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. Here, we review human studies of prenatal and adult exposures to PCBs and describe the state of knowledge regarding outcomes across domains related to cognition (e.g., IQ, language, memory, learning), attention, behavioral regulation and executive function, and social behavior, including traits related to attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). We also review current understanding of molecular mechanisms underpinning these associations, with a focus on dopaminergic neurotransmission, thyroid hormone disruption, calcium dyshomeostasis, and oxidative stress. Finally, we briefly consider contemporary sources of organohalogens that may pose human health risks via mechanisms of neurotoxicity common to those ascribed to PCBs.

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. These sex differences may reflect age-related reductions in the levels of gonadal hormones since these hormones have been shown experimentally to alter response to DA neurotoxicants. These findings may aid in better understanding the roles that sex and age play in modifying central DA function following exposure, not only to PCBs, but also to other DA neurotoxicants as well as further elucidating the role of gonadal hormones in influencing the initiation and/or progression of neurodegenerative disorders.

Meeting report: consensus statement-Parkinson's disease and the environment: collaborative on health and the environment and Parkinson's Action Network (CHE PAN) conference 26-28 June 2007.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. METHODS: In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. RESULTS: We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. CONCLUSIONS: PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for < 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.

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. Participants also underwent a neuropsychological battery consisting of 34 tests capable of detecting subtle deficits in cognition, motor function, affective state, and olfactory function. RESULTS: After adjustment for potential confounders, the results indicated that an increase in serum total PCB concentration from 250 to 500 ppb (lipid basis) was associated with a 6.2% decrease in verbal learning, as measured by California Verbal Learning Test trial 1 score (p = 0.035), and with a 19.2% increase in depressive symptoms, as measured by the Beck Depression Inventory (p = 0.007). CONCLUSIONS: The results suggest that exposure to PCBs may be associated with some measures of memory and learning and depression among adults 55-74 years of age whose current body burdens are similar to those of the general population. Although the results are useful in delineating the neuropsychological effects of low-level exposure to PCBs, further studies of whether older men and women are a sensitive subpopulation are needed.

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). There was a substantial increase of IgG in the substantia nigra (SN) and hypothalamus (HT) of brains from NZM88 mice compared to control NZW and BALB/c mice, whereas NZM2758 mice had more IgG in the cortex. The increased presence of IgG in the NPSLE-prone NZM88 mouse brain was paralleled by increased TNF-alpha and IL-12 in the SN and HT regions; significantly elevated expression of MHC Class-II was also observed in the SN of NZM88 mice and cortex of NZM2758 mice. A co-culture system of dopaminergic neurons and microglia was used to demonstrate that NZM88 sera modifies dopaminergic cell activity only in the presence of microglia and that TNF-alpha is synthesized and released in this co-culture. This study demonstrates a functional link between the autoantibodies, the activation of microglia, and neuronal function associated dopamine production, which is suggested to be causally related to the predominant NPSLE syndromes.

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. Twenty-four-hour exposure to an environmentally relevant mixture of PCBs reduced tissue DA and GABA concentrations, increased medium levels of DA and measures of oxidative stress in both the striatum and VM. Alterations in neurochemistry and increases in measures of oxidative stress were blocked in the presence of n-acetylcysteine (NAC). Although NAC treatment did not alter PCB-induced changes in DA neurochemistry, it did protect against reductions in GABA concentration. To determine whether alterations in the vesicular storage of DA were responsible for PCB-induced oxidative stress and consequent reductions in GABA levels, we depleted DA from the co-cultures using alpha-methyl-p-tyrosine (AMPT). AMPT reduced striatal and VM DA levels by 90% and 70%, respectively. PCB exposure, following DA depletion, neither increased levels of oxidative stress nor resulted in GABA depletion. These results suggest that PCB-induced alterations in the vesicular storage of DA, resulting in increased levels of unsequestered DA, leads to increased oxidative stress, depletion of tissue glutathione, and consequent reductions in tissue GABA concentrations.

