This page has only limited features, please log in for full access.
The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice. The online version contains supplementary material available at 10.1186/s40478-021-01240-4.
Madelyn C. Houser; W. Michael Caudle; Jianjun Chang; George T. Kannarkat; Yuan Yang; Sean D. Kelly; Danielle Oliver; Valerie Joers; Kathleen M. Shannon; Ali Keshavarzian; Malú Gámez Tansey. Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology. Acta Neuropathologica Communications 2021, 9, 1 .
AMA StyleMadelyn C. Houser, W. Michael Caudle, Jianjun Chang, George T. Kannarkat, Yuan Yang, Sean D. Kelly, Danielle Oliver, Valerie Joers, Kathleen M. Shannon, Ali Keshavarzian, Malú Gámez Tansey. Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology. Acta Neuropathologica Communications. 2021; 9 ():1.
Chicago/Turabian StyleMadelyn C. Houser; W. Michael Caudle; Jianjun Chang; George T. Kannarkat; Yuan Yang; Sean D. Kelly; Danielle Oliver; Valerie Joers; Kathleen M. Shannon; Ali Keshavarzian; Malú Gámez Tansey. 2021. "Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology." Acta Neuropathologica Communications 9, no. : 1.
Attention-Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders and manifests inattention, hyperactivity, and impulsivity symptoms in childhood that can last throughout life. Genetic and environmental studies implicate the dopamine system in ADHD pathogenesis. Work from our group and that of others indicates that deltamethrin insecticide and stress exposure during neurodevelopment leads to alterations in dopamine function, and we hypothesized that exposure to both of these factors together would lead to synergistic effects on DNA methylation of key genes within the midbrain, a highly dopaminergic region, that could contribute to these findings. Through targeted next-generation sequencing of a panel of cortisol and dopamine pathway genes, we observed hypermethylation of the glucocorticoid receptor gene, Nr3c1, in the midbrain of C57/BL6N males in response to dual deltamethrin and corticosterone exposures during development. This is the first description of DNA methylation studies of Nr3c1 and key dopaminergic genes within the midbrain in response to a pyrethroid insecticide, corticosterone, and these two exposures together. Our results provide possible connections between environmental exposures that impact the dopamine system and the hypothalamic-pituitary-adrenal axis via changes in DNA methylation and provides new information about the presence of epigenetic effects in adulthood after exposure during neurodevelopment.
Aimée I. Vester; Karen Hermetz; Amber Burt; Todd Everson; Carmen J. Marsit; William M. Caudle. Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice. Neurotoxicology and Teratology 2020, 80, 106887 -106887.
AMA StyleAimée I. Vester, Karen Hermetz, Amber Burt, Todd Everson, Carmen J. Marsit, William M. Caudle. Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice. Neurotoxicology and Teratology. 2020; 80 ():106887-106887.
Chicago/Turabian StyleAimée I. Vester; Karen Hermetz; Amber Burt; Todd Everson; Carmen J. Marsit; William M. Caudle. 2020. "Combined neurodevelopmental exposure to deltamethrin and corticosterone is associated with Nr3c1 hypermethylation in the midbrain of male mice." Neurotoxicology and Teratology 80, no. : 106887-106887.
Dopaminergic neurons express mixed lineage kinases which regulate the expression of cell death genes. In Parkinson's disease, cell death via apoptosis is prevalent, and previous work testing mixed lineage kinase inhibitors in animal models suggested the inhibitors had some neuroprotective potential. CLFB-1134 is a new, brain-penetrant inhibitor specific for MLK3, tested here in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopaminergic depletion and nigral neuron death in mice. After ensuring that treatment with CLFB-1134 did not alter conversion of MPTP to MPP+, we demonstrated CLFB-1134's inhibition of MLK3 and neuroprotective efficacy. Specifically we evaluated the integrity of the nigrostriatal dopamine system following MPTP by assessing protein expression, high performance liquid chromatography, and immunohistology with stereology. We found that CLFB-1134 achieves protection of striatal dopaminergic terminals and nigral cell bodies when dosed simultaneously or following MPTP treatment. By preventing phosphorylation of JNK and other downstream targets of MLK3, CLFB-1134 protects against the neurotoxin MPTP. Inhibition of MLK3 may be a valid target for future work investigating treatment of Parkinson's disease.
Elizabeth M. Kline; Laura M. Butkovich; Joshua M. Bradner; Jianjun Chang; Harris Gelbard; Val Goodfellow; W. Michael Caudle; Malú G. Tansey. The second generation mixed lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced nigral dopaminergic neuron loss. Experimental Neurology 2019, 318, 157 -164.
