Neurotoxicity of polychlorinated biphenyls and related organohalogens.

Halogenated organic compounds are pervasive in natural and built environments. Despite restrictions on the production of many of these compounds in most parts of the world through the Stockholm Convention on Persistent Organic Pollutants (POPs), many "legacy" compounds, including polychlorinated biphenyls (PCBs), are routinely detected in human tissues where they continue to pose significant health risks to highly exposed and susceptible populations. A major concern is developmental neurotoxicity, although impacts on neurodegenerative outcomes have also been noted.

Perfluoroalkyl substances, thyroid hormones, and neuropsychological status in older adults.

Minimal data exist regarding the neurotoxicity of perfluoroalkyl substances (PFASs) in aging populations and the possible mediating effects of thyroid hormones (THs). Hence, the aims of this study were to: (i) assess associations between PFASs and neuropsychological function, and (ii) determine if such associations are mediated by changes in circulating THs in an aging population. We measured perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), total thyroxine (T4) and free thyroxine (fT4) in serum and performed neuropsychological tests in 126 men and women aged 55-74 years and living in upper Hudson River communities.

Thyroid function and neuropsychological status in older adults.

Overt thyroid dysfunction is recognized as a risk factor for neuropsychological deficits in aging populations, yet evidence for how changes in levels of circulatory thyroid hormones impact specific neuropsychological domains is limited. Here we report cross-sectional associations between serum thyroid hormone concentrations and several neuropsychological function domains among men and women aged 55-74years. We administered neuropsychological tests to assess memory, learning, executive function, measures of attention, visuospatial function, affective state, and motor function.

Perfluoroalkyl substances and thyroid function in older adults.

Current understanding of the thyroid disruptive properties of perfluoroalkyl substances (PFASs), particularly in aging populations, is limited. The objectives of this study were to (i) assess associations between thyroid function, as measured by serum thyrotropin (thyroid stimulating hormone, TSH), free thyroxine (fT4), total thyroxine (T4), and total triiodothyronine (T3), and serum perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in an aging population and (ii) determine if other persistent organic pollutants with thyroid disruptive properties including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) modify such associations. We conducted a cross-sectional study of 87 men and women 55 to 74years of age, without clinically-diagnosed thyroid disease, who resided in upper Hudson River communities in New York.

Tibial bone lead, but not serum polychlorinated biphenyl, concentrations are associated with neurocognitive deficits in former capacitor workers.

Objective: To determine the relationships between tibial bone lead and serum polychlorinated biphenyl (PCB) concentrations and neurocognitive function.

Methods: The study population consisted of men and women former capacitor workers had been employed by the General Electric Corporation between 1946 and 1977. Regression analyses evaluated the association between neurocognitive function and lipid-adjusted serum PCB and tibia lead concentrations.

Developmental coexposure to polychlorinated biphenyls and polybrominated diphenyl ethers has additive effects on circulating thyroxine levels in rats.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants found in seafood and dairy products. PCBs and PBDEs are structurally similar chemicals and affect thyroid hormone function and behavior in children and laboratory rodents. Although coexposure frequently exists, the in vivo developmental effects of combined exposure to PCBs and PBDEs on thyroxine (T4) levels are unknown.

Polychlorinated biphenyls and polybrominated diphenyl ethers alter striatal dopamine neurochemistry in synaptosomes from developing rats in an additive manner.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are widespread environmental contaminants associated with changes in behavior and neurochemical function in laboratory animals and behavioral deficits in children. PCBs and PBDEs are found in food, especially in seafood and dairy products, and coexposure to these contaminants is likely. We examined the effects of an environmentally relevant mixture of PCBs (Fox River Mix [FRM]) and a PBDE mixture (DE-71) alone and in combination on synaptosomal and medium dopamine (DA) levels and the levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in striatal synaptosomes derived from postnatal days (PND) 7, PND14, or PND21 rats.

Estimating the half-lives of PCB congeners in former capacitor workers measured over a 28-year interval.

To date, most estimates of the half-life of polychlorinated biphenyls (PCBs) in humans have been based on relatively short follow-up periods. To address this issue, we determined the half-lives of PCB congeners of occupational origin in the serum of former capacitor workers as part of a study conducted in 2003-2006--approximately 28 years after their last occupational exposure. A total of 241 persons from a source population of 6798 former capacitor workers were interviewed and asked to donate a blood sample for serum PCB congener analysis.

Occupational exposure to PCBs reduces striatal dopamine transporter densities only in women: a beta-CIT imaging study.