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. Identifying early biomarkers of risk provides tangible approaches toward designing studies in animals and humans that yield a better understanding of environmental risk factors, and can help identify rational intervention strategies to mitigate these risks.

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. We also exposed mice deficient in the proinflammatory cytokine interleukin-6 (IL-6-/-) to PCBs, to explore the role of this specific cytokine in mediating PCB-induced DA neurodegeneration. Not only did the PCB-treated IL-6-/- mice exhibit a decrease in serum levels of IL-1beta and TNF-alpha, but they were also protected from PCB-induced striatal dopaminergic dysfunction, displaying no signs of toxicant-induced reductions in DA levels, or TH, DAT or synaptophysin expression. Taken together, these results suggest that: (1) PCB exposure results in a peripheral inflammatory response associated with striatal terminal degeneration; and (2) the absence of IL-6 prevents PCB-induced dopaminergic losses in the striatum.

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. PCB exposure also increased neuronal cell death in both the VM and the striatum and reduced the number of DA neurons in the VM. Decreases in both tyrosine hydroxylase and DA transporter protein expression were shown by Western blot analysis in PCB-exposed cocultures. There was also an increase in neuronal cell death, identified by Fluoro Jade B, prior to a reduction in the number of VM DA neurons; we hypothesize this increase to be partly due to a loss of gamma-aminobutyric acid (GABA) neurons. Indeed, Western blot analysis revealed up to a 50% reduction in both VM and striatal glutamic acid decarboxylase 65/67. Analysis of tissue PCB levels revealed that concentrations were at or below 10 ppm following all exposure paradigms. This coculture system provides an excellent model to examine the chronology of PCB-induced neurotoxic events in the developing basal ganglia. Our results suggest that PCB-induced neurotoxicity in the developing basal ganglia involves GABAergic neuronal dysfunction, in addition to PCBs' better-recognized effects on DA function. These findings have important implications for disease states such as Parkinson's disease and for developmental deficits associated with exposure to PCBs and toxicologically similar environmental contaminants.

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. After 3 DIV, the levels of striatal DA increased substantially, through 10 DIV. Tissue levels of DA metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) reflected changes in tissue DA concentrations, indicating that release and metabolism of DA are similar to these characteristics observed in vivo. Western blot analysis of TH protein expression revealed large increases in VM TH after only 3 DIV, followed by a decline in levels through 17 DIV; levels of striatal TH, in contrast, increased through this period. Additionally, DAT and GAD 65/67 expression increased, in both the VM and striatum, over 17 DIV. By 17 DIV, many measures of DA function had decreased from those assessed at 10 DIV, thus providing an approximate limit to the effective duration of use of this co-culture model. Our results provide a much-needed description of the neurochemical changes that occur during the maturation of VM and striatum in organotypic co-cultures. Additionally, these results provide a foundation for future studies to assess toxic challenges of the developing nigrostriatal DA system, in vitro.

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. MeHg decreased mitochondrial function (measured by the conversion of MTT to formazan) and increased ROS levels in striatal synaptosomes after 30 min exposure. Although co-incubation with the antioxidant Trolox significantly reduced MeHg-induced ROS levels, it failed to restore mitochondrial function. MeHg also increased cytosolic and mitochondrial calcium levels in striatal synaptosomes. These elevations were largely independent of extrasynaptosomal calcium, given that nominal calcium-free buffer with 20 microM EGTA did not prevent MeHg-induced increases in cytosolic calcium. In conclusion, we suggest that ROS are not the cause of mitochondrial dysfunction in striatal synaptosomes after MeHg exposure; rather, we propose that ROS formation is a downstream event that reflects MeHg-induced mitochondrial dysfunction due to increased mitochondrial calcium levels.

