Parkinson's Disease Research and Articles

Parkinsons's Disease research points to PCB exposure as one potential cause of Parkinsons Syndrome.

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The Studies - Parkinson’s Disease, Dopamine and PCBs

This is not a complete list of all Parkinsons Disease research related to PCB exposures. For more studies, visit the TOXNET database operated by the National Library of Medicine (the source of these abstracts). For more information and a summary of these 38 studies, see Parkinson's Table of Contents.

Study #1

diorthosubstituted PCBs may contribute to the pathogenesis of Parkinson's disease
Parkinson’s victims had significantly higher concentrations of total PCBs, and PCBs 153 and 180 in their brain tissue
study used PCB 180 and total PCBs

As it had previously been demonstrated that there were reduced brain dopamine concentrations in monkeys who had been given polychlorinated biphenyls (PCBs) chronically, we hypothesized that organochlorine compounds in general, and PCBs in particular, might be important in the pathogenesis of Parkinson's disease (PD). In a study of caudate nucleus obtained post mortem from patients with Parkinson's disease and from controls, there were significantly higher concentrations of the organochlorine insecticide dieldrin and the PCB congener 153 in the PD tissue. DDE, PCB congener 180, and total PCBs (matched with a commercial preparation) also tended to be higher in Parkinson's disease tissue. We think that this is important preliminary evidence that diorthosubstituted PCBs may contribute to the pathogenesis of Parkinson's disease, and a greater presence of organochlorine insecticides in the PD tissue suggests that this may be in part the explanation for the association between PD and rural living. (Corrigan et al, 1998)

Study #2

PCBs caused dose-dependent decreases in dopamine
PCB doses higher than 100 micrograms per milliliter caused 85% mortality of dopaminergic cells [Note: Parkinson’s Disease symptoms begin at 85% mortality of dopaminergic cells in the brain.]
cells showed increasing sensitivity over time to lower doses of PCBs
PCBs cause neurite elongation and decreased cellular dopamine levels
study used PCB commercial mixture Aroclor 1254

The effect of PCBs on developing dopaminergic cells were investigated. Rat-PC12 pheochromocytoma cells in monolayer cultures, both with and without treatment with murine nerve growth factor (NGF), were exposed to the PCB Aroclor-1254 for 15 days. Cultures were then analyzed for levels of DNA, catecholamines, metabolites, neurite outgrowth, lactate-dehydrogenase and DNA, and protein synthesis. Either in the absence, or simultaneously in the presence of NGF, exposure to Aroclor 1254, at concentrations up to 100 micrograms per milliliter, resulted in dose-dependent decreases in levels of cellular dopamine, which with increasing time of exposure, up to 3 days, became increasingly sensitive to lower concentrations of PCBs as evidenced by shifts of the dose-response curves to the left. Concentrations greater than this produced 85% cell mortality. Thymidine incorporation studies showed DNA synthesis to be decreased after 3 days exposure at only the highest concentrations of Aroclor-1254. Pretreatment of PC12 cells with NGF for 7 or 14 days prior to exposure to Aroclor 1254 afforded partial protection from the PCB-mediated decreases in cellular dopamine, consistent with the hypothesis that the cells have different sensitivities to the dopamine decreasing effects of PCBs, depending on the state of differentiation that they are in when exposure to PCBs occurs. Aroclor-1254 and NGF exposed cells demonstrated a dose dependent increase in neurite elongation. The authors conclude that PCBs cause neurite elongation and decreased cellular dopamine levels in PC12 cells. (Angus et al, 1994

Study #3

PCBs and mercury together are much more potent in decreasing dopamine than if they were separate [Note: Fox River and Green Bay fish contain both PCBs and mercury]
significant synergism between these two contaminants may involve an elevation of free intracellular calcium
fish-consumption guidelines may need to consider these interactions

Consumption of contaminated fish by pregnant women is associated with cognitive deficits [reduced brain function] in their infants and children. These fish contain many anthropogenic neurotoxicants making it difficult to determine which are responsible for the observed deficits. Thus, we have undertaken a series of experiments, using both striatal tissue obtained from adult rats and cerebellar granule cells obtained from early postnatal rats, to determine the active toxicants by initially comparing the neurotoxic effects of two fish-borne contaminants - polychlorinated biphenyls (PCBs) and methylmercury (MeHg). Striatal punch dopamine (DA) content was reduced in a dose dependent manner following exposure to a commercial mixture of PCBs at media concentrations greater than 10 ppm, but not following exposure to MeHg, at media concentrations ranging from 4 to 14 uM. Decreases in dopamine content were significantly greater than additive following exposure to both contaminants. Intracellular calcium concentrations in cerebellar granule cells were determined using flow cytometry and the calcium sensitive dye Fluo-4 and were elevated following exposure to the ortho-substituted PCV congener 2,2' (1 to 10 uM) or MeHg (1 to 2.5 uM). The increases were significantly greater than additive following exposure to both contaminants, We suggest that: (i) the significant synergism between these two contaminants may involve an elevation of free intracellular calcium and (ii) fish-consumption guidelines may need to consider these interactions. (Seegal et al, 2000)

Study #4

PCBs have long-lasting effects on dopamine and serotonin producing processes
study used PCB 77

In the present experiment, drug discrimination was examined in rats after maternal exposure to 3,3',4,4'-tetrachlorobiphenyl (PCB 77) using apomorphine (APO) as the training drug at a dose reported to act on dopamine D2 receptors. A group with maternal exposure to 6n-propyl-2-thiouracil (PTU) was included as a positive control for effects induced by PCB 77 on thyroid hormones. On gestational day (GD) 19 reduced levels of free and total thyroxine (FT4, TT4) and free triiodothyronine (FT3) were detected in dams exposed to PCB 77 or PTU. In the offspring decreases in levels of FT4 and TT4 were found in both treated groups on postnatal day (PND) 21, while reductions of FT3 were observed only in the PTU group. PTU-treated rats needed more daily sessions for successful discrimination between apomorphine and saline. There were no differences between groups in generalization tests and sessions with the D2/D3 agonist quinpirole, the D2 antagonist haloperidol plus APO, or with the GABAergic drug pentobarbital and only minor differences in sessions with the D1 agonist SKF-38393. Differences between controls and groups exposed to PCB 77 or PTU were detected in a blocking test using the mixed serotonin 5-HT1A agonist and partial D2 antagonist buspirone. This outcome suggests long-lasting effects by developmental exposure to PCB 77 on the interaction between dopaminergic and serotonergic processes which may be mediated by effects on thyroid hormone levels. (Lilienthal et al, 1997)

Study #5

PCB exposure results in alterations in serotonin metabolism but not dopamine metabolism in offspring of PCB exposed mothers, which differs from PCB induced neurotoxicity in adult animals
study used PCB commercial mixture Aroclor 1254