AMA StyleElizabeth M. Kline, Laura M. Butkovich, Joshua M. Bradner, Jianjun Chang, Harris Gelbard, Val Goodfellow, W. Michael Caudle, Malú G. Tansey. The second generation mixed lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced nigral dopaminergic neuron loss. Experimental Neurology. 2019; 318 ():157-164.
Chicago/Turabian StyleElizabeth M. Kline; Laura M. Butkovich; Joshua M. Bradner; Jianjun Chang; Harris Gelbard; Val Goodfellow; W. Michael Caudle; Malú G. Tansey. 2019. "The second generation mixed lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced nigral dopaminergic neuron loss." Experimental Neurology 318, no. : 157-164.
Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood and previous studies indicate the dopamine system plays a major role in ADHD pathogenesis. Two environmental exposures independently associated with dopaminergic dysfunction and ADHD risk include exposure to deltamethrin, a pyrethroid insecticide, and chronic stress. We hypothesized that combined neurodevelopmental exposure to both deltamethrin and corticosterone (CORT), the major stress hormone in rodents, would result in additive changes within the dopamine system. To study this, we developed a novel dual exposure paradigm and exposed pregnant C57BL/6 dams to 3 mg/kg deltamethrin through gestation and weaning, and their offspring to 25 μg/mL CORT dissolved in the drinking water through adulthood. Midbrain RNA expression as well as striatal and cortical protein expression of key dopaminergic components were investigated, in addition to ADHD-like behavioral tasks and electrochemical dopamine dynamics via fast-scan cyclic voltammetry. Given the well-described sexual dimorphism of ADHD, males and females were assessed separately. Males exposed to deltamethrin had significantly decreased midbrain Pitx3 expression, decreased cortical tyrosine hydroxylase (TH) expression, increased activity in the Y maze, and increased dopamine uptake rate in the dorsal striatum. These effects did not occur in males exposed to CORT only, or in males exposed to both deltamethrin and CORT, suggesting that CORT may attenuate these effects. Additionally, deltamethrin- and CORT-exposed females did not display these dopaminergic features, which indicates these changes are sex-specific. Our results show dopaminergic changes from the RNA through the functional level. Moreover, these data illustrate the importance of testing multiple environmental exposures together to better understand how combined exposures that occur in certain vulnerable populations could affect similar neurodevelopmental systems, as well as the importance of studying sex differences of these alterations.
Aimée I. Vester; Merry Chen; Carmen J. Marsit; W. Michael Caudle. A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure. Toxics 2019, 7, 24 .
AMA StyleAimée I. Vester, Merry Chen, Carmen J. Marsit, W. Michael Caudle. A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure. Toxics. 2019; 7 (2):24.
Chicago/Turabian StyleAimée I. Vester; Merry Chen; Carmen J. Marsit; W. Michael Caudle. 2019. "A Neurodevelopmental Model of Combined Pyrethroid and Chronic Stress Exposure." Toxics 7, no. 2: 24.
Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals. Of these, metals have received significant attention given their propensity to accumulate in the basal ganglia and participate in neurotoxic cascades, through the generation of reactive oxygen species as well as their pathogenic interaction with intracellular targets in the dopamine neuron. The association between metals and parkinsonism is of critical concern to subsets of the population that are occupationally exposed to metals, both through current practices, such as mining, and emerging settings, like E-waste and the manufacture of metal nanoparticles. This review will explore our current understanding of the molecular and pathological targets that mediate metal neurotoxicity and lead to parkinsonism and will highlight areas of critical research interests that need to be addressed.
W. Michael Caudle. Occupational Metal Exposure and Parkinsonism. Advances in Neurobiology 2017, 18, 143 -158.
AMA StyleW. Michael Caudle. Occupational Metal Exposure and Parkinsonism. Advances in Neurobiology. 2017; 18 ():143-158.
Chicago/Turabian StyleW. Michael Caudle. 2017. "Occupational Metal Exposure and Parkinsonism." Advances in Neurobiology 18, no. : 143-158.
Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.
Amy R. Dunn; Kristen A. Stout; Minagi Ozawa; Kelly M. Lohr; Carlie A. Hoffman; Alison I. Bernstein; Yingjie Li; Minzheng Wang; Carmelo Sgobio; Namratha Sastry; Huaibin Cai; W. Michael Caudle; Gary W. Miller. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proceedings of the National Academy of Sciences 2017, 114, E2253 -E2262.