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. Multivariable linear regressions were conducted to assess associations between PFASs and neuropsychological test scores. Mediation analyses were performed in a subset of 87 participants for whom information was available on both PFASs and THs. We calculated TH-mediated, non-TH mediated, and total effects of PFASs on neuropsychological test scores. Higher PFOA was associated with better performance in tasks of the California Verbal Learning Test and the Wisconsin Card Sorting Test. Higher PFOS was associated with improved performance in a Wechsler Memory Scale subtest and Block Design Subtest (BDT) total scores. There was no evidence of mediation by THs for PFOA-neuropsychological function associations. However, T4 and fT4 partially mediated the protective effect of PFOS on BDT total scores. Our findings do not suggest that PFASs are associated with poor neuropsychological function. There was some evidence of mediation for the association between PFASs and neuropsychological functions by THs, although some other modes of action also appear likely.

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. Surprisingly, the sera from IPD patients enhanced the DA content of MN9D cells differentiated with n-butyrate; the n-butyrate-differentiated MN9D cells had a greater concentration of DA (DA/mg total protein) than undifferentiated MN9D cells, especially early in culture. Although the IPD sera did not directly harm MN9D cellular viability or DA production, in the presence of the N9 microglial cell line, the amount of DA present in cultures of untreated or n-butyrate-treated MN9D cells was lowered by the IPD sera. The results suggest the involvement of antibodies in the decline of dopamine production and, thus, the potential of immune system participation in IPD.

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. Multivariable linear regression analyses were performed adjusting for age, sex, education, and cigarette smoking. Effects were reported as differences in test scores per one interquartile range (IQR) increase in hormone concentration. Higher total thyroxine (T4) and free thyroxine (fT4) were associated with improved visuospatial function, as measured by Block Design Subtest total scores; associated increments per IQR differences in T4 and fT4 were 15% and 19%, respectively (false discovery rate q-values <0.05). We also detected statistical interactions between age and fT4 for effects in tasks of memory and learning. Concurrent increases in age and fT4 were associated with deficits in memory and learning as measured by California Verbal Learning Test subtests (10% and 16% deficits in t-score and short delay free recall score, respectively). Our findings suggest that changes in thyroid hormones may have important implications for neuropsychological function in aging populations. Further large-scale studies with comprehensive thyroid function and neuropsychological outcome assessments are warranted to confirm these results.

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. MeHg induced ROS formation in synaptosomes from rats of all ages, although the increases were greatest in synaptosomes from the younger animals. MeHg also reduced mitochondrial metabolic function, as assessed by MTT reduction, as well as mitochondrial membrane potential; again, the greatest changes were seen in synaptosomes from early postnatal animals. These age-dependent differences in susceptibility to MeHg are most likely due to a less efficient ROS detoxifying system and lower activity of mitochondrial enzymes in tissue from young animals.

Manganese potentiates in vitro production of proinflammatory cytokines and nitric oxide by microglia through a nuclear factor kappa B-dependent mechanism.

Recent evidence suggests that the mechanism of manganese (Mn) neurotoxicity involves activation of microglia and/or astrocytes; as a consequence, neurons adjacent to the activated microglia may be injured. Mn modulation of proinflammatory cytokine expression by microglia has not been investigated. Therefore, the objectives of this research were to (1) assess whether Mn induces proinflammatory cytokine expression and/or modulates lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and (2) investigate possible mechanisms for such an induction. N9 microglia were exposed in vitro to increasing concentrations (50-1000 microM) of Mn in the presence or absence of LPS (10, 100, or 500 ng/ml). After various incubation times (up to 48 h), media levels of several cytokines and nitric oxide (NO) were determined, as was the expression of the inducible form of NO synthase (iNOS). Lactate dehydrogenase (LDH) release into the medium and the cellular uptake of Neutral Red were used as general measures for cytotoxicity. In the absence of LPS, Mn moderately increased interleukin-6 and tumor necrosis factor alpha (TNF-a) production only at higher Mn concentrations, which were cytotoxic. At all LPS doses, however, proinflammatory cytokine production was dose-dependently increased by Mn. Similarly, LPS-induced NO production and iNOS expression were substantially enhanced by Mn. Pharmacological manipulations indicated that nuclear factor kappa B (NFkappaB) activation is critical for the observed enhancement of cytokine and NO production. Within the context of inflammation, increased production of proinflammatory cytokines and NO by Mn could be an important part of the mechanism by which Mn exerts its neurotoxicity.

