Biomedical subjects

Theodore A Slotkin

Publications and source records attributed to Theodore A Slotkin.

At least 19 recordsLinked to original sources

PubMed2005

Quantitative morphological assessment reveals neuronal and glial deficits in hippocampus after a brief subtoxic exposure to chlorpyrifos in neonatal rats.

Neurochemical and behavioral studies indicate that the widely used organophosphorus insecticide, chlorpyrifos (CPF), evokes neurobehavioral teratogenicity with a wide window of vulnerability, ranging from embryonic life through postnatal development. Few studies have detailed morphological damage that corresponds to the operational deficits. We administered 5 mg/kg of CPF sc daily on postnatal days (PN) 11-14, a regimen that is devoid of systemic toxicity, but that elicits long-term cognitive impairment and disruption of cholinergic, catecholaminergic, and serotonergic synaptic function. On PN15 and 20, we conducted quantitative morphologic examinations of neurons and glia in CA1, CA3, and dentate gyrus regions of the hippocampus. Although hippocampal morphology after CPF exposure was normal on gross observation, morphometric analysis revealed a significant overall reduction in the total number of neurons and glia. Superimposed on this basic effect, CPF elicited a delayed-onset increase in the neuron/glia ratio that emerged by PN20, connoting selective gliotoxicity. The alterations in cell numbers were accompanied by significant perikaryal swelling and by enhanced development of astrocytic processes. Layer thickness also showed delayed-onset effects of CPF, with thinning of the CA1 and CA3 layers and enlargement of the dentate gyrus. Our results indicate that there are subtle morphological changes in the juvenile rat brain after neonatal CPF exposure that are detectable only with quantitative analysis and that correlate with regional and cell-specific targets identified earlier in neurochemical studies. The simultaneous targeting of neurons and glia by CPF is likely to play an important role in its developmental neurotoxicant effects.

Animals↗

PubMed2005

Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions.

Developmental exposure to unrelated neurotoxicants can nevertheless produce similar neurobehavioral outcomes. We examined the effects of developmental exposure to terbutaline, a tocolytic beta2-adrenoceptor agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide, on serotonin (5HT) systems. Treatments were chosen to parallel periods typical of human developmental exposures, terbutaline (10 mg/kg) on postnatal days (PN) 2-5 and CPF (5 mg/kg) on PN11-14, with assessments conducted on PN45, comparing each agent alone as well as sequential administration of both. Although neither treatment affected growth or viability, each elicited similar alterations in factors that are critical to the function of the 5HT synapse: 5HT1A receptors, 5HT2 receptors, and the presynaptic 5HT transporter (5HTT). Either agent elicited global increases in 5HT receptors and the 5HTT in brain regions possessing 5HT cell bodies (midbrain, brainstem) as well as in the hippocampus, which contains 5HT projections. For both terbutaline and CPF, males were affected more than females, although there were some regional disparities in the sex selectivity between the two agents. Both altered 5HT receptor-mediated cell signaling, suppressing stimulatory effects on adenylyl cyclase and enhancing inhibitory effects. When animals were exposed sequentially to both agents, the outcomes were no more than additive and, for many effects, less than additive, suggesting convergence of the two agents on a common set of developmental mechanisms. Our results indicate that 5HT systems represent a target for otherwise unrelated neuroteratogens.

Adenylyl Cyclase Inhibitors↗

PubMed2005

Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos.

