal than does prenatal or adolescent exposure to nicotine alone. Few prior studies have examined the potential modifying effects of gestational exposure to active maternal smoking on cognitive or brain functional response to tobacco smoking or nicotine withdrawal in adolescents. We examined visuospatial and verbal memory in 35 adolescent tobacco smokers with prenatal exposure to active maternal smoking and 26 adolescent tobacco smokers with no prenatal exposure to maternal smoking who were similar in age, educational attainment, general intelligence, and baseline plasma cotinine. Subjects were studied during ad libitum smoking and after 24 h of abstinence from smoking. A subset of subjects from each group also underwent functional magnetic resonance imaging while performing a visuospatial encoding and recognition task. Adolescent tobacco smokers with prenatal exposure experienced greater nicotine withdrawal-related deficits in immediate and delayed visuospatial memory relative to adolescent smokers with no prenatal exposure. Among adolescent smokers with prenatal exposure, nicotine withdrawal was associated with increased activation of left parahippocampal gyrus during early recognition testing of visuospatial stimuli and increased activation of bilateral hippocampus during delayed recognition testing of visuospatial stimuli. These findings extend prior preclinical work and suggest that, in human adolescent tobacco smokers, prenatal exposure to active maternal smoking is associated with alterations in medial temporal lobe function and concomitant deficits in visuospatial memory.

Adolescent↗

PubMed2005

Prenatal nicotine exposure alters the responses to subsequent nicotine administration and withdrawal in adolescence: Serotonin receptors and cell signaling.

Offspring of women who smoke during pregnancy are themselves more likely to take up smoking in adolescence, effects that are associated with a high rate of depression and increased sensitivity to withdrawal symptoms. To evaluate the biological basis for this relationship, we assessed effects on serotonin (5-hydroxytryptamine, 5HT) receptors and 5HT-mediated cellular responses in rats exposed to nicotine throughout prenatal development and then given nicotine in adolescence (postnatal days PN30-47.5), using regimens that reproduce plasma nicotine levels found in smokers. Evaluations were then made during the period of adolescent nicotine treatment and for up to one month after the end of treatment. Prenatal nicotine exposure, which elicits damage to 5HT projections in the cerebral cortex and striatum, produced sex-selective changes in the expression of 5HT(1A) and 5HT2 receptors, along with induction of adenylyl cyclase (AC), leading to sensitization of heterologous inputs operating through this signaling pathway. Superimposed on these effects, the AC response to 5HT was shifted toward inhibition. By itself, adolescent nicotine administration, which damages the same pathways, produced similar effects on receptors and the 5HT-mediated response, but a smaller overall induction of AC. Animals exposed to prenatal nicotine showed a reduced response to nicotine administered in adolescence, results in keeping with earlier findings of persistent desensitization. Our results indicate that prenatal nicotine exposure alters parameters of 5HT synaptic communication lasting into adolescence and changes the response to nicotine administration and withdrawal in adolescence, actions which may contribute to a subpopulation especially vulnerable to nicotine dependence.

Age Factors↗

PubMed2005

Adverse neurodevelopmental effects of dexamethasone modeled in PC12 cells: identifying the critical stages and concentration thresholds for the targeting of cell acquisition, differentiation and viability.