AMA StyleAmy R. Dunn, Kristen A. Stout, Minagi Ozawa, Kelly M. Lohr, Carlie A. Hoffman, Alison I. Bernstein, Yingjie Li, Minzheng Wang, Carmelo Sgobio, Namratha Sastry, Huaibin Cai, W. Michael Caudle, Gary W. Miller. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proceedings of the National Academy of Sciences. 2017; 114 (11):E2253-E2262.
Chicago/Turabian StyleAmy R. Dunn; Kristen A. Stout; Minagi Ozawa; Kelly M. Lohr; Carlie A. Hoffman; Alison I. Bernstein; Yingjie Li; Minzheng Wang; Carmelo Sgobio; Namratha Sastry; Huaibin Cai; W. Michael Caudle; Gary W. Miller. 2017. "Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease." Proceedings of the National Academy of Sciences 114, no. 11: E2253-E2262.
Many chemicals have been used to increase the safety of consumer products by reducing their flammability and risk for ignition. Recent focus on brominated flame retardants, such as polybrominated diphenyl ethers (PBDEs) has shown them to contribute to neurobehavioral deficits in children, including learning and memory. As the manufacture and use of PBDEs have been reduced, replacement chemicals, such as hexabromocyclododecane (HBCDD) have been substituted. Our current study evaluated the neurotoxicity of HBCDD, concentrating on dopaminergic innervation to the hippocampus. Using an in vivo model, we exposed male mice to HBCDD and then assessed alterations to the dopamine synapse 6 weeks later. These exposures elicited significant reductions in presynaptic dopaminergic proteins, including TH, COMT, MAO-B, DAT, VMAT2, and alpha-synuclein. In contrast, postsynaptic dopamine receptors were not impaired. These findings suggest that the mesohippocampal dopamine circuit is vulnerable to HBCDD and the dopamine terminal may be a selective target for alteration.
Camille Pham-Lake; Elizabeth B. Aronoff; Chad R. Camp; Aimee Vester; Sam J. Peters; W. Michael Caudle. Impairment in the mesohippocampal dopamine circuit following exposure to the brominated flame retardant, HBCDD. Environmental Toxicology and Pharmacology 2017, 50, 167 -174.
AMA StyleCamille Pham-Lake, Elizabeth B. Aronoff, Chad R. Camp, Aimee Vester, Sam J. Peters, W. Michael Caudle. Impairment in the mesohippocampal dopamine circuit following exposure to the brominated flame retardant, HBCDD. Environmental Toxicology and Pharmacology. 2017; 50 ():167-174.
Chicago/Turabian StyleCamille Pham-Lake; Elizabeth B. Aronoff; Chad R. Camp; Aimee Vester; Sam J. Peters; W. Michael Caudle. 2017. "Impairment in the mesohippocampal dopamine circuit following exposure to the brominated flame retardant, HBCDD." Environmental Toxicology and Pharmacology 50, no. : 167-174.
The synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, though SV2C with its restricted basal ganglia distribution has no known function. SV2C is emerging as a potentially relevant protein in Parkinson’s disease, as it is a genetic modifier of nicotine neuroprotection and sensitivity to L-DOPA. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of Parkinson’s disease (PD). Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted alpha-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Further, SV2C expression is dramatically altered in postmortem brain tissue from PD cases, but not in Alzheimer’s disease, progressive supranuclear palsy or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a novel mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction
Amy R. Dunn; Kristen A. Stout; Minagi Ozawa; Kelly M. Lohr; Alison I. Bernstein; Yingjie Li; Minzheng Wang; Carmelo Sgobio; Namratha Sastry; Huaibin Cai; W. Michael Caudle; Gary W. Miller. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease. bioRxiv 2016, 077586 .
AMA StyleAmy R. Dunn, Kristen A. Stout, Minagi Ozawa, Kelly M. Lohr, Alison I. Bernstein, Yingjie Li, Minzheng Wang, Carmelo Sgobio, Namratha Sastry, Huaibin Cai, W. Michael Caudle, Gary W. Miller. Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease. bioRxiv. 2016; ():077586.
Chicago/Turabian StyleAmy R. Dunn; Kristen A. Stout; Minagi Ozawa; Kelly M. Lohr; Alison I. Bernstein; Yingjie Li; Minzheng Wang; Carmelo Sgobio; Namratha Sastry; Huaibin Cai; W. Michael Caudle; Gary W. Miller. 2016. "Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease." bioRxiv , no. : 077586.