Exposure to apparently unrelated neurotoxicants can nevertheless converge on common neurodevelopmental events. We examined the long-term effects of developmental exposure of rats to terbutaline, a beta-adrenoceptor agonist used to arrest preterm labor, and the organophosphorus insecticide chlorpyrifos (CPF) separately and together. Treatments mimicked the appropriate neurodevelopmental stages for human exposures: terbutaline on postnatal days (PN) 2-5 and CPF on PN11-14, with assessments conducted on PN45. Although neither treatment affected growth or viability, each elicited alterations in CNS cell signaling mediated by adenylyl cyclase (AC), a transduction pathway shared by numerous neuronal and hormonal signals. Terbutaline altered signaling in the brainstem and cerebellum, with gender differences particularly notable in the cerebellum (enhanced AC in males, suppressed in females). By itself, CPF exposure elicited deficits in AC signaling in the midbrain, brainstem, and striatum. However, sequential exposure to terbutaline followed by CPF produced larger alterations and involved a wider spectrum of brain regions than were obtained with either agent alone. In the cerebral cortex, adverse effects of the combined treatment intensified between PN45 and PN60, suggesting that exposures alter the long-term program for development of synaptic communication, leading to alterations in AC signaling that emerge even after adolescence. These findings indicate that terbutaline, like CPF, is a developmental neurotoxicant, and reinforce the idea that its use in preterm labor may create a subpopulation that is sensitized to long-term CNS effects of organophosphorus insecticides.

Adenylyl Cyclases↗

PubMed2005

Modeling the developmental neurotoxicity of nicotine in vitro: cell acquisition, growth and viability in PC12 cells.

Although nicotine is a developmental neurotoxicant, it also can exert neuroprotective effects. In the current study, we used PC12 cells to determine the developmental phases in which these disparate actions are expressed and to compare the concentrations required for each. In undifferentiated cells, 1 or 10 microM nicotine had little or no effect on cell number (assessed by measuring DNA) but exerted positive trophic actions, characterized by transient enhancement of cell growth (increased total protein/DNA ratio) and persistent enhancement of cell viability (decreased proportions of cells stained with trypan blue). When differentiation was initiated with nerve growth factor, nicotine elicited a different spectrum of actions, with decreases in cell number, impaired neuritic outgrowth (reduced ratio of membrane/total protein) and weakened viability. In either undifferentiated or differentiating cells, nicotine increased lipid peroxidation (determined as thiobarbituric acid reactive species), providing evidence for oxidative damage. Our results indicate that nicotine exerts positive trophic effects primarily on undifferentiated cells, whereas with differentiation the effects undergo a transition to neurotoxicity. These findings support the view that the neurodevelopmental actions of nicotine depend not only upon the magnitude and duration of the exposure, but most importantly on the developmental stage (e.g., differentiation state) in which exposure occurs.

Analysis of Variance↗

PubMed2005

Effects of prenatal nicotine exposure on primate brain development and attempted amelioration with supplemental choline or vitamin C: neurotransmitter receptors, cell signaling and cell development biomarkers in fetal brain regions of rhesus monkeys.

Studies in developing rodents indicate that nicotine is a neuroteratogen that disrupts brain development by stimulating nicotinic acetylcholine receptors (nAChRs) that control neural cell replication and differentiation. We administered nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, achieving maternal plasma levels comparable to those in smokers (30 ng/ml). Fetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signaling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Similarly, indices of cell loss (reduced DNA), cell size and neuritic outgrowth (protein/DNA and membrane/total protein ratios) were distinct for each region and did not necessarily follow the rank order of nAChR upregulation, suggesting the involvement of additional mechanisms such as oxidative stress. We then attempted to offset the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Similarly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most susceptible to oxidative stress. Our results indicate that nicotine elicits neurodevelopmental damage that is highly selective for different brain regions, and that dietary supplements ordinarily thought to be neuroprotectant may actually worsen some of the adverse effects of nicotine on the fetal brain.

Adenylyl Cyclases↗

PubMed2005

Serotonergic cell signaling in an animal model of aging and depression: olfactory bulbectomy elicits different adaptations in brain regions of young adult vs aging rats.