The effect of maternal exposure to the commercial polychlorinated biphenyl (PCB) Aroclor-1254 (Aroclor) on regional brain serotonin levels in weanling and young adult rats was investigated. Pregnant Wistar-WU-rats received daily oral doses by gavage of 0, 5, or 25mg/kg Aroclor from day ten to 16 of gestation. Rats were sacrificed on day 21 or 90 postnatally. Brain region levels of neurotransmitters were determined by high pressure liquid chromatography. Neither dose of Aroclor affected maternal weight, number of offspring, or postnatal mortality. Alterations in 5-hydroxytryptamine (5HT or serotonin) metabolism occurred in the lateral olfactory tract (LOT), prefrontal cortex, and striatum and dorsal hippocampus of the offspring. The effects were characterized by increased concentrations of hydroxyindole-acetic-acid (5HIAA), the principal metabolite of 5HT, and increased 5HIAA/5HT ratios. The increases in 5HIAA levels and 5HIAA/5HT ratios occurred largely on postnatal day 90 in the LOT and prefrontal cortex, whereas the striatum and hippocampus showed only increases in 5HIAA. On postnatal day 21, slight increases in 5HIAA levels occurred in the LOT at the 25mg/kg dose. Other biogenic amines, norepinephrine, dopamine, and homovanillic acid, were unaffected by maternal PCB exposure. The authors conclude that exposure to Aroclor results in alterations in 5HT metabolism but not dopamine metabolism, which differs from Aroclor induced neurotoxicity in adult animals. (Morse et al, 1996)

Study #6

low doses of PCBs inhibit dopamine
inhibition of vesicular uptake may contribute to the decrease of dopamine
study used ortho-substituted PCBs

Studies have shown that polychlorinated biphenyls may affect cognitive functions both in human and also in experimental animals. One of the neurochemical parameters that is changed after exposure to these compounds is a reduction in the dopamine level in the brain, although the mechanism behind this reduction is not known. We have therefore investigated whether this reduction could be caused by an effect on vesicular uptake. ortho-Chlorinated biphenyls are found to be competitive inhibitors of dopamine transport into synaptic vesicles from rat brain with K(i) concentrations as low as 4 microM. In contrast, several nonortho-chlorinated biphenyls did not inhibit vesicular uptake. The inhibition was specific for dopamine, in that the uptake of glutamate and GABA was inhibited at higher PCB concentrations under identical conditions. The vesicular Mg-ATPase proton pump was also inhibited at higher concentrations of PCBs than the dopamine transport. Uptake of methylamine gave no indication of any disruption of the vesicular proton gradient. The inhibition of dopamine vesicular uptake by PCBs was competitive. Several of the ortho-PCBs also inhibited the binding of tetrabenazine, which is known to bind to a site close to the dopamine binding site, at the vesicular transporter. The results show that inhibition of vesicular uptake may contribute to the decrease of dopamine reported in nervous tissue after exposure to PCBs under different conditions. (Mariussen et al, 1999)

Study #7

PCBs affect dopamine and serotonin processes
study used PCBs 77 and 47

Previous experiments indicated that after treatment with the dopamine D2 receptor blocker haloperidol the resulting catalepsy was more pronounced in rats with maternal exposure to the coplanar PCB 3,3',4,4'-tetrachlorobiphenyl (3,4-TCB) than in rats exposed to the ortho-chlorinated congener 2,4-TCB and controls. In the present experiment drug discrimination in a standard two-lever task was examined in rats maternally exposed to 3,4-TCB using apomorphine at a dose reported to act on D2 receptors. Since impairment of thyroid function is suggested to mediate neurobehavioural effects of PCBs a group with perinatal exposure to propylthiouracil (PTU) was included as a positive control. PTU-treated rats needed more daily sessions than controls to reach the criterion for successful discrimination between apomorphine and saline. Differences between controls and groups exposed to 3,4-TCB or PTU were detected in a blocking test using the serotonin 5-HT1A agonist buspirone which is also a partial antagonist to the D2 receptor. This outcome suggests an effect of 3,4-TCB on the interaction between dopaminergic and serotonergic processes. (Lilienthal et al, 1996)

Study #8

PCBs induce serotonin release

The study investigates the relation between strains on humans due to certain chlorinated substances and changes in the immune system. Immunological parameters were analyzed by testing a group of persons (persons exposed to wood preservatives and PCB). In vitro tests were made to assess the effects of polychlorinated biphenyl with regard to the release of mediators of inflammation (chemoluminescence, leukotrienes, histamine, serotonin 12-HETE), cellular signal transduction (G proteins, proteinkinase C) and lymphocyte parameters (CD23-Fc epsilon RII, CD25; lg synthesis). Compared with untreated persons and the PCP test group PCB-exposed test persons show significantly lower PHA and ConA lymphocyte stimulation values. The release of soluble CD23 (Fc epsilon RII) was higher in exposed than in non-exposed persons. Thrombocyte aggregation, serotonin release and 12-HETE formation furnish evidence of the fact that polychlorinated biphenyls may induce and modulate cellular answers as a function of 1) the (abstract incomplete) (German Govt. Report, 1993)

Study #9

decreased dopamine after low dose of PCBs
PCB levels in the brain dropped after PCB exposures stopped
long term dysfunction that results in lowered brain dopamine is probably due to initial PCB damage
study used PCB commercial mixtures Aroclor 1016 and Aroclor 1260

Dopamine (DA) concentrations in the adult, nonhuman primate brain following the termination of exposure to polychlorinated biphenyls (PCBs) were investigated. Macaca-nemestrina adults were given 3.2mg/kg (3.2 ppm) of either Aroclor-1016 or Aroclor-1260 orally for 20 weeks (wk), a dose level that had been shown to decrease DA levels in animals tested immediately after exposure. In the current experiment, PCB administration was stopped and monkeys were sacrificed at 24wk and 44wk postexposure. Brain tissues were processed for high performance liquid chromatography analysis of DA and its metabolites 3-methoxy-4-hydroxy-phenylacetic-acid, and 3,4-dihydroxyphenylacetic-acid, as well as epinephrine, norepinephrine, and serotonin and its metabolite 5-hydroxyindoleacetic-acid. Gas chromatography was used for PCB analyses. Data were analyzed using analysis of variance. Results indicated that brain PCB levels declined after cessation of exposure. These decreases ranged from 46% in the substantia nigra to 76% in the putamen, with a total brain average decline of 65% in the case of Aroclor-1016. In the case of Aroclor-1260, the decreases ranged from 44% in the substantia nigra to 97% in the hypothalamus, with an average total brain decline of 74%. There were no statistically significant differences between the two postexposure groups. There were no discernible changes in brain DA levels in Aroclor-1016 and Aroclor-1260 exposed monkeys at 24wk or 44wk postexposure when compared with levels immediately following exposure. The authors conclude that the decreases in DA levels are independent of brain PCB concentrations and that the long term dysfunction that results in lowered brain DA concentrations is probably due to the initial damage. (Seegal et al, 1994)