The developmental period of the nervous system is carefully orchestrated and highly vulnerable to alterations. One crucial factor of a properly-functioning nervous system is the synapse, as synaptic signaling is critical for the formation and maturation of neural circuits. Studies show that genetic and environmental impacts can affect diverse components of synaptic function. Importantly, synaptic dysfunction is known to be associated with neurologic and psychiatric disorders, as well as more subtle cognitive, psychomotor, and sensory defects. Given the importance of the synapse in numerous domains, we wanted to delineate the effects of pesticide exposure on synaptic function. In this review, we summarize current epidemiologic and molecular studies that demonstrate organochlorine, organophosphate, and pyrethroid pesticide exposures target the developing synapse. We postulate that the synapse plays a central role in synaptic vulnerability to pesticide exposure during neurodevelopment, and the synapse is a worthy candidate for investigating more subtle effects of chronic pesticide exposure in future studies.
Aimee Vester; W. Michael Caudle. The Synapse as a Central Target for Neurodevelopmental Susceptibility to Pesticides. Toxics 2016, 4, 18 .
AMA StyleAimee Vester, W. Michael Caudle. The Synapse as a Central Target for Neurodevelopmental Susceptibility to Pesticides. Toxics. 2016; 4 (3):18.
Chicago/Turabian StyleAimee Vester; W. Michael Caudle. 2016. "The Synapse as a Central Target for Neurodevelopmental Susceptibility to Pesticides." Toxics 4, no. 3: 18.
Our understanding of the contribution exposure to environmental toxicants has on neurological disease continues to evolve. Of these, Parkinson’s disease (PD) has been shown to have a strong environmental component to its etiopathogenesis. However, work is still needed to identify and characterize environmental chemicals that could alter the expression and function of the nigrostriatal dopamine system. Of particular interest is the neurotoxicological effect of perfluorinated compounds, such as perfluorooctane sulfonate (PFOS), which has been demonstrated to alter aspects of dopamine signaling. Using in vitro approaches, we have elaborated these initial findings to demonstrate the neurotoxicity of PFOS to the SH-SY5Y neuroblastoma cell line and dopaminergic primary cultured neurons. Using an in vivo model, we did not observe a deficit to dopaminergic terminals in the striatum of mice exposed to 10 mg/kg PFOS for 14 days. However, subsequent exposure to the selective dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) significantly reduced the expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH), and resulted in an even greater reduction in DAT expression in animals previously exposed to PFOS. These findings suggest that PFOS is neurotoxic to the nigrostriatal dopamine circuit and this neurotoxicity could prime the dopamine terminal to more extensive damage following additional toxicological insults.
Rahul Patel; Joshua M. Bradner; Kristen A. Stout; William Michael Caudle. Alteration to Dopaminergic Synapses Following Exposure to Perfluorooctane Sulfonate (PFOS), in Vitro and in Vivo. Medical Sciences 2016, 4, 13 .
AMA StyleRahul Patel, Joshua M. Bradner, Kristen A. Stout, William Michael Caudle. Alteration to Dopaminergic Synapses Following Exposure to Perfluorooctane Sulfonate (PFOS), in Vitro and in Vivo. Medical Sciences. 2016; 4 (3):13.
Chicago/Turabian StyleRahul Patel; Joshua M. Bradner; Kristen A. Stout; William Michael Caudle. 2016. "Alteration to Dopaminergic Synapses Following Exposure to Perfluorooctane Sulfonate (PFOS), in Vitro and in Vivo." Medical Sciences 4, no. 3: 13.
Integration of the hypothalamic–pituitary–adrenal (HPA) axis and the limbic system through glucocorticoid signaling is imperative in initiating and regulating a suitable stress response following real or perceived threats. Dysfunction of these circuits that results in a persistent or inhibited glucocorticoid secretion can severely affect processing of stressful experiences and lead to risk for developing further psychiatric pathology. Exposure to toxic chemicals found in our environment, including pesticides, metals, and industrial compounds, have been shown to have significant impact on neurological health and disease. Indeed, studies have begun to identify the HPA axis and limbic system as potential targets of many of these environmental chemicals, suggesting a possible environmental risk for damage to the stress circuit and response to stressful stimuli. This review will focus on our current understanding of the impact exposure to environmental toxicants, including bisphenol A and lead, has on the synaptic physiology of the HPA axis and limbic system and how this contributes to an alteration in behavior output. Further, this discussion will provide a starting point to continue to couple novel toxicological and neurological approaches to elaborate our understanding of the influence of environmental chemicals on the stress response and pathology.
W. Michael Caudle. This can't be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response. Physiology & Behavior 2015, 166, 65 -75.
AMA StyleW. Michael Caudle. This can't be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response. Physiology & Behavior. 2015; 166 ():65-75.