We hypothesize that occupational exposure to PCBs is associated with a reduction in central dopamine (DA) similar to changes previously seen in PCB exposed adult non-human primates. To test that hypothesis, we used [(123)I]beta-CIT SPECT imaging to estimate basal ganglia DA transporter density in former capacitor workers. Women, but not men, showed an inverse relationship between lipid-adjusted total serum PCB concentrations and DA transporter densities in the absence of differences in serum PCB concentrations.

Methylmercury inhibits dopaminergic function in rat pup synaptosomes in an age-dependent manner.

Methylmercury (MeHg) is an environmental neurotoxicant that is especially harmful during brain development. Previously, we found greater sensitivity to MeHg-induced oxidative stress and greater loss of mitochondrial membrane potential in synaptosomes from early postnatal rats than in synaptosomes from older rat pups and adults. Here, we determine whether MeHg exposure also leads to greater changes in dopamine (DA) levels and dopamine transporter (DAT) function in synaptosomes from early postnatal rats.

Autoantibody-mediated neuroinflammation: pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model.

Autoantibodies play an important role in central nervous system manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE). Previous studies have shown that the lupus-prone NZM88 strain has major neural deficits and high titers of serum IgG to brain antigens. ELISA was performed to detect the presence of IgG in different brain regions of NZM88 mice and to compare the levels with NZM2758 mice and control strains (NZW and BALB/c).

Immunologic and neurodevelopmental susceptibilities of autism.

Symposium 5 focused on research approaches that are aimed at understanding common patterns of immunological and neurological dysfunction contributing to neurodevelopmental disorders such as autism and ADHD. The session focused on genetic, epigenetic, and environmental factors that might act in concert to influence autism risk, severity and co-morbidities, and immunological and neurobiological targets as etiologic contributors. The immune system of children at risk of autism may be therefore especially susceptible to psychological stressors, exposure to chemical triggers, and infectious agents.

Polychlorinated biphenyl exposure and neuropsychological status among older residents of upper Hudson River communities.

Background: Polychlorinated biphenyls (PCBs) may accelerate the cognitive and motor dysfunction found in normal aging, but few studies have examined these outcomes and PCB exposure among older adults.

Objective: We evaluated neuropsychological status and low-level PCB exposure among older adults living along contaminated portions of the upper Hudson River in New York.

Methods: A total of 253 persons between 55 and 74 years of age were recruited and interviewed, and provided blood samples for congener-specific PCB analysis.

Polychlorinated biphenyl-induced oxidative stress in organotypic co-cultures: experimental dopamine depletion prevents reductions in GABA.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been demonstrated to be toxic to the dopamine (DA) systems of the central nervous system. One proposed mechanism for PCB-induced DA neurotoxicity is inhibition of the vesicular monoamine transporter (VMAT); such inhibition results in increased levels of unsequestered DA and DA metabolism leading to oxidative stress. We have used an organotypic co-culture system of developing rat striatum and ventral mesencephalon (VM) to determine whether alterations in the vesicular storage of DA, resulting from PCB exposure and consequent induction of oxidative stress, leads to GABA and DA neuronal dysfunction.

Methylmercury-induced changes in mitochondrial function in striatal synaptosomes are calcium-dependent and ROS-independent.

The brain is the main target organ for methylmercury (MeHg), a highly toxic compound that bioaccumulates in aquatic systems, leading to high exposure in humans who consume large amounts of fish. The mechanisms responsible for MeHg-induced changes in neuronal function are, however, not yet fully understood. In the present study we investigated whether MeHg-induced elevations in reactive oxygen species (ROS) or intracellular calcium are responsible for altering mitochondrial metabolic function in rat striatal synaptosomes.

Polychlorinated biphenyl-induced neurotoxicity in organotypic cocultures of developing rat ventral mesencephalon and striatum.

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants that are highly toxic to the developing nervous system, particularly via their disruption of dopamine (DA) function. In order to characterize the effects of PCBs on the developing basal ganglia DA system, we utilized an organotypic coculture system of developing rat striatum and ventral mesencephalon (VM). Exposure of the cocultures to an environmentally relevant mixture of PCBs for 1, 3, 7, or 14 days reduced tissue DA concentrations and increased medium levels of DA, homovanillic acid, and 3,4-dihydroxyphenylacetic acid.

Polychlorinated biphenyls induce proinflammatory cytokine release and dopaminergic dysfunction: protection in interleukin-6 knockout mice.

Proinflammatory cytokines are not only important mediators of brain development, but also pose an increased risk for neurodegeneration following exposure to neurotoxicants or trauma. We have used the ubiquitous environmental and occupational neurotoxicant polychlorinated biphenyls (PCBs) to investigate the putative role of inflammatory agents in mediating processes involved in basal ganglia dysfunctions. PCBs induced inflammatory responses in C57BL/6 adult male mice, significantly elevating serum levels of IL-6 (31%), IL-1beta (71%) and TNF-alpha (22%) and significantly reducing striatal dopamine (DA, 21%), tyrosine hydroxylase (TH, 26%), dopamine transporter (DAT, 39%), and synaptophysin (29%) concentrations.