Study #10

significant decrease in dopamine
study used PCB commercial mixture Aroclor 1254

A series of subchronic feeding experiments were undertaken employing powdered rat chow adulterated with either 500 or 1000 parts per million (ppm) Aroclor-1254 in order to determine what changes occurred in male Wistar-rats as a result of such treatment. Following a 30 day exposure the animals were sacrificed. Polychlorinated biphenyl (PCB) exposure slowed the normal increase in weight gain but there was no statistical relationship between the change in body weight and neurochemical change. PCB exposure caused a significant decrease in striatal dopamine (DA) concentrations. The major metabolites of DA, homovanillic-acid (HVA) and 3,4-dihydroxyphenylacetic-acid (DOPAC), also decreased significantly following exposure. Neuronal turnover was also changed. The DOPAC ratios were significantly decreased. HVA/DA ratios were also affected by exposure. No statistically significant changes in striatal concentrations or activity of norepinephrine or serotonin were noted. In the lateral olfactory tract (LOT), Aroclor-1254 exposure did not cause statistically significant decreases in DA concentration, but there were dose dependent decreases in metabolite concentrations. No differences in biogenic amine function other than for DA were noted in the LOT. Chow contaminated with acetone (67641) showed no differences from those treated only with the PCB. In the 1000ppm treatment group, total PCB concentrations in the hippocampus, striatum and LOT were 52.6, 41.6, and 30.4 micrograms/gram wet weight, respectively, while in the 500ppm group the total PCB concentrations were 29.6, 16.2, and 14.3 micrograms/gram wet weight, respectively. (Seegal et al, 1991)

Study #11

low PCB doses reduce serotonergic cell numbers (1 ppm PCB levels --- and higher --- are commonly found along the Fox River and Green Bay)
study used PCB commercial mixture Aroclor 1254

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that exert neurotoxic effects during embryonic development. The present study demonstrates that early embryonic exposure to a mixture of PCBs (Aroclor 1254) results in a decrease in serotonergic cell growth. Using a novel, marine invertebrate embryo model, Spisula solidissima, immunocytochemistry, and confocal microscopy techniques, a dose-dependent decrease in serotonergic cell number was quantified within 24 h of exposure. This effect was seen with doses as low as 1 ppm Aroclor 1254. These findings demonstrate that environmentally relevant doses of Aroclor 1254 impair development of the serotonergic nervous system. (Smith et al, 1999)

Study #12

PCBs decrease brain dopamine concentrations
both lightly and highly chlorinated PCBs are responsible for changes in neurochemical function
study used PCB commercial mixtures Aroclor-1016 and 1260

The effects of aroclor-1016 and aroclor-1260 on brain catecholamine concentrations were studied in monkeys. Adult male Macaca-nemestrina were given 0.8, 1.6, or 3.2mg/kg aroclor-1016 or aroclor-1260 daily orally for 20 weeks. They were observed for clinical signs of toxicity and behavioral dysfunction. They were killed after 20 weeks and the brains were removed. The brains were dissected into the caudate, putamen, globus pallidus, substantia nigra, hippocampus, and hypothalamus which were assayed for dopamine, 3-methoxy-4-hydroxyphenylacetic-acid (HVA), 3,4-dihydroxyphenylacetic-acid (DOPAC), norepinephrine, epinephrine, serotonin, 5-hydroxyindoleacetic-acid, aroclor-1016, and aroclor-1260. The concentrations of polychlorinated biphenyl (PCB) congeners in the brain regions were determined. Neither aroclor-1016 nor aroclor-1260 caused any clinical signs of toxicity or behavioral changes. Aroclor-1016 significantly decreased the concentrations of dopamine, HVA, and DOPAC in the caudate, putamen, substantia nigra, and hypothalamus. Aroclor-1260 significantly decreased the concentrations of dopamine, DOPAC, and HVA in the caudate, putamen, and hypothalamus. Total brain aroclor-1016 concentrations ranged from 1 to 5 parts per million (ppm). 2,4,4'-Trichlorobiphenyl (7012375) (TrCB), 2,4,2',4'-tetrachlorobiphenyl (2437798), and 2,5,2',5'-tetrachlorobiphenyl (35693993) were the major aroclor-1016 congeners detected in all brain regions. TrCB comprised 60 to 80% of the total PCB content. Aroclor-1260 concentrations ranged from 18 to 28ppm. Thirteen aroclor-1260 congeners were detected. Most were hexa and hepta di-ortho substituted compounds. The distribution of PCB congener residues did not vary significantly among the brain regions. The authors conclude that both lightly and highly chlorinated ortho substituted nonplanar congeners are responsible for the changes in neurochemical function seen in adult nonhuman primates exposed to PCBs. Aroclor-1016 and aroclor-1260 decrease brain dopamine concentrations by similar mechanisms. (Seegal et al, 1991)

Study #13

PCBs induce permanent functional and neurochemical changes in adults when given to newborns during the peak of rapid brain growth

We have recently reported that environmental toxicants, such as DDT, PCBs, pyrethroids, and nicotine can induce permanent functional and neurochemical changes in adult mice when given to neonatal mice during the peak of rapid brain growth. In the present investigation the neurotoxic effects following neonatal exposure to paraquat (N,N'-dimethyl-4,4'-bipyridylium), a broad-spectrum herbicide with structural similarity to the 1-methyl-4-phenylpyridium ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which can induce Parkinson's syndrome, and MPTP were studied. Five groups of mice were given paraquat or MPTP orally: group 1, vehicle; groups 2 and 3, MPTP 0.3 and 20 mg/kg; groups 4 and 5, paraquat 0.07 and 0.36 mg/kg when 10 and 11 days old. Neonatal spontaneous motor activity was tested on Day 18 in mice given paraquat 0.36 mg/kg body wt. Adult spontaneous motor activity testing was performed at ages 60 and 120 days. On Day 125 the mice were decapitated and the co (abstract incomplete) (Fredriksson et al, 1993)

Study #14

genetic factors may alter the susceptibility to the effects of PCBs on dopamine synthesis
PCBs may inhibit tyrosine-hydroxylase activity and dopamine synthesis through an indirect mechanism
study used PCBs 4,15 and 52

The influences of polychlorinated biphenyls (PCBs) on tyrosine-hydroxylase activity and dopamine synthesis in the rat brain were examined to test the hypothesis that ortho substituted PCBs selectively decrease dopamine synthesis by inhibiting tyrosine-hydroxylase, while other substituted congeners do not. Corpus striatum samples obtained from male Sprague-Dawley-rats and Long-Evans-hooded-rats were minced and exposed to PCB congener doses of 30 to 100 micromolar. Dopamine synthesis was determined by measuring the tyrosine-hydroxylase activity in striatal minces. Soluble tyrosine-hydroxylase activity in the corpus striatum was quantified according to a nonenzymatic decarboxylation method. Tyrosine-hydroxylase activity was significantly decreased in the striatal minces of Long-Evans-hooded-rats and Sprague-Dawley-rats exposed to the ortho substituted 2,2'-dichlorobiphenyl . Enzyme activity was not inhibited in the striatal minces of Long-Evans-hooded-rats exposed to the ortho meta substituted 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TeCB) or the para substituted 4,4'-dichlorobiphenyl (4,4'-DCB). The tyrosine-hydroxylase activity of the striatal minces of Sprague-Dawley-rats was significantly and dose dependently inhibited following exposure to 2,2',5,5'-TeCB. Exposure to 4,4'-DCB did not alter the tyrosine-hydroxylase activity of the striatal minces obtained from Sprague-Dawley-rats. None of the PCB congeners affected the activity of soluble tyrosine-hydroxylase in either rat strain. The authors conclude that genetic factors may alter the susceptibility of animal strains to the effects of PCBs on dopamine synthesis. Ortho substituted PCBs may inhibit tyrosine-hydroxylase activity and dopamine synthesis through an indirect mechanism. (Choksi et al, 1997)