Chicago/Turabian StyleW. Michael Caudle. 2015. "This can't be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response." Physiology & Behavior 166, no. : 65-75.
Over the last several decades, the use of halogenated organic compounds has become the cause of environmental and human health concerns. Of particular notoriety has been the establishment of the neurotoxicity of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). The subsequent banning of PBDEs has led to greatly increased use of 1,2,5,6,9,10-hexabromocyclododecane (HBCDD, also known as HBCD) as a flame retardant in consumer products. The physiochemical similarities between HBCDD and PBDEs suggest that HBCDD may also be neurotoxic to the dopamine system, which is specifically damaged in Parkinson disease (PD). The purpose of this study was to assess the neurotoxicity of HBCDD on the nigrostriatal dopamine system using an in vitro and in vivo approach. We demonstrate that exposure to HBCDD (0–25 μM) for 24 h causes significant cell death in the SK-N-SH catecholaminergic cell line, as well as reductions in the growth and viability of TH + primary cultured neurons at lower concentrations (0–10 μM) after 72 h of treatment. Assessment of the in vivo neurotoxicity of HBCDD (25 mg/kg for 30 days) resulted in significant reductions in the expression of the striatal dopamine transporter and vesicular monoamine transporter 2, both of which are integral in mediating dopamine homeostasis and neurotransmission in the dopamine circuit. However, no changes were seen in the expression of tyrosine hydroxylase in the dopamine terminal, or striatal levels of dopamine. To date, these are the first data to demonstrate that exposure to HBCDD disrupts the nigrostriatal dopamine system. Given these results and the ubiquitous nature of HBCDD in the environment, its possible role as an environmental risk factor for PD should be further investigated.
Kelly R. Genskow; Joshua M. Bradner; Muhammad M. Hossain; Jason Richardson; W. Michael Caudle. Selective damage to dopaminergic transporters following exposure to the brominated flame retardant, HBCDD. Neurotoxicology and Teratology 2015, 52, 162 -169.
AMA StyleKelly R. Genskow, Joshua M. Bradner, Muhammad M. Hossain, Jason Richardson, W. Michael Caudle. Selective damage to dopaminergic transporters following exposure to the brominated flame retardant, HBCDD. Neurotoxicology and Teratology. 2015; 52 ():162-169.
Chicago/Turabian StyleKelly R. Genskow; Joshua M. Bradner; Muhammad M. Hossain; Jason Richardson; W. Michael Caudle. 2015. "Selective damage to dopaminergic transporters following exposure to the brominated flame retardant, HBCDD." Neurotoxicology and Teratology 52, no. : 162-169.
In recent years, the contribution of exposure to environmental toxicants has been recognized as a significant contributor to the etiopathogenesis of parkinsonism. Of these toxicants, exposure to pesticides, metals, solvents used in manufacturing processes, as well as flame-retardant chemicals used in consumer and commercial products, has received the greatest attention as possible risk factors. Related to this, individuals who are exposed to these compounds at high concentrations or for prolonged periods of time in an occupational setting appear to be one of the more vulnerable populations to these effects. Our understanding of which compounds are involved and the potential molecular pathways that are susceptible to these chemicals and may underlie the pathogenesis has greatly improved. However, there are still hundreds of chemicals that we are exposed to in the environment for which we do not have any information on their potential neurotoxicity on the nigrostriatal dopamine system. Thus, using our past accomplishments as a blueprint, future endeavors should focus on elaborating upon these initial findings in order to identify specific and relevant chemical toxicants in our environment that can impact the risk of parkinsonism and work towards a means to attenuate or abolish their effects on the human population.
W. Michael Caudle. Occupational exposures and parkinsonism. Handbook of Clinical Neurology 2015, 131, 225 -239.
AMA StyleW. Michael Caudle. Occupational exposures and parkinsonism. Handbook of Clinical Neurology. 2015; 131 ():225-239.
Chicago/Turabian StyleW. Michael Caudle. 2015. "Occupational exposures and parkinsonism." Handbook of Clinical Neurology 131, no. : 225-239.