Aging involves neuronal and synaptic loss, and maintenance of function depends on adaptations in cellular responsiveness. We studied olfactory bulbectomy (OBX), a model that recapitulates monoaminergic dysfunction in depression, in 10-week vs 19-month-old rats, and evaluated 5HT (5-hydroxytryptamine, serotonin) mechanisms. OBX elicited little change in 5HT1A receptors in the cerebral cortex or striatum of either age group. In contrast, 5HT2 receptors showed disparate effects, with a decrease in the cerebral cortex of young OBX but not aging OBX rats, whereas the latter group showed a selective decrease in striatal 5HT2 receptors. Greater differences were apparent for 5HT-mediated cell signaling, assessed for the adenylyl cyclase (AC) cascade. In young animals, 5HT had a stimulatory effect on AC that was unaltered by OBX. However, in aging animals, the pattern of 5HT responses showed marked alterations in response to OBX: under basal conditions, stimulatory effects were enhanced but when AC was activated with forskolin, 5HT became markedly inhibitory in the striatum of aged OBX animals. Assessment of the relative AC responses to two direct stimulants that act on different epitopes of the enzyme, forskolin and Mn2+, pointed to a shift in the AC isoform and/or its ability to associate with G-proteins as the mechanism underlying the age-related differences for OBX effects. These data indicate that there are biological distinctions in the response of 5HT systems to OBX in young adult vs aging animals, which, if present in geriatric depression, could provide a mechanistic basis for differences in responses to antidepressants that act on 5HT.

Adaptation, Physiological↗

PubMed2005

Nicotine therapy in adulthood reverses the synaptic and behavioral deficits elicited by prenatal exposure to phenobarbital.

A major objective in identifying the mechanisms underlying neurobehavioral teratogenicity is the possibility of designing therapies that reverse or offset drug- or toxicant-induced neural damage. In our previous studies, we identified deficits in hippocampal muscarinic cholinergic receptor-induced membrane translocation of protein kinase C (PKC)gamma as the likely mechanism responsible for adverse behavioral effects of prenatal phenobarbital exposure. We therefore explored whether behavioral and synaptic defects could be reversed in adulthood by nicotine administration. Pregnant mice were given milled food containing phenobarbital to achieve a daily dose of 0.5-0.6 g/kg from gestational days 9-18. In adulthood, offspring showed deficits in the Morris maze, a behavior dependent on the integrity of septohippocampal cholinergic synaptic function, along with the loss of the PKCgamma response. Phenobarbital-exposed and control mice then received nicotine (10 mg/kg/day) for 14 days via osmotic minipumps. Nicotine reversed the behavioral deficits and restored the normal response of hippocampal PKCgamma to cholinergic receptor stimulation. The effects were regionally specific, as PKCgamma in the cerebellum was unaffected by either phenobarbital or nicotine; furthermore, in the hippocampus, PKC isoforms unrelated to the behavioral deficits showed no changes. Nicotine administration thus offers a potential therapy for reversing neurobehavioral deficits originating in septohippocampal cholinergic defects elicited by prenatal drug or toxicant exposures.

Animals↗

PubMed2004

Administration of nicotine to adolescent rats evokes regionally selective upregulation of CNS alpha 7 nicotinic acetylcholine receptors.

Alpha 7 Nicotinic acetylcholine receptors (nAChRs) play a role in axonogenesis, synaptogenesis and synaptic plasticity, and are therefore targets for developmental neurotoxicants. We administered nicotine to adolescent rats and evaluated the effects on alpha 7 nAChRs in the striatum, brainstem and cerebellum. During the period of nicotine administration (30-47.5 days of age), nicotine elicited alpha 7 nAChR upregulation with a regional hierarchy of striatum>brainstem>cerebellum. Values returned to normal or became slightly subnormal almost immediately after the cessation of treatment (50 days of age) with no further changes through 75 days of age. The temporal and regional patterns of the effects on alpha 7 nAChRs were distinct from those reported earlier for the alpha 4 beta 2 subtype, and neither adult nor fetal/neonatal administration upregulates the alpha 7 subtype in the striatum. Targeting of the striatum is thus unique to nicotine exposure during adolescence and parallels earlier work showing regionally selective effects of this treatment on synaptic signaling. We obtained preliminary evidence for nicotine-induced oxidative stress as a potential contributory mechanism. 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.

