Although banned in the 1970s, significant levels of the organochlorine pesticide heptachlor are still present in the environment raising concern over potential human exposure. In particular, organochlorine pesticides have been linked to an increased risk of Parkinson's disease. Studies from our laboratory and others have demonstrated that exposure of laboratory animals to heptachlor alters the levels and function of the dopamine transporter (DAT), an integral component of dopaminergic neurotransmission and a gateway for the dopaminergic neurotoxin MPTP. In this study, we examined the effects of developmental exposure to heptachlor on DAT, and other key components of the dopaminergic system, including the vesicular monoamine transporter 2 (VMAT2), tyrosine hydroxylase (TH), and aromatic amino acid decarboxylase (AADC). Female C57BL/6J mice received 0 or 3 mg/kg heptachlor in peanut butter every 3 days for 2 weeks prior to breeding and throughout gestation and lactation until the offspring were weaned on postnatal day (PND) 21. On postnatal day 28, DAT, VMAT2, and TH levels were increased by 100, 70, and 30%, respectively, with no change in AADC levels or total dopamine levels. The ratio of DAT:VMAT2 was increased 29%. Since an increase in the DAT:VMAT2 ratio appears to predict susceptibility of brain regions to Parkinson's disease (PD) and results in increased toxicity of MPTP, these results suggest that alterations of the dopaminergic system by developmental heptachlor exposure may increase the susceptibility of dopamine neurons to toxic insult.
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.
Introduction: Parkinson's disease (PD) is a neurodegenerative condition associated with aging characterized by loss of dopamine-producing neurons in the substantia nigra pars compacta and a reduction in dopamine levels in the striatum. PD is commonly treated using dopamine-replacement medication called levodopa. Levodopa has decreasing efficacy over time. Periods when levodopa is not effective at controlling symptoms of PD are called “OFF-time” or “medication-related motor fluctuations,” (MRMF). One characteristic of PD is unilateral side of symptom onset. Previous studies have found that side of onset was associated with differential motor and cognitive PD-related symptoms. The main study objective was to examine differences in left and right onset PD patients and OFF-time as measured by the Movement Disorders Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) Part IV Sum Score and Part IV item scores.
Methods: 64 individuals with mild-moderate PD (age: M(SD) = 68.72 (8.88)), years with PD: M(SD) = 6.61 (5.05); Hoehn and Yahr stage Med (1st, 3rd quartile) = 2.0 (2.0, 3.0) were assessed with the MDS-UPDRS parts I-IV. We conducted two-tailed independent sample t-tests to examine the differences between PD patients with left versus right onset.
Results: Right onset PD was significantly associated with more overall MRMF (p = 0.01), more OFF-time (p = 0.04), greater impact of motor fluctuations on daily life (p = 0.02) and more complex (unpredictable) MRMF (p = 0.01).
Conclusion: People with right onset PD have more complications with levodopa treatment. Alternative and/or adjuvant treatments to levodopa may be particularly beneficial for those with right onset PD.
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.
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.
Increasingly, exposure to various chemicals found in our environment has been found to be a significant contributor to the risk of developing neurological disease, such as Parkinson disease, autism spectrum disorder, as well as other deficits in thought and function. Exposure to these compounds during critical periods of neurodevelopment, encompassing exposures that occur in utero, during infancy, childhood, and adolescence, represents a time period of nervous system growth that is uniquely vulnerable to disruption by environmental chemicals. Indeed, a contemporary hypothesis suggests that the pathological cascade associated with many common neurological disorders has its origin in disturbances of normal neurodevelopment. Moreover, alterations to the ontogeny of the synapse and neurotransmitter signaling during neurodevelopment may be a premier pathological event that underlies neuropsychiatric and neurodegenerative disease. To interrogate the impact of exposure to a ubiquitous environmental chemical, the pesticide, endosulfan, on development of neurotransmitter circuits, we coupled in vitro and in vivo platforms to evaluate its effect on the formation of GABAergic, glutamatergic, and dopaminergic pathways in the frontal cortex. With this approach we found exposure of cortical neurons, in vitro, exhibited a marked reduction in the length of their neurite process as well as the number of synaptic connections. Further investigation using an in vivo model of developmental exposure identified significant alterations to pre and postsynaptic proteins involved in neurotransmitter handling and signaling in each of the neurotransmitter systems investigated. These findings suggest that exposure to endosulfan during vulnerable periods of neurodevelopment can alter the normal development and potential function of neurotransmission in the frontal cortex. Interestingly, the alterations identified in our study closely mimic the pathological markers associated with schizophrenia, which shows disturbances in synaptic proteins important for GABAergic, glutamatergic, and dopaminergic signaling in the frontal cortex. These findings provide important support for the impact of exposure to environmental chemicals during neurodevelopment and risk for neurological disease.
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.
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.
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.
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.