Study #15

ortho-chlorinated PCBs reduced dopamine levels by decreasing potassium ions through non Ah receptor mechanisms
study used PCB commercial mixture Aroclor 1254 --- and PCBs 52, 126, 105, 128 and 153

The effects of polychlorinated biphenyls (PCBs) on dopamine release from rat pheochromocytoma-PC12 cells were examined. PC12 cells were incubated with 0 to 100 micrograms per milliliter (microg/ml) aroclor-1254 , 2,2',5,5'-tetrachlorobiphenyl (TeCB), 3,3',4,4',5-pentachlorobiphenyl (33PeCB), 2,3',4,4',5-pentachlorobiphenyl (23PeCB), 2,2',3,3',4,4'-hexachlorobiphenyl (223HxCB), or 2,2',4,4',5,5'-hexachlorobiphenyl (223HxCB) for 3 days. The effects on basal and potassium ion evoked (induced by adding 56 millimolar potassium-chloride to the culture medium) release on dopamine release from the cells were determined. Changes in the dopamine and DNA content of the cells were measured. Aroclor-1254 induced concentration dependent decreases in basal and potassium ion evoked releases of dopamine and cellular dopamine levels. The lowest aroclor-1254 concentration causing these effects was 10microg/ml. Aroclor-1254 at this concentration did not alter cellular DNA content. Higher concentrations significantly decreased DNA content. TeCB and 224HxCB caused concentration dependent decreases in basal and potassium ion evoked release of dopamine. The decreases occurred at concentrations, up to 50microg/ml, that did not affect cellular DNA content. 23PeCB and 223HxCB significantly decreased potassium ion evoked dopamine release at concentrations of up to 50microg/ml. Basal dopamine release and cellular DNA content were not affected. 33PeCB induced concentration dependent increases in basal dopamine release and decreases in potassium ion evoked dopamine release. These changes occurred at concentrations that did not alter cellular DNA levels. All PCB congeners caused similar decreases in cellular dopamine levels. The authors conclude that o-chlorinated PCBs such as TeCB, 223HxCB, 224HxCB, and 23PeCB induce decreases in potassium ion evoked dopamine release that appear to be mediated by non aromatic hydrocarbon receptor mediated mechanisms. The decreases reflect a reduction in cellular dopamine levels. (Angus et al, 1996)

Study #16

inhibition of tyrosine uptake was not the primary mechanism by which PCBs reduce dopamine levels
study used PCB commercial mixture Aroclor 1254 --- and PCBs 52, 128, and 153

PC12 cells were used to examine the mechanisms by which polychlorinated biphenyls (PCBs) reduce cellular levels of dopamine (DA). In cells treated 3 days with Aroclor 1254, 2,2',5,5'-tetrachlorobiphenyl (2,2',5,5'-TCB), or 2,2',3,3',4,4'-hexachlorobiphenyl (2,2',3,3',4,4'-HCB), the PCB-mediated reduction in 3H-tyrosine uptake was observed only at high PCB concentrations that produced a reduction in DNA levels. The PCB congener, 2,2',4,4',5,5'-hexachlorobiphenyl (2,2',4,4',5,5'-HCB) did not produce a reduction in 3H-tyrosine uptake at any concentration tested. Thus, there were PCB concentrations at which a reduction in DA levels did not coincide with a decrease in 3H-tyrosine uptake, suggesting that inhibition of tyrosine uptake was not the primary mechanism by which PCBs reduce DA levels. Aroclor 1254-treated cells also exhibited elevated levels of DOPA, further supporting the conclusion that tyrosine levels were not limiting. Incubation of Aroclor 1254-pretreated cells with 3H-tyrosine resulted in a (abstract incomplete) (Angus et al, 1997)

Study #17

low PCB exposures to adults decreased dopamine concentrations in adults
3 ortho-substituted types of PCBs decreased dopamine concentrations
study used PCB commercial mixture Aroclor 1016

A series of experiments were presented designed to determine if subchronic exposure of adult nonhuman primates to polychlorinated biphenyls (PCBs) decreases dopamine (DA) concentrations; indicate which PCB congeners accumulate in brain; and determine if these PCB congeners may be directly responsible for the observed changes in central nervous system neurochemistry. Macaca-nemestrina were fed bread soaked with a corn-oil and Aroclor-1016 PCB mixture. The animals were dosed at levels of 0, 0.8, 1.6, or 3.2mg/kg/day for 20 weeks. Following the 20 week exposure period the animals were sacrificed. The changes observed in DA concentrations following exposure were associated with only three ortho substituted, nonplanar congeners. Furthermore, these congeners altered in-vitro cellular concentrations of DA suggesting that they, and neither PCB metabolites nor poorly retained congeners, were directly responsible for the changes observed in in-vivo neurochemistry. The authors state that information derived from these experiments not only will allow a more accurate estimate of risk following exposure to mixtures of PCBs, but also will allow an investigation of the mechanisms by which PCBs alter central nervous system function. (Seegal et al, 1990)

Study #18

some PCB increase dopamine, others decrease dopamine
study used PCB 47 and 77

Offspring of Sprague-Dawley derived dams were exposed to either 2,4, 2',4'-tetrachlorobiphenyl (TCB) (1, 10, or 20 mg/(kg.day)) or 3,4,3', 4'-TCB (0.1 or 1 mg/(kg.day)) from gestational Day 6 through weaning by providing the dams with cookies adulterated with the appropriate amount and type of PCB. Male and female offspring were sacrificed on postnatal Days 35, 60, and 90, and brain concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, were determined in the frontal cortex, caudate nucleus and substantia nigra by high-performance liquid chromatography with electrochemical detection. In utero and lactational exposure to 3,4,3',4'-TCB resulted in significant elevations in concentrations of dopamine in the frontal cortex, and of dopamine and its metabolites in the substantia nigra that persisted into adulthood. In contrast, in utero and lactational exposure to 2,4,2',4'-TCB resulted in significant decreases in concentrations of dopamine in the frontal cortex and caudate nucleus that also persisted into adulthood. We suggest that the reductions in brain dopamine concentrations are a consequence of ortho-substituted PCB congener-induced inhibition of the synthesis of dopamine during critical periods of development acting, perhaps, in concert with PCB-induced changes in cholinergic receptor function. On the other hand, the persistent elevations in brain dopamine and metabolite concentrations following perinatal exposure to 3,4,3',4'-TCB may be mediated by alterations in steroid hormone function during key developmental periods. (Seegal et al, 1997)

Study #19

behavioral abnormalities
reduced concentrations of catecholamines such as norepinephrine and dopamine
non-dioxin-like PCBs have a high potency for decreasing brain dopamine levels
study used PCB 77