The contribution of environmental toxicants to the etiology and risk of Parkinson's disease (PD) has been clearly established, with organochlorine insecticides routinely shown to damage the nigrostriatal dopamine pathway. Although PD is generally considered an adult onset disease, it has been postulated that exposure to environmental contaminants or other factors early in life during critical periods of neurodevelopment could alter the dopaminergic circuit and predispose individuals to developing PD. Recent epidemiological evidence has found exposure to the organochlorine insecticide endosulfan to be a risk factor for PD. However, the specific dopaminergic targets or vulnerable developmental time points related to endosulfan exposure have not been investigated. Thus, we sought to investigate dopaminergic neurotoxicity following developmental exposure to endosulfan as well as following an additional challenge with MPTP. Our in vitro findings demonstrate a reduction in SK-N-SH cells and ventral mesencephalic primary cultures after endosulfan treatment. Using an in vivo developmental model, exposure to endosulfan during gestation and lactation caused a reduction in DAT and TH in the striatum of male offspring. These alterations were exacerbated following subsequent treatment with MPTP. In contrast, exposure of adult mice to endosulfan did not elicit dopaminergic damage and did not appear to increase the vulnerability of the dopamine neurons to MPTP. These findings suggest that development during gestation and lactation represents a critical window of susceptibility to endosulfan exposure and development of the nigrostriatal dopamine system. Furthermore, these exposures appear to sensitize the dopamine neurons to additional insults that may occur later in life.
W. Wyatt Wilson; Lauren P. Shapiro; Joshua M. Bradner; W. Michael Caudle. Developmental exposure to the organochlorine insecticide endosulfan damages the nigrostriatal dopamine system in male offspring. NeuroToxicology 2014, 44, 279 -287.
AMA StyleW. Wyatt Wilson, Lauren P. Shapiro, Joshua M. Bradner, W. Michael Caudle. Developmental exposure to the organochlorine insecticide endosulfan damages the nigrostriatal dopamine system in male offspring. NeuroToxicology. 2014; 44 ():279-287.
Chicago/Turabian StyleW. Wyatt Wilson; Lauren P. Shapiro; Joshua M. Bradner; W. Michael Caudle. 2014. "Developmental exposure to the organochlorine insecticide endosulfan damages the nigrostriatal dopamine system in male offspring." NeuroToxicology 44, no. : 279-287.
Exposure to environmental contaminants, such as organochlorine insecticides during critical periods of neurodevelopment has been shown to be a major contributor to several neuropsychological deficits seen in children, adolescence, and adults. Although the neurobehavioral outcomes resulting from exposure to these compounds are known the neurotransmitter circuitry and molecular targets that mediate these endpoints have not been identified. Given the importance of the frontal cortex in facilitating numerous neuropsychological processes, our current study sought to investigate the effects of developmental exposure to the organochlorine insecticide, endosulfan, on the expression of specific proteins associated with neurotransmission in the frontal cortex. Utilizing in vitro models we were able to show endosulfan reduces cell viability in IMR‐32 neuroblastoma cells in addition to reducing synaptic puncta and neurite outgrowth in primary cultured neurons isolated from the frontal cortex of mice. Elaborating these findings to an in vivo model we found that developmental exposure of female mice to endosulfan during gestation and lactation elicited significant alterations to the GABAergic (GAT1, vGAT, GABAA receptor), glutamatergic (vGlut and GluN2B receptor), and dopaminergic (DAT, TH, VMAT2, and D2 receptor) neurotransmitter systems in the frontal cortex of male offspring. These findings identify damage to critical neurotransmitter circuits and proteins in the frontal cortex, which may underlie the neurobehavioral deficits observed following developmental exposure to endosulfan and other organochlorine insecticides. Synapse 68:485–497, 2014.
W. Wyatt Wilson; Wellington Onyenwe; Joshua M. Bradner; Sadie E. Nennig; W. Michael Caudle. Developmental exposure to the organochlorine insecticide endosulfan alters expression of proteins associated with neurotransmission in the frontal cortex. Synapse 2014, 68, 485 -497.
AMA StyleW. Wyatt Wilson, Wellington Onyenwe, Joshua M. Bradner, Sadie E. Nennig, W. Michael Caudle. Developmental exposure to the organochlorine insecticide endosulfan alters expression of proteins associated with neurotransmission in the frontal cortex. Synapse. 2014; 68 (11):485-497.
Chicago/Turabian StyleW. Wyatt Wilson; Wellington Onyenwe; Joshua M. Bradner; Sadie E. Nennig; W. Michael Caudle. 2014. "Developmental exposure to the organochlorine insecticide endosulfan alters expression of proteins associated with neurotransmission in the frontal cortex." Synapse 68, no. 11: 485-497.
