T A Slotkin

Duke University Medical Center, Durham, North Carolina, United States

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Publications (534)1865.87 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Nicotine and chlorpyrifos are developmental neurotoxicants that target serotonin systems. We examined whether prenatal nicotine exposure alters the subsequent response to chlorpyrifos given postnatally. Pregnant rats received nicotine throughout gestation at 3mg/kg/day, a regimen designed to achieve plasma levels seen in smokers; chlorpyrifos was given to pups on postnatal days (PN) 1-4 at 1mg/kg, just above the detection threshold for brain cholinesterase inhibition. We assessed long-term effects from adolescence (PN30) through full adulthood (PN150), measuring the expression of serotonin receptors and serotonin turnover (index of presynaptic impulse activity) in cerebrocortical brain regions encompassing the projections that are known targets for nicotine and chlorpyrifos. Nicotine or chlorpyrifos individually increased the expression of serotonin receptors, with greater effects on males than on females and with distinct temporal and regional patterns indicative of adaptive synaptic changes rather than simply an extension of initial injury. This interpretation was confirmed by our finding an increase in serotonin turnover, connoting presynaptic serotonergic hyperactivity. Animals receiving the combined treatment showed a reduction in these adaptive effects on receptor binding and turnover relative to the individual agents, or even an effect in the opposite direction; further, normal sex differences in serotonin receptor concentrations were dissipated or reversed, an effect that was confirmed by behavioral evaluations in the Novel Objection Recognition Test. In addition to the known liabilities associated with maternal smoking during pregnancy, our results point to additional costs in the form of heightened vulnerability to neurotoxic chemicals encountered later in life. Copyright © 2015. Published by Elsevier Inc.
    Brain Research Bulletin 01/2015; 111. DOI:10.1016/j.brainresbull.2015.01.003 · 2.97 Impact Factor
  • Theodore A Slotkin, Frederic J Seidler
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    ABSTRACT: This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex-selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. Copyright © 2014. Published by Elsevier Inc.
    Brain Research Bulletin 12/2014; 110. DOI:10.1016/j.brainresbull.2014.12.003 · 2.97 Impact Factor
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    ABSTRACT: Although nicotine accounts for a great deal of the neurodevelopmental damage associated with maternal smoking or second-hand exposure, tobacco smoke contains thousands of potentially neurotoxic compounds. We used PC12 cells, a standard in vitro model of neurodifferentiation, to compare tobacco smoke extract (TSE) to nicotine, matching TSE exposure (with its inherent nicotine content) to parallel concentrations of nicotine, or to benzo[a]pyrene, a tobacco combustion product. TSE promoted the transition from cell replication to differentiation, resulting in fewer, but larger cells with greater neurite extension. TSE also biased differentiation into the dopaminergic versus the cholinergic phenotype, evidenced by an increase in tyrosine hydroxylase activity but not choline acetyltransferase. Nicotine likewise promoted differentiation at the expense of cell numbers, but its effect on growth and neurite extension was smaller than that of TSE; furthermore, nicotine did not promote the dopaminergic phenotype. Benzo[a]pyrene had effects opposite to those of TSE, retarding neurodifferentiation, which resulted in higher cell numbers, smaller cells, reduced neurite information, and impaired emergence of both dopaminergic and cholinergic phenotypes. Our studies show that the complex mixture of compounds in tobacco smoke exerts direct effects on neural cell replication and differentiation that resemble those of nicotine in some ways but not others, and most importantly, that are greater in magnitude than can be accounted for from just the nicotine content of TSE. Thus, fetal tobacco smoke exposure, including lower levels associated with second-hand smoke, could be more injurious than would be anticipated from measured levels of nicotine or its metabolites.