The neurochemical effects of polychlorinated biphenyls (PCBs) were reviewed. The general chemical and toxicological properties of and sources of exposure to PCBs were described. PCBs have been widely used in electrical and other industries for more than 40 years. The appearance of PCBs in ecosystems and documented cases of accidental poisoning led to their being banned in 1977. Environmental contamination with PCBs today is widespread, even occurring in Arctic regions. Studies in humans that were exposed during development to PCBs and related compounds such as polychlorinated dibenzo-p-dioxins and furans have revealed significant alterations in neurological development and cognitive functions. Consideration was also given to studies examining the effects of 3,4,3',4'-tetrachlorobiphenyl (32598133) (PCB 77) in rodents, the effects of acute and repeated PCB exposure, associated mechanisms, and structure/activity relationships underlying the effects of PCBs. Studies have shown that developmental exposure to PCB 77 can cause behavioral abnormalities such as head bobbing and rotational movements and impaired acquisition of a shock avoidance task in rodents. Acute and chronic exposure to high concentrations of PCBs have been associatedwith reduced concentrations of catecholamines such as norepinephrine and dopamine in a number of brain regions in rats or monkeys. Exposures to low concentrations appear to disrupt brain dopamine metabolism. Coplanar PCB congeners have been shown in both in-vivo and in-vitro studies to exhibit 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) (TCDD) like behavior by binding to the Ah receptor. Noncoplanar PCBs (nonTCDD like PCBs) show little affinity for the Ah receptor; however, nonTCDD like PCBs that appear in the brain following in-vivo exposure have a high potency for decreasing brain dopamine levels. The effects of PCBs other than on neurotransmitters were also discussed. PCBs have been shown to inhibit calcium homeostasis and induce changes in thyroid function. The effects on thyroid function during development are thought to represent a possible mechanism for some of the PCB induced developmental effects seen in humans and in animal experiments. Future research needs for PCB neurochemical research were summarized. (Tilson et al, 1997)

Study #20

decreased dopamine content
interfered with calcium homeostatic mechanisms and intracellular second messenger systems

Like dioxin, some polychlorinated biphenyl (PCB) congeners produce toxicity by binding to an aryl hydrocarbon (Ah) receptor. Other PCB congeners that have little or no activity at the Ah receptor have been shown to accumulate in the brain following in vivo exposure and decrease dopamine content. Subsequent research has found that non-dioxin-like PCBs also interfere with calcium homeostatic mechanisms and intracellular second messenger systems in vitro in neuronal cultures and brain subcellular fractions. The biological significance of these effects of PCBs in nervous system preparations is not known, although a number of calcium-dependent processes are important for nervous system function and development. Structure-activity relationship (SAR) studies based on measures of PCB-induced alterations in protein kinase C (PKC) translocation and Ca2+-buffering indicate that congeners with chlorine substitutions at the ortho-position are active in vitro, while non-ortho congene (abstract incomplete) (Tilson et al, 1998)

Study #21

only non-coplanar PCB congeners reduce dopamine content in the adult central nervous system
both coplanar and non-coplanar PCBs alter brain dopamine during development
either increases or decreases in brain dopamine concentrations induce deficits in working memory
study used PCBs 47, 77, and 126

Polychlorinated biphenyls (PCBs) have been associated with cognitive deficits in perinatally-exposed humans and behavioral and neurochemical changes in animals. In order to determine the relationship between PCB congener structure and neurotoxic effect, we have exposed both cells in culture and animals to individual PCB congeners. Using pheochromocytoma cells we have shown that only non-coplanar PCBs reduce cellular dopamine (DA) content. Similarly, only non-coplanar PCB congeners reduce DA content in adult rat striatal slices. Finally, exposure of the adult non-human primate to complex mixtures of PCBs decreases brain DA content with brain PCB residues consisting of only non-coplanar PCBs--suggesting that the reductions in brain DA are due to these congeners. We hypothesize that only non-coplanar PCB congeners reduce DA content in the adult central nervous system. However, both coplanar and non-coplanar PCBs alter brain DA during development: perinatal exposure to a non-coplanar congener (2,2',4,4'-TCB) decreases brain DA while coplanar congeners (3,3',4,4'-TCB and 3,3',4,4',5-PCB) elevate brain DA. These age-dependent differences in the neurochemical effects of structurally-disparate PCB congeners may involve effects on: (i) DA synthesis (mediated by changes in intra-cellular signal transduction pathways?) and (ii) neuroendocrine systems that modulate the development of biogenic amine neurotransmitters. In turn, either increases or decreases in brain DA concentrations induce deficits in working memory. (Seegal et al, 1998)

Study #22

significant decreases in levels of dopamine
study used PCBs 77 and 118

A study was conducted on the toxic effects of 3,3',4,4'-tetrachlorobiphenyl (32598133) (PCB-77) and 2,3',4,4',5-pentachlorobiphenyl (32598144) (PCB-118) following dietary exposure. The effects of PCB-77 and PCB-118 on various biological parameters were assessed following treatment of Sprague-Dawley-rats with up to 10,000 parts per billion (ppb) PCB-77 or PCB-118 for 13 weeks. No clinical evidence of toxicity was observed. Increases in the absolute and relative spleen weights of male rats treated with 1,000 or 10,000ppb PCB-77 were noted. Treatment related biochemical changes included increases in the activity of hepatic microsomal ethoxyresorufin-O-deethylase in animals treated with the highest doses of PCB-77 or PCB-118. A significant decrease in the liver vitamin-A content was seen as well in animals treated with the highest dose of PCB-77. An increase in the concentration of 3,4-dihydroxyphenylacetic-acid was seen in the brains of males exposed to the highest dose of PCB-77 while females treated with 2,000ppb PCB-118 exhibited significant decreases in levels of dopamine and homovanillic-acid in selected areas of the brain. Histopathologic treatment related alterations were identified in the livers, thyroid glands, spleens, kidneys, and bone marrow of both PCB-77 and PCB-118 treated animals. A dose dependent accumulation of PCB-118 was noted in the fat and liver of treated animals with lower levels identified in the kidneys, brains, and hearts. In contrast, measurable PCB-77 levels were detected only in the fat and liver of the highest dose animals. Based on these data the no observed adverse effect level for PCB-77 was calculated to be 100ppb in the diet or 8.7 micrograms/kilogram body weight per day while that for PCB-118 was 200ppb in the diet or 17 micrograms/kilogram body weight per day. (Chu et al, 1995)

Study #23

one dose of modest PCB levels during pregnancy effects dopamine regulation in the offspring
study used PCB 169 and total PCBs

Polychlorinated biphenyls (PCBs) and dioxins are potentially toxic compounds which occur widely in the environment. Their effects on the growth and development of infants at the levels currently found in highly industrialised western countries is not well known. This Dutch multicenter study, combining animal and human studies, tries to answer this question. Animal studies showed that PCB 169, given once during pregnancy at a dose of 1.8 g kg-1 bodyweight, has an effect on developmental parameters, dopamine regulation and fertility. Effects on thyroid hormones were also found in animals, probably due to both a competitive binding of PCB metabolites to the thyroxine binding protein and increased glucuronidation. Perhaps to compensate for this, an increased diodase activity in the brain was found. Human studies involved 400 mother-infant pairs, half of them being breast-fed, the other half were fed a formula devoid of PCBs and dioxins. PCB levels were measured in serum and dioxin and PCB levels in breastmilk. Levels were found to be as high as previously found in highly industrialised countries. Growth and development were carefully documented, but no data are as yet available. In pregnant women, a significant negative correlation was found between some dioxin and PCB congeners in milk and plasma thyroid hormones, while newborn infants showed higher thyroid stimulating hormone (TSH) at higher levels of dioxin exposure. In summary, data from this combined multicenter study involving animals and humans increases our insight into the potentially negative effects of PCBs and dioxins on growth and development. (Sauer et al, 1994)