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. Both TCB and PtCB increased UWW, but this effect was blocked after exposure to the anti-estrogen ICI 182,780. Neither o-TCB nor HCB altered UWW. These results demonstrate that certain coplanar PCB congeners and/or their metabolites, are estrogenic, and suggest that exposure during critical periods of neuronal development may increase central DA concentrations, and by inference, alter behavior.

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). The 6% oil dose was selected because it is equivalent to the amount of oil in the 20% lyophilized fish diet. The experimental diets were fed until weaning on postnatal day (PND) 21, at which time all pups were placed on the rat chow diet. Starting on approximately PND77, one male and one female from each litter began a cognitive test battery using 2-lever operant chambers. PO groups failed to reach the same level of performance as the controls on the delayed spatial alternation (DSA) task and also showed decreased performance on delay trials. FA analyses of the diets found that the n-6/n-3 ratios for the PO fish and oil groups were reduced to 2.5 and 3.2, respectively, vs. 6.9 for controls. Analysis of brain tissue taken from pups on PND21 confirmed that the n-6/n-3 ratios within the brain were significantly reduced from 1.18 for controls to 0.87 and 0.90 for PO fish and oil groups, respectively. Specifically, the PO diets significantly increased long-chain n-3 FAs (20:5 n-3 and 22:6 n-3) and decreased long-chain n-6 FAs (20:4 n-6 and 22:4 n-6) in the brain. Thus, the observed delayed spatial alternation impairments in rats fed PO fish and fish oil are hypothesized to have resulted from the altered n-6/n-3 FA ratios.

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). In vitro exposure of striata from these mice to varying concentrations of PCBs for 4 h concentration-dependently decreased tissue DA content and increased the concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the media, a phenomenon already observed, although of smaller magnitude, with rat tissues. These effects were independent of the turning preference of the mice. Although the DA content initially did not differ among the striatal tissue from R, L, and NP mice, following 4 h of incubation in control medium (without PCBs), there was significantly greater DA content in striata from R mice in comparison to that from either L or NP mice. This difference was also apparent after 6 h of incubation, and it was not due to differences in DA turnover or cytotoxicity. Rather, the greater DA content in the striata of R mice was due to increased DA synthesis, since tyrosine hydroxylase (TH) activity was greater in striata from R mice than in striata from either L or NP mice. These differences in striatal DA synthesis, if present in vivo, may explain the observed greater nocturnal turning activity of the R mice. Additionally, the in vitro analyses suggest that striata from R mice have differential responses to stress compared with striata from L or NP mice. With regard to the effects of PCBs, however, it appears that (1) striata derived from mice with different turning preference are equally sensitive to this dopaminergic toxicant and (2) mice appear more sensitive to PCBs than rats.

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. Geometric means (standard deviations) of serum PFOS and PFOA were 31.6 (1.7) ng/mL and 9.17 (1.72) ng/mL, respectively. Multivariable linear regression analyses indicated that one interquartile range difference in PFOS corresponded to 4% and 9% increases in fT4 and T4 respectively. We detected statistical interactions between PFOA and age for effects on fT4 and T4; joint increases in PFOA and age were associated with increases in fT4 and T4, of 3% and 7%, respectively. We also detected statistical interactions between PFOS and total PCBs for the effect on T3 and between PFOA and total PBDEs for the effect on TSH. Our results suggest that PFASs are associated with subtle alterations in thyroid hormone levels in this population, and that these associations are likely to vary by age, and levels of PCBs and PBDEs.