Age Factors↗

PubMed2004

Cholinergic synaptic signaling mechanisms underlying behavioral teratogenicity: effects of nicotine, chlorpyrifos, and heroin converge on protein kinase C translocation in the intermedial part of the hyperstriatum ventrale and on imprinting behavior in an avian model.

A wide variety of otherwise unrelated neuroteratogens elicit a common set of behavioral defects centering around cholinergic contributions to cognitive function. We utilized the developing chick to overcome confounds related to maternal effects and compared the actions of nicotine, chlorpyrifos, and heroin on cholinergic signaling in the intermedial part of the hyperstriatum ventrale (IMHV), which controls imprinting behavior. Chicken eggs were injected with nicotine (10 mg/kg of egg), chlorpyrifos (10 mg/kg of egg), or heroin (20 mg/kg of egg; all doses below the threshold for dysmorphology) on incubation days (ID) 0 and 5, and then tests were conducted posthatching. All three compounds elicited significant deficits in imprinting behavior. We also found defects in cholinergic synaptic signaling specifically involving the muscarinic receptor-mediated membrane translocation of protein kinase C (PKC)-gamma and in the basal levels of both PKCgamma and PKCbetaII, the two isoforms known to be relevant to behavioral performance. In contrast, there were no alterations in the response of PKCalpha, an isoform that does not contribute to the behavior, nor were cytosolic levels of any of the isoforms affected. Taken together with similar results obtained in rodents, our findings suggest that disparate neuroteratogens all involve signaling defects centering on the ability of cholinergic receptors to elicit PKCgamma translocation/activation and that this effect is direct, i.e., not mediated by maternal confounds. The chick thus provides a suitable model for the rapid screening of neuroteratogens and elucidation of the mechanisms underlying behavioral anomalies.

Analysis of Variance↗

PubMed2004

Alpha7 nicotinic acetylcholine receptors targeted by cholinergic developmental neurotoxicants: nicotine and chlorpyrifos.

Alpha7 nicotinic acetylcholine receptors (nAChRs) play a role in axonogenesis, synaptogenesis and synaptic plasticity, and are therefore potential targets for developmental neurotoxicants. We administered nicotine to neonatal rats during discrete periods spanning the onset and peak of axonogenesis/synaptogenesis, focusing on three brain regions with disparate distributions of cell bodies and neural projections: brainstem, forebrain and cerebellum. Nicotine treatment on postnatal days (PN) 1-4 had little or no effect on alpha7 nAChRs but treatment during the second (PN11-14) or third (PN21-24) weeks elicited significant decrements in receptor expression in brainstem and cerebellum, regions containing cell bodies that project to the forebrain. Exposure to chlorpyrifos, a neurotoxicant pesticide that acts partially through cholinergic mechanisms, also elicited deficits in alpha7 nAChRs during the second postnatal week but not the first week. For both nicotine and chlorpyrifos, the effects on alpha7 nAChRs were distinct from those on the alpha4beta2 subtype. Continuous prenatal nicotine exposure, which elicits subsequent, postnatal deficits in axonogenesis and synaptogenesis, also produced delayed-onset changes in alpha7 nAChRs, characterized by reductions in the forebrain and upregulation in the brainstem and cerebellum, a pattern consistent with impaired axonogenesis/synaptogenesis and reactive sprouting. Males were more sensitive to the persistent effects of prenatal nicotine exposure on alpha7 nAChRs, a pattern that mimics neurobehavioral deficits resulting from this treatment. 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.

Acetylcholine↗

PubMed2004

Transiently overexpressed alpha2-adrenoceptors and their control of DNA synthesis in the developing brain.