Study #24

decreased cell dopamine
altered locomotor activity and decreased brain dopamine function
study used PCBs 4 and 126

Some polychlorinated biphenyls (PCBs) have been reported to alter locomotor activity and decrease brain dopamine function in laboratory animals. PCBs with ortho- and/or parachlorine substitutions and varying number of chlorinations are known to decrease cell dopamine content in vitro and have been detected in brains of animals exposed to PCBs, suggesting that the neurotoxicity could be mediated by ortho-substituted congeners. Dopamine or other neurotransmitter uptake and release phenomena are dependent on the maintenance of intracellular Ca2+ homeostasis, and perturbations in Ca2+ homeostasis could lead to altered cell function and/or death. We compared the effects of two PCB congeners on Ca2+ homeostasis in cerebellar granule cells: 2,2'-dichlorobiphenyl (DCBP), a putative neurotoxic congener, and 3,3',4,4',5-pentachlorobiphenyl (PCBP), a presumed nonneurotoxic congener. In cerebellar granule cells (6-8 days in vitro), DCBP was cytotoxic as indicated by a significant increase in LDH leakage at 200 m (abstract incomplete) (Kodavanti et al, 1993)

Study #25

dopamine function in offspring is altered by PCBs in both the womb and/or through breastfeeding
dopamine changes persist even when PCBs are no longer found in the brain
lower-chlorinated ortho-substituted PCBs affect dopamine levels (therefore, they’re not as "non-toxic" as some believed)
study used PCB commercial mixture Aroclor 1016 --- PCBs 28 and 47 were found in the brain

We have determined the neurochemical sequelae of perinatal exposure of the rat to Aroclor 1016 in order to assess the role that lightly chlorinated PCBs play in altering nervous system function. Offspring of Wistar-derived rats were exposed from either day 9 of gestation to birth (gestational exposure) or from birth to weaning (lactational exposure) via maternal exposure to rat chow containing either 30 or 100 ppm of Aroclor 1016. Offspring were sacrificed at various ages and their brains analyzed for dopamine (DA) by HPLC with electrochemical detection and PCB concentrations determined by glass capillary GC with electron capture detection. In contrast to the decreases in DA concentrations observed following adult exposure, perinatal exposure significantly increased brain DA concentrations. Brain PCB levels increased with dose with the highest levels seen in lactationally-exposed animals. The major congeners in brain were 2,4,4' and 2,4,2',4'. PCBs could not be detected in the brains of animals beyond 35 days of age, although DA continued to be elevated. These results demonstrate that ortho-substituted PCBs are neuroteratogens, that despite higher PCB levels in lactationally-exposed animals both gestational and lactational exposure similarly altered dopamine function and that these changes in neurochemical function persisted in the absence of PCBs in brain. (Seegal, 1992)

Study #26

ortho-substituted PCBs bind to (and interfere with) important sites for brain chemical formation, including dopamine
study examined PCBs 1, 4, 10, 19, 54, and 153

Ortho-Substituted polychlorinated biphenyls (PCBs) make up a large part of the PCB residue found in the environment and human tissues. Our laboratory as well as others have demonstrated that ortho-substituted congeners exhibit important biological activities by aryl hydrocarbon (Ah) receptor-independent mechanisms, including changes in second messenger systems necessary for normal cell function and growth. Previous structure-activity relationship (SAR) studies on second messengers and transthyretin (TTR; prealbumin) binding focused little attention on the ortho-substituted PCBs. Disruption of thyroid hormone (TH) transport is one potentially important mechanism by which PCBs can alter TH homeostasis. A more systematic study of PCB binding to TTR, a major TH transport protein, was undertaken, in which the role of ortho-substitution was more thoroughly investigated. Results from this study indicated that the ortho-only substituted PCB series showed significant binding activity and the relative affinities were 2,2',6 > 2,2' = 2,6 >> 2 = 2,2',6, 6'. As anticipated on the basis of steric considerations, bromine was shown to be more active as an ortho-substituent where the relative affinity of 2,2'-Br was equivalent to 2,2',6-Cl. The congener patterns (di-meta-substitution in one or both rings) most closely resembling the diiodophenolic ring of thyroxine (T(4)) showed the highest binding activity. Multiple ortho-substituents were shown to decrease binding activity in such patterns. Congener patterns (single meta-substitution in one or both rings) more closely resembling the monoiodophenolic ring of T(3) showed significantly lower binding activity, consistent with the relatively low binding activity of T(3) and smaller size of chlorine compared to iodine. The addition of ortho-substitution to such patterns gave variable results depending on the substituent relationship (adjacency or nonadjacency) to the pattern. Some patterns such as 2, 2',4,4',5,5' showed good binding activity and represent common congeners in the commercial Aroclor mixtures and in the environment. The binding potencies of ortho-PCBs to TTR may represent a signature SAR that predicts specific biologic/toxic effects. In this regard, the binding potencies were consistent with measured biological activities of these PCBs, including effects on cell dopamine content, Ca(2+) homeostasis, and protein kinase C translocation in neuronal cells and brain homogenate preparations. (Chauhan et al, 2000)

Study #27

PCB induced behavioral changes may in part be caused by an alteration in brain dopamine concentration.
fetus or newborn PCB exposure results in increased neurotransmitter concentrations while adult exposure results in decreased concentrations
dopamine was decreased through inhibition of tyrosine-hydroxylase activity
PCB exposed monkeys were learning impaired on spatial tasks but facilitated learning on object tasks
PCB effects are not easily comparable to dioxin --- therefore, toxic equivalency factors (TEFs) are not appropriate
study used PCB commercial mixture Aroclor 1016 and 1248

The neurotoxic risk and behavioral effects of exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) in complex mixtures were reviewed. In comparing the toxicological effects of ortho substituted and coplanar PCB congeners, the inappropriateness of using a toxic equivalency factor (TEF) based on molecular planarity to assess risk was addressed. Epidemiological studies of PCB perinatally exposed children were mentioned. Electrophysiology, neurobehavioral toxicology, measurement of neuroanatomical changes, and neurochemical toxicology were described as methods to assess changes in neurosystem function due to environmental toxicants. The biochemistry and measurement of dopamine (DA) and its association with PCB exposure was explained. Neurochemical results of PCB congener exposure suggested that perinatal exposure results in increased neurotransmitter concentrations while adult exposure results in decreased concentrations. In-vitro studies described demonstrated that decreased DA levels were caused by the inhibition of tyrosine-hydroxylase activity by ortho substituted PCB congeners. A study of the behavioral effects of rhesus-monkey transplacental and transmammary exposure to Aroclor-1016 (12674112), Aroclor-1248 (12672296), or 2,3,7,8-tetrachlorodibenzo-p-dioxin (1746016) (TCDD) was described. The toxicants were conventionally assigned TEFs of 0, 0.00002, and 1, respectively. Behavior tests demonstrated that PCB exposed monkeys were learning impaired on two spatial tasks but showed facilitated learning on an object task. In contrast, TCDD exposed monkeys were learning impaired on object tasks but showed facilitated learning on spatial tasks. As the effect of Aroclor-1016, a mixture of ortho substituted PCBs, was comparable to Aroclor-1248, containing Ah active congeners, the use of TEF was again questioned. The authors conclude that PCB induced behavioral changes may in part be caused by an alteration in brain DA concentration. (Seegal et al, 1994)