    Neurotoxicology and Teratology 05/2014; 43. DOI:10.1016/j.ntt.2014.03.002 · 3.22 Impact Factor
  • Neurotoxicology and Teratology 05/2014; 43:88-89. DOI:10.1016/j.ntt.2014.04.043 · 3.22 Impact Factor
  • Theodore A Slotkin, Jennifer Card, Frederic J Seidler
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    ABSTRACT: Nicotine exposure in adolescence produces lasting changes in subsequent behavioral responses to addictive agents. We gave nicotine to adolescent rats (postnatal days PN30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in adulthood (PN90-107), focusing on cerebrocortical serotonin levels and utilization (turnover) as an index of presynaptic activity of circuits involved in emotional state. Our evaluations encompassed responses during the period of adult nicotine treatment (PN105) and withdrawal (PN110, PN120, PN130), as well as long-term changes (PN180). In males, prior exposure to nicotine in adolescence greatly augmented the increase in serotonin turnover evoked by nicotine given in adulthood, an interaction that was further exacerbated during withdrawal. The effect was sufficiently large that it led to significant depletion of serotonin stores, an effect that was not seen with nicotine given alone in either adolescence or adulthood. In females, adolescent nicotine exposure blunted or delayed the spike in serotonin turnover evoked by withdrawal from adult nicotine treatment, a totally different effect from the interaction seen in males. Combined with earlier work showing persistent dysregulation of serotonin receptor expression and receptor coupling, the present results indicate that adolescent nicotine exposure reprograms future responses of 5HT systems to nicotine, changes that may contribute to life-long vulnerability to relapse and re-addiction.
    Brain research bulletin 01/2014; DOI:10.1016/j.brainresbull.2014.01.004 · 2.97 Impact Factor
  • Theodore A Slotkin, Jennifer Card, Frederic J Seidler
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    ABSTRACT: This study explores how glucocorticoids sensitize the developing brain to the organophosphate pesticide, chlorpyrifos. Pregnant rats received a standard therapeutic dose (0.2mg/kg) of dexamethasone on gestational days 17-19; pups were given subtoxic doses of chlorpyrifos on postnatal days 1-4, (1mg/kg, <10% cholinesterase inhibition). We evaluated serotonin (5HT) synaptic function from postnatal day 30 to day 150, assessing the expression of 5HT receptors and the 5HT transporter, along with 5HT turnover (index of presynaptic impulse activity) in brain regions encompassing all the 5HT projections and cell bodies. These parameters are known targets for neurodevelopmental effects of dexamethasone and chlorpyrifos individually. In males, chlorpyrifos evoked overall elevations in the expression of 5HT synaptic proteins, with a progressive increase from adolescence to adulthood; this effect was attenuated by prenatal dexamethasone treatment. The chlorpyrifos-induced upregulation was preceded by deficits in 5HT turnover, indicating that the receptor upregulation was an adaptive response to deficient presynaptic activity. Turnover deficiencies were magnified by dexamethasone pretreatment, worsening the functional impairment caused by chlorpyrifos. In females, chlorpyrifos-induced receptor changes reflected relative sparing of adverse effects compared to males. Nevertheless, prenatal dexamethasone still worsened the 5HT turnover deficits and reduced 5HT receptor expression in females, demonstrating the same adverse interaction. Glucocorticoids are used in 10% of U.S. pregnancies, and are also elevated in maternal stress; accordingly, our results indicate that this group represents a large subpopulation that may have heightened vulnerability to developmental neurotoxicants such as the organophosphates.
    Brain research bulletin 11/2013; DOI:10.1016/j.brainresbull.2013.10.014 · 2.97 Impact Factor
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    ABSTRACT: Glucocorticoids are the consensus treatment given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so human developmental coexposures to these two agents are common. This study explores how prenatal dexamethasone exposure modifies the neurobehavioral teratology of chlorpyrifos, one of the most widely used organophosphates. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. Dexamethasone did not alter brain chlorpyrifos concentrations, nor did either agent alone or in combination affect brain thyroxine levels. Assessments were carried out from adolescence through adulthood encompassing T-maze alternation, Figure 8 maze (locomotor activity, habituation), novelty-suppressed feeding and novel object recognition tests. For behaviors where chlorpyrifos or dexamethasone individually had small effects, the dual exposure produced larger, significant effects that reflected additivity (locomotor activity, novelty-suppressed feeding, novel object recognition). Where the individual effects were in opposite directions or were restricted to only one agent, we found enhancement of chlorpyrifos' effects by prenatal dexamethasone (habituation). Finally, for behaviors where controls displayed a normal sex difference in performance, the combined treatment either eliminated or reversed the difference (locomotor activity, novel object recognition). Combined exposure to dexamethasone and chlorpyrifos results in a worsened neurobehavioral outcome, providing a proof-of-principle that prenatal glucocorticoids can create a subpopulation with enhanced vulnerability to environmental toxicants.