During brain development, neurotransmitters act as trophic factors controlling the patterns of cell replication and differentiation. Alpha2-adrenoceptors (alpha2ARs) are transiently overexpressed in zones with high mitotic activity and we evaluated whether these receptors are linked to DNA synthesis in the perinatal rat brain. Acute administration of clonidine (2 mg/kg), an alpha2AR agonist, elicited dramatic decreases in DNA synthesis in the forebrain, brainstem, and cerebellum whether given on gestational day (GD) 21, or on postnatal days (PN) 1 or 8. However, alpha2AR blockade elicited by yohimbine (2.5 mg/kg) also resulted in decreased DNA synthesis on GD21 and PN8, albeit to a smaller extent than with clonidine. Yohimbine was able to blunt the effects of clonidine, verifying that both drugs are acting through the same receptor population. Because betaARs are also known to regulate DNA synthesis, we used propranolol (10 mg/kg) blockade of betaARs to evaluate whether the alpha2AR effects were mediated by presynaptic autoreceptors that regulate the release of norepinephrine and consequent betaAR responses; the effects of yohimbine were still discernible in the presence of propranolol. Accordingly, transiently overexpressed alpha2ARs in the developing brain participate in the control of DNA synthesis in a biphasic manner, with promotional actions at low, endogenous levels of stimulation, but inhibitory effects when stimulation is high. Effects on alpha2ARs are likely to contribute to long-term consequences of adrenergic agents used in obstetrics or neurotoxicants that affect adrenergic activity.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

Cholinergic systems in brain development and disruption by neurotoxicants: nicotine, environmental tobacco smoke, organophosphates.

Acetylcholine and other neurotransmitters play unique trophic roles in brain development. Accordingly, drugs and environmental toxicants that promote or interfere with neurotransmitter function evoke neurodevelopmental abnormalities by disrupting the timing or intensity of neurotrophic actions. The current review discusses three exposure scenarios involving acetylcholine systems: nicotine from maternal smoking during pregnancy, exposure to environmental tobacco smoke (ETS), and exposure to the organophosphate insecticide, chlorpyrifos (CPF). All three have long-term, adverse effects on specific processes involved in brain cell replication and differentiation, synaptic development and function, and ultimately behavioral performance. Many of these effects can be traced to the sequence of cellular events surrounding the trophic role of acetylcholine acting on its specific cellular receptors and associated signaling cascades. However, for chlorpyrifos, additional noncholinergic mechanisms appear to be critical in establishing the period of developmental vulnerability, the sites and type of neural damage, and the eventual outcome. New findings indicate that developmental neurotoxicity extends to late phases of brain maturation including adolescence. Novel in vitro and in vivo exposure models are being developed to uncover heretofore unsuspected mechanisms and targets for developmental neurotoxicants.

Adult↗

PubMed2004

Altered localization of choline transporter sites in the mouse hippocampus after prenatal heroin exposure.

Prenatal heroin exposure disrupts hippocampal cholinergic synaptic function and related behaviors. Biochemical studies indicate an increase in the number of presynaptic high-affinity choline transporter (HACT) sites, as assessed by [3H]hemicholinium-3 (HC-3) binding. The present study was designed to assess whether this effect involves global upregulation of the transporter, or whether disruption occurs with a specific tempero-spatial distribution. Pregnant mice were given 10mg/kg per day of heroin subcutaneously on gestational days (GD) 9-18. Autoradiographic distribution of HC-3 binding sites was evaluated in the hippocampus of the offspring at postnatal days 15, 25, and 53. These results, suggestive of hippocampal "miswiring," are likely to explain the net impairment of cholinergic synaptic function after prenatal heroin exposure, despite the simultaneous upregulation of both presynaptic cholinergic activity and postsynaptic receptors. Understanding the subregional selectivity of hippocampal defects can lead to the development of strategies that may potentially enable therapeutic interventions to offset or reverse the neurobehavioral defects.

Acetylcholine↗

PubMed2004

Does pharmacotherapy for preterm labor sensitize the developing brain to environmental neurotoxicants? Cellular and synaptic effects of sequential exposure to terbutaline and chlorpyrifos in neonatal rats.