Recent studies have identified exposure to polybrominated diphenyl ethers (PBDEs) as a risk factor for deficits in cognitive functioning seen in children as well as adults. Additionally, similar alterations in learning and memory have also been observed in animal models of PBDE exposure. However, given these findings, the molecular alterations that may underlie these neurobehavioral endpoints have not been identified. As the frontal cortex is involved in modulating several cognitive functions, the purpose of our study was to investigate the possible changes to the GABAergic and glutamatergic neurotransmitter systems located in the frontal cortex following exposure to the PBDE mixture, DE-71. Primary cultured neurons isolated from the frontal cortex showed a dose-dependent reduction in neurons as well as neurite outgrowth. Furthermore, evaluation of DE-71 neurotoxicity in the frontal cortex using an in vivo model showed alterations to specific proteins involved in mediating GABA and glutamate neurotransmission, including GAD67, vGAT, vGlut, and GABA(A) 2α receptor subunit. Interestingly, these alterations appeared to be preferential for the GABA and glutamate systems located in the frontal cortex. These findings identify specific targets of PBDE neurotoxicity and provide a possible molecular mechanism for PBDE-mediated neurobehavioral deficits that arise from the frontal cortex.
Joshua M. Bradner; Tiffany A. Suragh; W. Michael Caudle. Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71. Toxicology 2013, 312, 48 -55.
AMA StyleJoshua M. Bradner, Tiffany A. Suragh, W. Michael Caudle. Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71. Toxicology. 2013; 312 ():48-55.
Chicago/Turabian StyleJoshua M. Bradner; Tiffany A. Suragh; W. Michael Caudle. 2013. "Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71." Toxicology 312, no. : 48-55.
In the last several decades polybrominated diphenyl ethers (PBDEs) have replaced the previously banned polychlorinated biphenyls (PCBs) in multiple flame retardant utilities. As epidemiological and laboratory studies have suggested PCBs as a risk factor for Parkinson's disease (PD), the similarities between PBDEs and PCBs suggest that PBDEs have the potential to be neurotoxic to the dopamine system. The purpose of this study was to evaluate the neurotoxic effects of the PBDE mixture, DE-71, on the nigrostriatal dopamine system and address the role of altered dopamine handling in mediating this neurotoxicity. Using an in vitro model system we found DE-71 effectively caused cell death in a dopaminergic cell line as well as reducing the number of TH + neurons isolated from VMAT2 WT and LO animals. Assessment of DE-71 neurotoxicity in vivo demonstrated significant deposition of PBDE congeners in the brains of mice, leading to reductions in striatal dopamine and dopamine handling, as well as reductions in the striatal dopamine transporter (DAT) and VMAT2. Additionally, DE-71 elicited a significant locomotor deficit in the VMAT2 WT and LO mice. However, no change was seen in TH expression in dopamine terminal or in the number of dopamine neurons in the substantia nigra pars compacta (SNpc). To date, these are the first data to demonstrate that exposure to PBDEs disrupts the nigrostriatal dopamine system. Given their similarities to PCBs, additional laboratory and epidemiological research should be considered to assess PBDEs as a potential risk factor for PD and other neurological disorders.
Joshua M. Bradner; Tiffany A. Suragh; W. Wyatt Wilson; Carlos R. Lazo; Kristen A. Stout; Hye Mi Kim; Min Z. Wang; Douglas I. Walker; Kurt D. Pennell; Jason R. Richardson; Gary W. Miller; W. Michael Caudle. Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: Role of dopamine handling in neurotoxicity. Experimental Neurology 2012, 241, 138 -147.
AMA StyleJoshua M. Bradner, Tiffany A. Suragh, W. Wyatt Wilson, Carlos R. Lazo, Kristen A. Stout, Hye Mi Kim, Min Z. Wang, Douglas I. Walker, Kurt D. Pennell, Jason R. Richardson, Gary W. Miller, W. Michael Caudle. Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: Role of dopamine handling in neurotoxicity. Experimental Neurology. 2012; 241 ():138-147.
Chicago/Turabian StyleJoshua M. Bradner; Tiffany A. Suragh; W. Wyatt Wilson; Carlos R. Lazo; Kristen A. Stout; Hye Mi Kim; Min Z. Wang; Douglas I. Walker; Kurt D. Pennell; Jason R. Richardson; Gary W. Miller; W. Michael Caudle. 2012. "Exposure to the polybrominated diphenyl ether mixture DE-71 damages the nigrostriatal dopamine system: Role of dopamine handling in neurotoxicity." Experimental Neurology 241, no. : 138-147.