    Neurotoxicology and Teratology 10/2013; 41. DOI:10.1016/j.ntt.2013.10.004 · 3.22 Impact Factor
  • Theodore A Slotkin
    JAMA Psychiatry 07/2013; 70(9). DOI:10.1001/jamapsychiatry.2013.1951 · 12.01 Impact Factor
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    ABSTRACT: Although organophosphate pesticides are not usually characterized as "endocrine disruptors," recent work points to potential, long-term reductions of circulating thyroid hormones after developmental exposures to chlorpyrifos that are devoid of observable toxicity. We administered chlorpyrifos to developing rats on gestational days 17-20 or postnatal days 1-4, regimens that produce distinctly different, sex-selective effects on neurobehavioral performance. The prenatal regimen produced a small, but statistically significant reduction in brain thyroxine levels from juvenile stages through adulthood; in contrast, postnatal exposure produced a transient elevation in young adulthood. However, in neither case did we observe the sex-selectivity noted earlier for neurobehavioral outcomes of these specific treatment regimens, or as reported earlier for effects on serum T4 in developing mice. Thus, although chlorpyrifos has the potential to disrupt thyroid status sufficiently to alter brain thyroid hormone levels, the effect is small, and any potential contribution to neurobehavioral abnormalities remains to be proven.
    04/2013; 36(2):284-287. DOI:10.1016/j.etap.2013.04.003
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    Theodore A Slotkin, Jennifer Card, Frederic J Seidler
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    ABSTRACT: BACKGROUND: Polycyclic aromatic hydrocarbons are suspected developmental neurotoxicants but human exposures typically occur in combination with other neurotoxic contaminants. OBJECTIVE/METHODS: We explored the effects of benzo(a)pyrene (BaP) on neurodifferentiation in PC12 cells, in combination with a glucocorticoid (dexamethasone, used in preterm labor), an organophosphate pesticide (chlorpyrifos) or nicotine. RESULTS: By itself, BaP suppressed the transition from cell division to neurodifferentiation, resulting in increased cell numbers at the expense of cell growth, neurite formation and development of dopaminergic and cholinergic phenotypes. Dexamethasone enhanced the effect of BaP on cell numbers and altered the impact on neurotransmitter phenotypes; whereas BaP alone shifted differentiation away from the cholinergic phenotype and toward the dopaminergic phenotype, in the presence of dexamethasone, it did the opposite. Chlorpyrifos coexposure augmented BaP inhibition of cell growth and enhanced the BaP-induced shift in phenotype toward a higher proportion of dopaminergic cells. Nicotine had no effect on BaP-induced changes in cell number or growth, but synergistically enhanced the BaP suppression of differentiation into both dopaminergic and cholinergic phenotypes equally. CONCLUSION: Our results indicate that, although BaP can act directly as a developmental neurotoxicant, its impact is greatly modified by coexposure to other, commonly encountered neurotoxicants from prenatal drug therapy, pesticides, or tobacco. Accordingly, neurodevelopmental effects attributable to polycyclic aromatic hydrocarbons may be quite different depending on which other agents are present and their concentrations relative to each other.
    Environmental Health Perspectives 04/2013; 121(7). DOI:10.1289/ehp.1306528 · 7.03 Impact Factor
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    ABSTRACT: Early-life exposures to brominated diphenyl ethers (BDEs) lead to neurobehavioral abnormalities later in life. Although these agents are thyroid disruptors, it is not clear whether this mechanism alone accounts for the adverse effects. We evaluated the impact of 2,2',4,4',5-pentabromodiphenyl ether (BDE99) on PC12 cells undergoing neurodifferentiation, contrasting the effects with chlorpyrifos, a known developmental neurotoxicant. BDE99 elicited decrements in the number of cells, evidenced by a reduction in DNA levels, to a lesser extent than did chlorpyrifos. This did not reflect cytotoxicity from oxidative stress, since cell enlargement, monitored by the total protein/DNA ratio, was not only unimpaired by BDE99, but was actually enhanced. Importantly, BDE99 impaired neurodifferentiation into both the dopamine and acetylcholine neurotransmitter phenotypes. The cholinergic phenotype was affected to a greater extent, so that neurotransmitter fate was diverted away from acetylcholine and toward dopamine. Chlorpyrifos produced the same imbalance, but through a different underlying mechanism, promoting dopaminergic development at the expense of cholinergic development. In our earlier work, we did not find these effects with BDE47, a BDE that has greater endocrine disrupting and cytotoxic effects than BDE99. Thus, our results point to interference with neurodifferentiation by specific BDE congeners, distinct from cytotoxic or endocrine mechanisms.