It is increasingly clear that environmental toxicants target specific human subpopulations. In the current study, we examined the effects of prior developmental exposure to a beta(2)-adrenoceptor agonist used to arrest preterm labor, terbutaline, on the subsequent effects of exposure to the organophosphate insecticide, chlorpyrifos (CPF). Neonatal rats were given terbutaline on postnatal day (PN) 2-5, followed by CPF on PN11-14. Although neither treatment affected growth or viability, each elicited alterations in indices of brain cell differentiation and cholinergic innervation in the immediate posttreatment period (PN15), persisting into adulthood (PN60). Biomarkers of brain cell number (DNA concentration and content), cell size (protein/DNA ratio) and neuritic projections (membrane/total protein) were affected by either agent alone, with patterns consistent with neuronal and neuritic damage accompanied by reactive gliosis. The combined exposure augmented these effects by both additive and synergistic mechanisms. Similarly, choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was affected only by combined exposure to both terbutaline and CPF. Indices of cholinergic synaptic activity [hemicholinium-3 and m(2)-muscarinic acetylcholine receptor binding] showed impairment after exposure to either terbutaline or CPF but the effects were more severe when the treatments were combined. These findings suggest that terbutaline, like CPF, is a developmental neurotoxicant, and that its use in the therapy of preterm labor may create a subpopulation that is sensitized to the adverse neural effects of a subsequent exposure to organophosphate insecticides.

Acetylcholinesterase↗

PubMed2004

Morphologic effects of subtoxic neonatal chlorpyrifos exposure in developing rat brain: regionally selective alterations in neurons and glia.

The widely used organophosphate insecticide, chlorpyrifos (CPF), elicits neurobehavioral teratogenesis with exposure windows ranging from the embryonic neural tube stage through postnatal development. To explore the morphologic changes occurring in late-stage exposure, newborn rats were given 5 mg/kg of CPF s.c. daily on postnatal days (PN) 11-14, a regimen that is devoid of systemic toxicity, but that elicits long-term cognitive impairment. On PN15 and 20, we examined the septal nucleus, striatum and somatosensory cortex. Across all three regions, CPF elicited a significant decrease in the number of glial cells. Superimposed on this basic pattern, there were region-specific alterations in the number and type of neurons, and neuronal perikaryal dimensions. In the septal nucleus, the CPF group exhibited an increase in the number of neurons on PN20, representing a delay in the normal maturational decline; there was a parallel decrease in the glial/neuronal ratio. In the striatum, the number of neurons per unit area was reduced in the CPF group, accompanied by perikaryal hypertrophy, as evidenced by an increase in the average neuronal cell diameter. In the somatosensory cortex, the distribution of cell sizes indicated a decrease in the proportion of small, nonpyramidal cells. Thus, there are subtle morphological changes in the juvenile rat brain after neonatal CPF exposure that are detectable with quantitative analysis and that correlate with later emergence of behavioral alterations. Furthermore, the current findings support the hypothesis that CPF interferes with gliogenesis, a relatively late event in brain development; accordingly, the vulnerable period for adverse effects of CPF is likely to extend into childhood or adolescence.

Analysis of Variance↗

PubMed2004

Chlorpyrifos exposure during neurulation: cholinergic synaptic dysfunction and cellular alterations in brain regions at adolescence and adulthood.

The developmental neurotoxicity of chlorpyrifos (CPF) involves multiple mechanisms, thus rendering the immature brain susceptible to adverse effects over a wide window of vulnerability. Earlier work indicated that CPF exposure at the neural tube stage elicits apoptosis and disrupts mitotic patterns in the brain primordium but that rapid recovery ensues before birth. In the current study, we assessed whether defects in cholinergic synaptic activity emerge later in development. CPF was given to pregnant rats on gestational days 9-12, using regimens devoid of overt maternal or fetal toxicity. We then examined subsequent development of acetylcholine systems and compared the effects to those on general biomarkers of cell development. Choline acetyltransferase (ChAT), a constitutive marker for cholinergic nerve terminals, was increased in the hippocampus and striatum in adolescence and adulthood. In contrast, hemicholinium-3 (HC-3) binding to the presynaptic choline transporter, an index of nerve impulse activity, was markedly subnormal. Furthermore, m2-muscarinic cholinergic receptor binding was significantly reduced, instead of showing the expected compensatory upregulation for reduced neural input. CPF also elicited delayed-onset alterations in biomarkers of cell packing density, cell number, cell size and neuritic projections, involving brain regions both with and without reductions in indices of cholinergic activity. In combination with earlier results, the current findings indicate that the developing brain, and especially the hippocampus, is adversely affected by CPF regardless of whether exposure occurs early or late in brain development, and that defects emerge in adolescence or adulthood even in situations where normative values are initially restored in the immediate post-exposure period.