The use of dexamethasone (DEX) to prevent respiratory distress in preterm infants is suspected to produce neurobehavioral deficits. We used PC12 cells to model the effects of DEX on different stages of neuronal development, utilizing exposures from 24 h up to 11 days and concentrations from 0.01 to 10 microM, simulating subtherapeutic, therapeutic, and high-dose regimens. In undifferentiated cells, even at the lowest concentration, DEX inhibited DNA synthesis and produced a progressive deficit in the number of cells as evaluated by DNA content, whereas cell growth (evaluated by the total protein to DNA ratio) and cell viability (Trypan blue exclusion) were promoted. When cell differentiation was initiated with nerve growth factor, the simultaneous inclusion of DEX still produced a progressive deficit in cell numbers and promoted cell growth and viability while retarding the development of neuritic projections as monitored by the membrane/total protein ratio. Again, even 0.01 microM DEX was effective. We next assessed effects at mid-differentiation by introducing nerve growth factor for 4 days followed by coexposure to DEX. Although effects on cell number, growth, and neurite extension were still detectable, the outcomes were generally less notable. DEX also shifted the fate of PC12 cells away from the cholinergic phenotype and toward the adrenergic phenotype, with the maximum effect achieved at the outset of differentiation. Our results indicate that DEX directly disrupts neuronal cell replication, differentiation, and phenotype at concentrations below those required for the therapy of preterm infants, providing a mechanistic link between glucocorticoid use and neurodevelopmental sequelae.

Animals↗

PubMed2005

Imbalances emerge in cardiac autonomic cell signaling after neonatal exposure to terbutaline or chlorpyrifos, alone or in combination.

During early neonatal development, the future reactivity of the heart to cardiac autonomic stimulation is programmed by the timing and intensity of the arrival of parasympathetic and sympathetic inputs. In neonatal rats, we examined the effects of exposure to terbutaline, a beta-adrenoceptor (betaAR) agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide that acts in part through inhibition of cholinesterase, using scenarios mimicking the likely developmental stages corresponding to peak human exposures: postnatal days (PN) 2-5 for terbutaline and PN11-14 for CPF. Terbutaline evoked a progressive deficit in cardiac betaAR binding but did not interfere with the ability of the receptors to stimulate adenylyl cyclase (AC). Terbutaline also reduced expression of m2 muscarinic acetylcholine receptors and suppressed their ability to inhibit AC. Surprisingly, CPF produced similar actions, a decrement in betaAR and m2 muscarinic receptor binding and a loss of the cholinergic AC response, and also augmented the ability of betaARs to stimulate AC. The effects of CPF are thus unlikely to reside in cholinergic hyperstimulation resulting from cholinesterase inhibition but instead involve other actions converging on receptors and cell signaling. Exposure to both agents, terbutaline followed by CPF, produced a summation of the two individual effects. Our findings at the level of cell signaling thus indicate that neonatal exposure to terbutaline or CPF, or sequentially to both agents, results in an imbalance of cardiac autonomic inputs favoring increased excitability, an outcome that may have an impact on cardiovascular responses.

Adenylyl Cyclases↗

PubMed2005

Cholinergic receptor subtypes in the olfactory bulbectomy model of depression.

The connection between smoking and depression, the antidepressant actions of nicotine and the targeting of nicotinic acetylcholine receptors (nAChRs) by monoamine re-uptake inhibitors all point to a potential role of nAChRs in the etiology and/or symptomatology of depression. In the current study, we evaluated nAChR subtypes in brain regions of rats subjected to olfactory bulbectomy (OBX), a standard animal model that recapitulates many of the behavioral and neurochemical alterations thought to underlie human depression. Comparisons were made both to sham-operated controls and unoperated animals. OBX led to upregulation of cerebrocortical alpha4beta2 nAChRs and downregulation of striatal alpha7 nAChRs as compared to either the sham-operated or unoperated groups. Striatal alpha4beta2 nAChRs were also downregulated but the sham surgery by itself produced a partial effect, masking the contribution of the OBX lesion. In agreement with earlier studies, we also found downregulation of muscarinic AChRs (both m1 and m2 subtypes) in the striatum when comparing the OBX group to sham-operated controls, but because sham surgery evoked mAChR upregulation, the effect was not apparent when the OBX animals were contrasted to the unoperated group. Accordingly, caution needs to be exercised in interpreting studies of cholinergic function in the OBX model that do not include unoperated animals as an additional comparison group. Our results reinforce a relationship between depression and nAChR expression and point to the need for parallel studies in human depression that might lead to the design of novel therapies targeting specific nAChR subtypes.