Dopaminergic development of prenatal ventral mesencephalon and striatum in organotypic co-cultures.

Using organotypic co-cultures of rat embryonic day 14 (E14) ventral mesencephalon (VM) and E21 striatum, we have described the developmental changes in (i) dopamine (DA) neurochemistry; (ii) numbers of DA neurons; and (iii) protein expression of tyrosine hydroxylase (TH), DA transporter (DAT), and glutamic acid decarboxylase (GAD 65/67), over 17 days in vitro (DIV). Co-cultures demonstrated changes in DA development similar to those observed in vivo. The numbers of VM DA neurons remained relatively constant, while levels of VM DA progressively increased through 10 DIV.

Serum antibodies from Parkinson's disease patients react with neuronal membrane proteins from a mouse dopaminergic cell line and affect its dopamine expression.

Evidence exists suggesting that the immune system may contribute to the severity of idiopathic Parkinson's disease (IPD). The data presented here demonstrates that antibodies in the sera of patients with IPD have increased binding affinity to dopaminergic (DA) neuronal (MN9D cell line) membrane antigens in comparison to antibodies in sera from healthy controls. In general, the degree of antibody reactivity to these antigens of the mouse MN9D cell line appears to correlate well with the disease severity of the IPD patients contributing sera, based on the total UPDRS scores.

The effects of methylmercury on mitochondrial function and reactive oxygen species formation in rat striatal synaptosomes are age-dependent.

Methylmercury (MeHg) is especially toxic to the developing central nervous system. In order to understand the reasons for this age-dependent vulnerability, we compared the effects of MeHg on formation of reactive oxygen species (ROS) and mitochondrial function in striatal synaptosomes obtained from rats of various ages. Basal ROS levels were greater, and basal mitochondrial function was lower, in synaptosomes from younger animals, compared to adult animals.

Delayed spatial alternation impairments in adult rats following dietary n-6 deficiency during development.

Dietary n-3 fatty acid (FA) deficiencies during development can cause learning and memory impairments, but the functional effects of dietary n-6 FA deficiencies, reflected in a lowered n-6/n-3 ratio, are less clear. We investigated the effects of maternal diets containing fish oils, resulting in lowered n-6/n-3 ratios, on a spatial working memory task in their offspring. Starting on gestational day 6, Sprague-Dawley timed-pregnant rats were placed on one of three experimental diets: control (unadulterated powdered rat chow), Pacific Ocean (PO) fish (powdered rat chow containing 20% (w/w) lyophilized PO salmon), or PO oil (powdered rat chow containing 6% (w/w) oil extracted from PO salmon).

Coplanar PCB congeners increase uterine weight and frontal cortical dopamine in the developing rat: implications for developmental neurotoxicity.

We show that developmental exposure of the laboratory rat to the coplanar polychlorinated biphenyl (PCB) congener 3,4,3',4'-tetrachlorobiphenyl (TCB) and the structurally similar congener 3,4,5,3',4'-pentachlorobiphenyl (PtCB) elevates dopamine (DA) concentrations in the prefrontal cortex (PFC). To determine whether these coplanar congeners are estrogenic, and may thus contribute to the elevations in PFC DA, we measured uterine wet weight (UWW) in prepubertal rats exposed to TCB or PtCB. For comparison, additional animals were exposed to either the ortho-substituted congener 2,4,2',4'-tetrachlorobiphenyl (o-TCB) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), a coplanar congener highly resistant to metabolism.

Influence of polychlorinated biphenyls and turning preference on striatal dopamine metabolism.

Male BALB/c mice, assessed for spontaneous nocturnal rotation that has been linked with functional differences in striatal dopamine (DA) content, were divided into right (R), left (L), and no turning preference (NP) groups. Both total turning activity and turning in the preferred direction were greatest in the R mice. To determine whether turning preference influences the response to exposure to an environmental toxicant known to reduce striatal DA function, striatal tissues from R, L, or NP mice were exposed to polychlorinated biphenyls (PCBs).

Methyl mercury influences growth-related signaling in MCF-7 breast cancer cells.

Environmental contaminants have been shown to alter growth-regulating signaling pathways through molecular mechanisms that are mainly unclear. Here we report that within a narrow concentration range (0.5-1 microM) methyl mercury (MeHg) significantly stimulated growth of MCF-7 cells, induced Ca(2+) mobilization, and activated extracellular signal-regulated kinase (1/2) (Erk1/2).