The exposure of the human population to environmental contaminants is recognized as a significant contributing factor for the development of Parkinson's disease (PD) and other forms of parkinsonism. While pesticides have repeatedly been identified as risk factors for PD, these compounds represent only a subset of environmental toxicants that we are exposed to on a regular basis. Thus, non-pesticide contaminants, such as metals, solvents, and other organohalogen compounds have also been implicated in the clinical and pathological manifestations of these movement disorders and it is these non-pesticide compounds that are the subject of this review. As toxic exposures to these classes of compounds can result in a spectrum of PD or PD-related disorders, it is imperative to appreciate shared clinico-pathological characteristics or mechanisms of action of these compounds in order to further delineate the resultant disorders as well as identify improved preventive strategies or therapeutic interventions.
W. Michael Caudle; Thomas S. Guillot; Carlos R. Lazo; Gary Miller. Industrial toxicants and Parkinson's disease. NeuroToxicology 2012, 33, 178 -188.
AMA StyleW. Michael Caudle, Thomas S. Guillot, Carlos R. Lazo, Gary Miller. Industrial toxicants and Parkinson's disease. NeuroToxicology. 2012; 33 (2):178-188.
Chicago/Turabian StyleW. Michael Caudle; Thomas S. Guillot; Carlos R. Lazo; Gary Miller. 2012. "Industrial toxicants and Parkinson's disease." NeuroToxicology 33, no. 2: 178-188.
Background: It is commonly believed that the mesolimbic dopamine (DA) system participates in the etiology of alcoholism. One of the most important regulators of DA synaptic transmission is the DA transporter (DAT). We examined the effects of the genetic reduction or deletion of DAT on voluntary ethanol consumption and ethanol-induced sedation. Methods: Ethanol preference and consumption were assessed in the two-bottle choice paradigm, and the depressant effects of ethanol were evaluated by measuring sleep time after acute injection of ethanol. Results: The latent period to lose the righting reflex was shorter in both knock-out mice (DAT-KO) and heterozygote mice (HET) than in wild-type (WT) mice. No significant difference was found among the three genotypes in the ethanol blood concentration at the onset of regaining the righting reflex. Females of all genotypes consumed more fluid than males of the same genotype. HET and DAT-KO females had increased total fluid consumption compared with WT females. DAT-KO males had increased fluid consumption compared with WT and HET males. Ethanol preference and consumption were not different among male mice of different genotypes. WT and HET females demonstrated significantly higher ethanol consumption than males. HET female mice did not differ from WT mice in ethanol preference. There was no difference between HET and WT mice in the preference for saccharin or quinine solutions. DAT-KO females avoided ethanol, and their consumption and preference were lower than in WT and HET females, despite markedly increased total intake. DAT-KO mice also demonstrated altered taste preference for saccharin and quinine. Conclusions: Partial deletion of DAT results in increased fluid consumption in female mice but does not change ethanol preference in either sex. Complete deletion of DAT reduces ethanol preference in female mice; this may be due to a combination of the pharmacological actions of DAT deletion and alterations in fluid consumption and taste discrimination.
Katerina V. Savelieva; W. Michael Caudle; Geoffrey S. Findlay; Marc G. Caron; Gary W. Miller. Decreased Ethanol Preference and Consumption in Dopamine Transporter Female Knock-Out Mice. Alcoholism: Clinical and Experimental Research 2002, 26, 758 -764.
AMA StyleKaterina V. Savelieva, W. Michael Caudle, Geoffrey S. Findlay, Marc G. Caron, Gary W. Miller. Decreased Ethanol Preference and Consumption in Dopamine Transporter Female Knock-Out Mice. Alcoholism: Clinical and Experimental Research. 2002; 26 (6):758-764.
Chicago/Turabian StyleKaterina V. Savelieva; W. Michael Caudle; Geoffrey S. Findlay; Marc G. Caron; Gary W. Miller. 2002. "Decreased Ethanol Preference and Consumption in Dopamine Transporter Female Knock-Out Mice." Alcoholism: Clinical and Experimental Research 26, no. 6: 758-764.
Katerina V Savelieva; W Michael Caudle; Geoffrey S Findlay; Marc G Caron; Gary W Miller. Decreased ethanol preference and consumption in dopamine transporter female knock-out mice. Alcoholism: Clinical and Experimental Research 2002, 26, 1 .
AMA StyleKaterina V Savelieva, W Michael Caudle, Geoffrey S Findlay, Marc G Caron, Gary W Miller. Decreased ethanol preference and consumption in dopamine transporter female knock-out mice. Alcoholism: Clinical and Experimental Research. 2002; 26 (6):1.
Chicago/Turabian StyleKaterina V Savelieva; W Michael Caudle; Geoffrey S Findlay; Marc G Caron; Gary W Miller. 2002. "Decreased ethanol preference and consumption in dopamine transporter female knock-out mice." Alcoholism: Clinical and Experimental Research 26, no. 6: 1.