Alkaloids↗

PubMed2005

The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent.

Fetal or neonatal exposure to chlorpyrifos (CPF) or related organophosphate pesticides leads to abnormalities of brain cell development, synaptic function, and behavior. Recent studies in rats indicate profound effects on serotonin (5HT) systems that originate during CPF exposure and that are still present at 2 months posttreatment in the young adult. To determine if these changes are permanent, we administered 1 mg/kg of CPF daily to neonatal rats on postnatal days 1-4, a regimen devoid of systemic toxicity, and examined 5HT synaptic markers at 5 months of age: radioligand binding to 5HT1A and 5HT2 receptors and to the 5HT transporter. There were global elevations in all three synaptic proteins, with pronounced sex selectivity (effects on males>females) and a regional hierarchy of effects, viz. striatum>midbrain approximately brainstem>cerebral cortex. Because there is a normal sex disparity for 5HT synaptic proteins, with females having higher values than males, the increase caused by CPF exposure in males completely eliminated this difference. 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.

Animals↗

PubMed2005

Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination.

The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms other than inhibition of cholinesterase. In the current study, we examined the ability of CPF to evoke lipid peroxidation in the developing brain of fetal and neonatal rats. CPF given to pregnant rats on gestational days 17-20 or to neonatal rats on postnatal days 1-4, failed to elicit increases in thiobarbituric acid-reactive species (TBARS) in brain regions even when the dose was raised above the threshold for systemic toxicity and hepatic damage. In contrast, CPF administration during the second postnatal week, the peak period of neuronal cell differentiation and synaptogenesis, did evoke significant increases in TBARS even at a dose devoid of systemic toxicity. Terbutaline, which is chemically unrelated to CPF and which stimulates neuronal cell metabolism through direct actions on beta-adrenoceptors, also elicited oxidative damage in the developing brain with greater sensitivity in the second postnatal week. These results indicate that diverse compounds can exert convergent effects on brain development through their shared potential to elicit oxidative stress, and that the net outcome is dependent upon specific developmental stages in which metabolic demand is especially high. Furthermore, given the common use of terbutaline in the therapy of preterm labor, and the nearly ubiquitous exposure of the human population to organophosphorus pesticides, the combined oxidative burden of exposure to both agents may contribute to the worsened neurodevelopmental outcomes noted in animal models of such dual exposures.

Adrenergic beta-Agonists↗

PubMed2005

Prenatal stress elicits regionally selective changes in basal FGF-2 gene expression in adulthood and alters the adult response to acute or chronic stress.

Exposure to stress during pregnancy influences the trajectory of brain development resulting in permanent alterations that may contribute to increased susceptibility to subsequent cognitive or neuropsychiatric disorders. In this manuscript, we examined the effects of prenatal stress on the expression of basic fibroblast growth factor (FGF-2), an important molecular regulator of development and plasticity, in adult male rats under basal conditions as well as in response to acute or chronic stress. Baseline FGF-2 mRNA levels were differentially influenced by gestational stress in a variety of brain regions, with significant decreases in prefrontal cortex and increases in entorhinal cortex and striatum. By itself, postnatal stress similarly decreased trophic factor expression in prefrontal cortex while evoking stimulation elsewhere. Gestational stress altered the pattern of FGF-2 expression in response to adult stress, completely reversing the pattern in the prefrontal cortex (stimulatory instead of inhibitory), blunting the response in the entorhinal cortex and desensitizing the response in the striatum. These effects point to a unique interference of chronic prenatal stress with both ongoing FGF-2 expression and its responses to subsequent stressors, lasting into adulthood. Given the multifaceted role of FGF-2 in synaptic development, maintenance and plasticity, these data provide detailed mechanistic evidence as to how prenatal stress elicits lifelong effects on synaptic function. The abnormal modulation of FGF-2 gene expression in specific brain regions in response to subsequent stress in adulthood may impair the normal adaptive responses of the cell to challenging situations.

Acute Disease↗