Study #28

Great Lakes fish significantly reduce brain dopamine levels, causing deficits in brain function in children of fish-eating mothers
PCBs reduce brain dopamine levels in the lab, but at much higher PCB doses than found in Great Lakes fish
other contaminants present in Great Lakes fish may interact synergistically with PCBs to produce greater neurotoxicity
PCBs may serve as a marker for other contaminants responsible for the observed effects
study measured total PCBs in fish, but used only one type (PCB 47) in the lab [Researcher may have missed important types of PCBs in the fish]

Epidemiological studies have demonstrated an association between consumption, by women, of contaminated Great Lakes salmon and deficits in cognitive performance in the children of these women. Although significant statistical associations between polychlorinated biphenyl (PCB) body burdens and these negative outcomes suggest that PCBs may be responsible, the fetus and neonate are also exposed to other fish-borne neurotoxicants. In this manuscript we present data from two developmental studies that support the hypothesis that PCBs may serve either as a marker for other contaminants that are responsible for the observed effects, or that other contaminants present in the fish interact synergistically with the PCBs to produce the observed neurotoxicity. In the first study we demonstrated that exposure of rats to diets containing lyophilized Great Lakes salmon, resulting in exposure to as little as 13.9 micrograms/(kg small middle dotday) of total PCBs, induced significant reductions in regional brain dopamine (DA) concentrations. In the second study, we demonstrated that exposure of rats to the ortho-substituted PCB congener (2,4,2', 4'-tetrachloro- biphenyl) at 1, 10 or 20 mg/(kg small middle dotday) also induced significant reductions in DA concentrations in the same brain regions although only at the two highest doses-levels at least 100-fold higher than seen in the first study. On the basis of these developmental neurochemical studies we suggest that the reported cognitive deficits in children exposed in utero and during lactation to fish-borne contaminants may be due either to contaminants other than PCBs or to complex interactions between PCBs and other neurotoxicants present in the fish. (Seegal, 1999)

Study #29

PCBs decrease cell dopamine levels through interaction at brain sites which prefer ortho substituted or ortho,para substituted PCB congeners
PCBs, and not their metabolites, are the toxicants
study examined 43 types of PCBs

The structure/activity relationship for various polychlorinated biphenyl (PCB) congeners was described through measures of cell dopamine content to test the neurotoxic capabilities of ortho substituted PCB congeners. Cultured PC12 cells were treated with 10 to 200 micromolars of 43 individual PCB congeners. After 6 hours of exposure, the cells were removed, washed and cellular catecholamines were extracted. Dopamine levels were determined by high performance liquid chromatography with electrical detection and PCB analysis was conducted via gas chromatography. Neurotoxic action of the congeners was assessed through decreases in cell dopamine content. Results showed that the most potent congeners were those with ortho chlorine or ortho,para chlorine substitutions. Chlorination in the meta position was associated with reduced dopamine content in ortho substituted congeners but little effect in ortho,para substituted congeners was seen. Increases in congener chlorination were not paralleled by potency decreases although total chlorination of a ring did seem to reduce potency. No association was exhibited between potency and cellular PCB content or gas chromatographic retention time. Results indicated that PCBs, and not their metabolites are the toxicants. The authors conclude that PCBs decrease cell dopamine content through interaction at sites characterized by a preference for ortho substituted or ortho,para substituted congeners. (Shain et al, 1991)

Study #30

PCBs inhibit tyrosine hydroxylase and L-aromatic amino acid decarboxylase, two enzymes involved in the synthesis of dopamine.
PCBs did not appear to disrupt the pattern of receptor development, and did not appear to result in up regulation.
study used PCB commercial mixture Aroclor 1254

Polychlorinated biphenyls (PCBs) are a class of halogenated aromatic hydrocarbons that have been shown to cause neurological dysfunction in humans and laboratory animals. PCBs have been shown to inhibit tyrosine hydroxylase and L-aromatic amino acid decarboxylase, two enzymes involved in the synthesis of dopamine. This inhibition may lead to a decrease in dopamine concentration. This project explores the possibility that dopamine receptors may up regulate in order to compensate for the postulated decrease in dopamine concentration. Pregnant Sprague-Dawley rats were administered 4 mg/kg/day Arochlor 1254 in safflower oil p.o. beginning on gestation day 6 and ending on post-natal day 22. Pups from each group were sacrificed at post-natal days 15, 23, 31, or 70, and brains were removed and frozen for subsequent receptor analysis. Bmax and Kd for D1 and D2 receptors were determined in membrane preparations from the corpus striatum for each group using 3H-SCH 23390 and 3H-spiperone, respectively. Receptor binding analysis indicated no apparent change in Bmax and Kd values for ages 23, 31 and 70 days. However, there were differences in the age 15 day animals. A slight decrease was noted in the D1 receptor Bmax1 but the Kd was unchanged. The D2 receptor Bmax and Kd values were both decreased. The treatment with PCBs did not appear to disrupt the pattern of receptor development, and did not appear to result in up regulation. (Guarisco et al, 1999)

Study #31

decreased dopamine concentration
females appear more sensitive than males
study used PCB 28

The toxicity of 2,4,4'-trichlorobiphenyl (PCB 28) was investigated in rats after a 90-d dietary exposure. Groups of 10 male and 10 female weanling Sprague-Dawley rats were administered PCB 28 in the diet at 0, 0.05, 0.50, 5.0, or 50.0 ppm for 13 wk. Growth rate and food consumption were not affected by treatment, and no clinical signs of toxicity were observed. Mottled liver was noted in both control and PCB-treated males, but was found with increased incidence in the highest treatment group. Increased urinary ascorbic acid and hepatic microsomal ethoxyresorufin O-deethylase activity were observed in the 50.0 ppm group of both sexes. The vitamin A content in liver, lung, and kidney was not significantly affected by treatment. Analysis of brain biogenic amines showed a decreased dopamine concentration in the substantia nigra region of female rats receiving 0.5 ppm PCB 28 and higher doses. Female rats appeared to be more sensitive than males to the neurochemical effects of PCB 28. Dose-dependent histol (abstract incomplete) (Chu et al, 1996)