    Neurotoxicology and Teratology 02/2013; 37. DOI:10.1016/j.ntt.2013.02.001 · 3.22 Impact Factor
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    ABSTRACT: Glucocorticoids are routinely given in preterm labor and are also elevated by maternal stress; organophosphate exposures are virtually ubiquitous, so coexposures to these two agents are pervasive. We administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg); offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces barely-detectable (<10%) inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of dexamethasone and chlorpyrifos given individually. Dexamethasone did not enhance the systemic toxicity of chlorpyrifos, as evidenced by weight gain and measurements of cholinesterase inhibition during chlorpyrifos treatment. Nevertheless, it enhanced the loss of presynaptic ACh function selectively in females, who ordinarily show sparing of organophosphate developmental neurotoxicity relative to males. Females receiving the combined treatment showed decrements in choline transporter binding and choline acetyltransferase activity that were unique (not found with either treatment alone), as well as additive decrements in nicotinic receptor binding. On the other hand, males given dexamethasone showed no augmentation of the effects of chlorpyrifos. Our findings indicate that prior dexamethasone exposure could create a subpopulation that is especially vulnerable to the adverse effects of organophosphates or other developmental neurotoxicants.
    Neurotoxicology and Teratology 02/2013; DOI:10.1016/j.ntt.2013.02.002 · 3.22 Impact Factor
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    ABSTRACT: Obesity is associated with mood disorders, but underlying mechanisms are not well understood. We have recently described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high sucrose or a high fat diet with BCAA induces anxiety-like behavior in rats compared to control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin, but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water, but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high energy diets with BCAA causes neurobehavioral impairment. Since BCAA are spontaneously elevated in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.
    AJP Endocrinology and Metabolism 12/2012; 304(4). DOI:10.1152/ajpendo.00373.2012 · 4.09 Impact Factor
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    ABSTRACT: Background: An emerging literature suggests that environmental chemicals may play a role in the development of childhood obesity and metabolic disorders, especially when exposure occurs early in life. Objective: Here we assess the association between these health outcomes and exposure to maternal smoking during pregnancy as part of a broader effort to develop a research agenda to better understand the role of environmental chemicals as potential risk factors for obesity and metabolic disorders. Methods: PubMed was searched up to 8 March 2012 for epidemiological and experimental animal studies related to maternal smoking or nicotine exposure during pregnancy and childhood obesity or metabolic disorders at any age. A total of 101 studies—83 in humans and 18 in animals—were identified as the primary literature. Discussion: Current epidemiological data support a positive association between maternal smoking and increased risk of obesity or overweight in offspring. The data strongly suggest a causal relation, although the possibility that the association is attributable to unmeasured residual confounding cannot be completely ruled out. This conclusion is supported by findings from laboratory animals exposed to nicotine during development. The existing literature on human exposures does not support an association between maternal smoking during pregnancy and type 1 diabetes in offspring. Too few human studies have assessed outcomes related to type 2 diabetes or metabolic syndrome to reach conclusions based on patterns of findings. There may be a number of mechanistic pathways important for the development of aberrant metabolic outcomes following perinatal exposure to cigarette smoke, which remain largely unexplored. Conclusions: From a toxicological perspective, the linkages between maternal smoking during pregnancy and childhood overweight/obesity provide proof-of-concept of how early-life exposure to an environmental toxicant can be a risk factor for childhood obesity.