Acetyl Coenzyme A↗

PubMed2004

Beta-adrenoceptor modulation of transiently overexpressed alpha 2-adrenoceptors in brain and peripheral tissues: cellular mechanisms underlying the developmental toxicity of terbutaline.

Terbutaline, a selective beta(2)-adrenoceptor (beta(2)AR) agonist, is widely used as a tocolytic to arrest preterm labor but recent studies indicate that excessive betaAR stimulation can alter the expression and function of other neurotransmitter receptors that are essential to fetal/neonatal development. In many immature tissues, alpha(2)-adrenergic receptors (alpha(2)ARs) are overexpressed and the receptors are thought to play a role in cell proliferation and architectural assembly. We evaluated whether betaAR agonists perturb the expression of alpha(2)ARs in central and peripheral tissues during various developmental stages in the fetal and neonatal rat. In peripheral tissues (heart, liver, kidney) administration of terbutaline (10mg/kg s.c. for 4 days) elicited decrements in alpha(2)AR expression only during a critical developmental window that differed for each tissue; terbutaline was more effective than isoproterenol, a mixed beta(1)/beta(2) agonist. Neonatal destruction of sympathetic nerves with 6-hydroxydopamine (6-OHDA) had a biphasic effect, initially reducing alpha(2)ARs but subsequently elevating receptor expression. In contrast to the effects in the periphery, terbutaline administration promoted alpha(2)AR expression in neonatal brain regions with effects preferential to males. As the rat is an altricial species, these results during late gestation and the early neonatal period indicate that betaAR input modulates alpha(2)AR expression during developmental stages in which betaAR tocolytics are likely to be used. Disruption of alpha(2)AR expression and function may therefore contribute to adverse effects that have been noted in the offspring of pregnant women treated with terbutaline.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

Guidelines for developmental neurotoxicity and their impact on organophosphate pesticides: a personal view from an academic perspective.

The appropriate regulation of drugs, chemicals and environmental contaminants requires the establishment of clear and accepted guidelines for developmental neurotoxicity. Ideally, these guidelines should encompass the ability to assess widely disparate classes of compounds through routine tests, with high throughput and low cost. Increasingly, however, the progress in primary research from academic laboratories deviates from this goal, focusing instead on categorizing novel effects of toxicants, development of new testing paradigms, and extension of techniques into molecular biology. The differing objectives of academic science as opposed to those of regulatory agencies or industry, are driven in part, by the priorities of the agencies that fund primary research. Recent work on organophosphate pesticides (OPs) such as chlorpyrifos (CPF) illustrate this dichotomy. Originally, OPs were thought to affect brain development through their ability to elicit cholinesterase inhibition and consequent cholinergic hyperstimulation. This common mechanism allowed for parallels to be drawn between standard measures of systemic toxicity, gross morphological examinations, and exposure testing utilizing an easily-assessed surrogate endpoint, plasma cholinesterase activity. In the past decade, however, it has become increasingly evident that CPF, and probably other OPs, have direct effects on cellular processes that are unique to brain development, and that these effects are mechanistically unrelated to inhibition of cholinesterase. The identification and pursuit of these mechanisms and their consequences for brain development represent new and exciting scientific findings, while at the same obscuring the ability to sustain a uniform approach to neurotoxicity guidelines or biomarkers of exposure. In the future, a new set of test paradigms, relying on primary work in cell culture, invertebrates, or non-mammalian models, followed by more targeted examinations of specific processes in mammalian models, may unite cutting-edge academic research with the need for establishing flexible guidelines for developmental neurotoxicity.

Animals↗