Study #32

PCBs reduce tissue dopamine and elevate media dopamine

Consumption of contaminated Great Lakes fish by pregnant women is associated with decreased birth weight and deficits in cognitive function in their infants and children. These fish contain many known and suspected anthropogenic neurotoxicants, making it difficult to determine which contaminant(s) are responsible for the observed deficits. We have undertaken a series of experiments to determine the relevant toxicants by comparing the neurotoxic effects of two of these contaminants--polychlorinated biphenyls (PCBs) and methylmercury (MeHg)--both of which are recognized neurotoxicants. Striatal punches obtained from adult rat brain were exposed to PCBs only, MeHg only, or the two in combination, and tissue and media concentrations of dopamine (DA) and its metabolites were determined by high performance liquid chromatography. Exposure to PCBs only reduced tissue DA and elevated media DA in a dose-dependent fashion. Exposure to MeHg only did not significantly affect either measure. However, when striatal (abstract incomplete) (Bemis et al, 1999)

Study #33

the mature mammalian nervous system is sensitive to a brief exposure to PCBs
PCBs alter dopamine levels differently in different areas of the brain
study used PCB commercial mixture Aroclor 1254 and 1260

Adult male rats were gavaged with a mixture of polychlorinated biphenyls (PCBs; Aroclors 1254 and 1260) at either 500 or 1000 mg/kg body weight. Concentrations of dopamine (DA) and its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in caudate nucleus and lateral olfactory tract on postgavage Days 1, 3, 7 and 14. DA and DOPAC concentrations in caudate decreased after exposure to PCBs, as did HVA ratios. DA concentrations in the lateral olfactory tract were unaffected, although DOPAC/DA ratios decreased. These results demonstrate that the mature mammalian nervous system is sensitive to a brief exposure to PCBs and that regional differences exist in the neurochemical sequelae of exposure to PCBs. (Seegal et al, 1986)

Study #34

the variable composition of PCB residues in the environment and different PCB mechanisms of toxicity complicate the development of scientifically based regulations and risk assessments.

Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, and toxic contaminants in the environment. Individual PCB congeners exhibit different physicochemical properties and biological activities that result in different environmental distributions and toxicity profiles. The variable composition of PCB residues in environmental matrices and their different mechanisms of toxicity complicate the development of scientifically based regulations for the risk assessment. In this article various approaches for the assessment of risks of PCBs have been critically examined. Recent developments in the toxic equivalency factor (TEF) approach for the assessment of toxic effects due to dioxin-like PCBs have been examined. PCB exposure studies that describe non-dioxin-like toxic effects, particularly neurobehavioral effects and their effective doses in animals were compiled. A comparative assessment of effective doses for dioxin-like and non-dioxin-like effects by PCBs has been made to evaluate the relati (abstract incomplete) (Giesy et al, 1998)

Study #35

PCBs block dopamine synthesis by inhibiting tyrosine hydroxylase (which produces a chemical called L-dopa, which in turn stimulates production of dopamine.)
PCBs may also interfere with vesicular monoamine transporter (affecting storage or release of dopamine)
study used PCB commercial mixtures Aroclor 1254 and 1260

Striatal slices from adult male Wistar-derived rats were exposed to a 1:1 mixture of Aroclor 1254:1260 at concentrations in media of 10, 20, 40, 60 or 100 ppm for 6 hr. Following exposure, slices and media were analyzed by high-performance liquid chromatography for dopamine (DA) and its metabolites. PCBs caused a significant dose-dependent decrease in slice DA content at concentrations greater than 20 ppm. Media concentrations of DA and its metabolites were significantly increased by PCB exposure greater than 60 ppm, indicating that, in addition to their suggested role in inhibiting DA synthesis, PCBs may interfere with either vesicular storage or release of DA. These data suggest that in addition to the recognized action of PCBs in inhibiting tyrosine hydroxylase, PCBs may also interfere with the vesicular monoamine transporter, and thereby suggest an additional mechanism by which DA concentrations and metabolism may be altered by PCB exposure. (Chishti et al, 1996)

Study #36

PCBs did not cause any significant changes in dopamine concentrations
study used PCB commercial mixture Aroclor 1016

Several reports have indicated that polychlorinated biphenyls (PCB) alter development of biogenic amines in the brain, impair behavioral performance and disrupt maturation of the thyroidal axis. The current study examines whether these developmental effects of PCB are correlative. Timed pregnant Long-Evans rats were gavaged with the PCB mixture Aroclor 1016 (10 mg/kg) daily from GD 6 to term. After parturition, the nursing dams continued to receive PCB for two more days. Thereafter, PCB was given directly to the pups daily (10 mg/kg, p.o.) for duration of the study. At various ages from PD 2 to PD 28, rats were sacrificed and six brain regions (pre-frontal cortex, striatum, hippocampus, diencephalon, cerebellum, midbrain + brainstem) were removed and analyzed for dopamine (DA) and norepinephrine (NE) concentration by HPLC. Serum samples were collected and analyzed for triiodothyronine (T3) and thyroxine (T4) by radioimmunoassay. Behaviorally, rats were evaluated for spatial learning and memory task with T-maze and Morris maze tests on PD 23 and PD 70 respectively. Under this dose and treatment design, Aroclor 1016 produced small but persistent shortfalls in neonatal body weight gain, although brain region weights were not affected. PCB also did not cause any significant changes in DA or NE in any of the brain regions examined. Correspondingly, both control and PCB-treated rats performed with equal proficiency in the T-maze and the Morris maze. In contrast, Aroclor 1016 treatment produced a significant reduction of total serum T4 in the rat pups, although circulating T3 remained unaffected. The reduction of thyroxine was transient and became attenuated by weaning despite the continuous PCB treatment. Our results are generally consistent with previous findings of PCB-induced thyrotoxicity, but these effects are not accompanied by significant perturbations of catecholamine systems in the developing brain or demonstrable neurobehavioral deficits. (Zahalka et al, 1994)

Study #37

PCBs increased serum levels of dopamine

The effects of dietary polychlorinated biphenyls (PCB) and excess tyrosine on serum and liver lipids, urinary ascorbic acid and catecholamines were compared in male Wistar rats. Serum levels of cholesterol, urinary ascorbic acid, norepinephrine, epinephrine, dopamine and histamine were significantly increased in rats given either PCB or excess tyrosine. The hypercholesterolaemia induced by PCB or excess tyrosine was blocked by the adrenergic alpha-blocker, phenoxybenzamine. The present results suggest causal interrelations between the hypercholesterolaemia induced by dietary PCB or excess tyrosine and the secretion of catecholamines. (Nagoaka et al, 1986)

Study #38

cell suicide is a sensitive and early indicator of acute and chronic chemical stress, loss of cellular function and structure, and organismal health

The process of apoptosis, often coined programmed cell death, involves cell injury induced by a variety of stimuli including xenobiotics [manmade chemicals] and is morphologically, biochemically, and physiologically distinct from necrosis. Apoptotic death is characterized by cellular changes such as cytoplasm shrinkage, chromatin condensation, and plasma membrane asymmetry. This form of cell suicide is appealing as a general biomarker of response in that it is expressed in multiple cell systems (e.g. immune, neuron formation or xenobiotic stress.) Studies reviewed here suggest that apoptosis is a sensitive and early indicator of acute and chronic chemical stress, loss of cellular function and structure, and organismal health. Examples are provided of the application of this methodology in studies of health of lake trout (Salvelinus namaycush) in the Laurentian Great Lakes. (Sweet et al, 1999)

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