    Environmental Health Perspectives 12/2012; 121(2). DOI:10.1289/ehp.1205404 · 7.03 Impact Factor
  • Virginia A. Rauh, Theodore A. Slotkin, Ravi Bansal
    Proceedings of the National Academy of Sciences 08/2012; 109(33):2196-E2196. DOI:10.1073/pnas.1209095109 · 9.81 Impact Factor
  • Theodore A Slotkin, Frederic J Seidler
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    ABSTRACT: Terbutaline, a β(2)-adrenoceptor agonist, is used off-label for long-term management of preterm labor; such use is associated with increased risk of neurodevelopmental disorders, including autism spectrum disorders. We explored the mechanisms underlying terbutaline's effects on development of peripheral sympathetic projections in developing rats. Terbutaline administration on postnatal days 2-5 led to immediate and persistent deficiencies in cardiac norepinephrine levels, with greater effects in males than in females. The liver showed a lesser effect; we reasoned that the tissue differences could represent participation of retrograde trophic signaling from the postsynaptic site to the developing neuronal projection, since hepatic β(2)-adrenoceptors decline in the perinatal period. Accordingly, when we gave terbutaline earlier, on gestational days 17-20, we saw the same deficiencies in hepatic norepinephrine that had been seen in the heart with the later administration paradigm. Administration of isoproterenol, which stimulates both β(1)- and β(2)-subtypes, also had trophic effects that differed in direction and critical period from those elicited by terbutaline; methoxamine, which stimulates α(1)-adrenoceptors, was without effect. Thus, terbutaline, operating through trophic interactions with β(2)-adrenoceptors, impairs development of noradrenergic projections in a manner similar to that previously reported for its effects on the same neurotransmitter systems in the immature cerebellum. Our results point to the likelihood of autonomic dysfunction in individuals exposed prenatally to terbutaline; in light of the connection between terbutaline and autism, these results could also contribute to autonomic dysregulation seen in children with this disorder.
    Neurotoxicology and Teratology 07/2012; DOI:10.1016/j.ntt.2012.07.003 · 3.22 Impact Factor
  • Theodore A Slotkin, Jennifer Card, Frederic J Seidler
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    ABSTRACT: Prenatal coexposures to glucocorticoids and organophosphate pesticides are widespread. Glucocorticoids are elevated by maternal stress and are commonly given in preterm labor; organophosphate exposures are virtually ubiquitous. We used PC12 cells undergoing neurodifferentiation in order to assess whether dexamethasone enhances the developmental neurotoxicity of chlorpyrifos, focusing on models relevant to human exposures. By themselves, each agent reduced the number of cells and the combined exposure elicited a correspondingly greater effect than with either agent alone. There was no general cytotoxicity, as cell growth was actually enhanced, and again, the combined treatment evoked greater cellular hypertrophy than with the individual compounds. The effects on neurodifferentiation were more complex. Chlorpyrifos alone had a promotional effect on neuritogenesis whereas dexamethasone impaired it; combined treatment showed an overall impairment greater than that seen with dexamethasone alone. The effect of chlorpyrifos on differentiation into specific neurotransmitter phenotypes was shifted by dexamethasone. Either agent alone promoted differentiation into the dopaminergic phenotype at the expense of the cholinergic phenotype. However, in dexamethasone-primed cells, chlorpyrifos actually enhanced cholinergic neurodifferentiation instead of suppressing this phenotype. Our results indicate that developmental exposure to glucocorticoids, either in the context of stress or the therapy of preterm labor, could enhance the developmental neurotoxicity of organophosphates and potentially of other neurotoxicants, as well as producing neurobehavioral outcomes distinct from those seen with either individual agent.
    Neurotoxicology and Teratology 07/2012; 34(5):505-12. DOI:10.1016/j.ntt.2012.07.002 · 3.22 Impact Factor

Publication Stats

16k Citations
1,865.87 Total Impact Points


  • 1973–2015
    • Duke University Medical Center
      • • Department of Pharmacology and Cancer Biology
      • • Department of Psychiatry and Behavioral Science
      • • Department of Biochemistry
      Durham, North Carolina, United States
  • 1982–2013
    • Duke University
      • Nicholas School of the Environment
      Durham, North Carolina, United States
  • 2005
    • U.S. Food and Drug Administration
      • Division of Neurotoxicology
      Washington, D. C., DC, United States
  • 2004
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 1999
    • All India Institute of Medical Sciences
      • Department of Anatomy
      New Delhi, NCT, India