Novel inter-hemispheric white matter connectivity in the BTBR mouse model of autism.

Alterations in the volume, density, connectivity and functional activation of white matter tracts are reported in some individuals with autism and may contribute to their abnormal behaviors. The BTBR (BTBR T+tf/J) inbred strain of mouse, is used to model facets of autism because they develop low social behaviors, stereotypical and immune changes similar to those found in people with autism. Previously, it was thought a total absence of corpus callosal interhemispheric connective tissues in the BTBR mice may underlie their abnormal behaviors. However, postnatal lesions of the corpus callosum do not precipitate social behavioral problems in other strains of mice suggesting a flaw in this theory. In this study we used digital pathological methods to compare subcortical white matter connective tracts in the BTBR strain of mice with those found in the C57Bl/6 mouse and those reported in a standardized mouse brain atlas. We report, for the first time, a novel connective subcortical interhemispheric bridge of tissue in the posterior, but not anterior, cerebrum of the BTBR mouse. These novel connective tissues are comprised of myelinated fibers, with reduced myelin basic protein levels (MBP) compared to levels in the C57Bl/6 mouse. We used electrophysiological analysis and found increased inter-hemispheric connectivity in the posterior hemispheres of the BTBR strain compared with the anterior hemispheres. The conduction velocity was slower than that reported in normal mice. This study shows there is novel abnormal interhemispheric connectivity in the BTBR strain of mice, which may contribute to their behavioral abnormalities.

Developmental PCB exposure induces hypothyroxinemia and sex-specific effects on cerebellum glial protein levels in rats.

Polychlorinated biphenyls (PCBs) are persistent lipophilic environmental contaminants which are found in fatty tissues of humans and wild-life alike. Maternal transfer of PCBs to offspring is easily achieved across the placenta and via lactation. In male rats, perinatal PCB exposure induces behavioral abnormalities, in addition to hypothyroxinemia and white matter changes. There are sex differences in white matter volume synthesis and density in adult and aged rodents. Yet whether PCB exposure effects on white matter are sex-specific is unclear, because the previous studies were conducted in male offspring. Furthermore, although hypothyroxinemia induced by PCB exposure is thought to trigger white matter changes, PCBs also affect interleukin-6 (IL-6) expression, and IL-6 regulates white matter growth. We hypothesized that perinatal PCB exposure would have sex-specific effects on white matter development associated with altered IL-6 levels. We found that female offspring had higher levels of myelin basic protein (MBP) than males did, at postnatal day (PND) 7, 18 and 21. PCB exposure induced hypothyroxinemia in males and females at PND7, 14, 21, and 42. PCB exposure also increased MBP and reduced glial fibrillary acidic protein (GFAP) levels in males at PND21, but had the opposite effect in females. In addition, at PND14 and 21, PCB exposure elevated IL-6 levels in male offspring only. The induction of sex-specific changes in white matter proteins, in the absence of sex differences in thyroxine levels after PCB exposure, suggests that serum thyroxine levels do not directly contribute to the white matter alterations. Instead, IL-6 may contribute to increased MBP levels in males, whereas in females estromimetic and thyromimetic PCB metabolites may affect white matter development. This data adds to an increasing body of literature showing that perinatal insults induce sex-specific effects in offspring.

Sex effects of interleukin-6 deficiency on neuroinflammation in aged C57Bl/6 mice.

High levels of Interleukin-6 (IL-6) are associated with an increased risk of dementia in the elderly and can increase neuroinflammation in mice. Dementia is more frequent in females, and IL-6 is regulated by estrogen, suggesting that elevated IL-6 levels may contribute to neuroinflammation and dementia particularly in women. Therefore we hypothesized that IL-6 deficient ((-/-)) female mice would have lower aging-related neuroinflammation than wild type (WT). We quantified neuroinflammatory markers which are affected by aging, and regulated by both estrogen and IL-6; glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), interferon gamma (IFNgamma), lipid peroxidation (MDA), and synaptic density (SNAP25) and in IL-6(-/-) and WT C57Bl/6 mice. To determine age effects we used mid-age (18months) and old-age (24months) mice, and to determine region specific effects we used the hippocampus which is impaired in dementia and the cerebellum which is unimpaired in dementia. Unexpectedly, there were no effects of IL-6 deficiency on GFAP, MDA or SNAP25 levels in females, but IL-6 deficiency was associated with lower cerebellar MBP (p<0.05) levels. Interestingly, the old-aged IL-6(-/-) males had higher GFAP and MDA levels (p<0.05) in both the hippocampus and cerebellum, in addition to a greater body weight than WT. We suggest that IL-6 is important for promoting myelin synthesis in aged females, and that drugs which inhibit the synthesis of IL-6 in males may inadvertently affect fatty acid metabolism and augment aging-related neuroinflammation.

Reduced glutathione is highly expressed in white matter and neurons in the unperturbed mouse brain--implications for oxidative stress associated with neurodegeneration.

Oxidative stress is implicated in the pathogenesis of many neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. The depletion of glutathione (GSH) a powerful antioxidant renders cells particularly vulnerable to oxidative stress. Isolated neuronal and glial cell culture studies suggest that glia rather than neurons have greatest reserves of GSH, implying that neurons are most sensitive to oxidative stress. However, pathological in vivo studies suggest that GSH associated enzymes are elevated in neurons rather than astrocytes. The active, reduced form of GSH is rapidly degraded thus making it difficult to identify the location of GSH in post-mortem tissue. Therefore, to determine whether GSH is more highly expressed in neurons or astrocytes we perfused mouse brains with a solution containing NEM which reacts with the sulfhydryl group of GSH, thus locking the active form in situ, prior to immunostaining with an anti-GS-NEM antibody. We obtained brightfield and fluorescent digital images of sections stained with DAPI and antibodies directed against GS-NEM, glial fibrillary acidic protein (GFAP) in regions containing the hippocampus, striatum, frontal cortex, midbrain nuclei, cerebellum and reticular formation neurons. GSH was most abundant in neurons and white matter in all brain regions, and only in occasional astrocytes lining the third and fourth ventricles. High levels of GSH in neurons and white matter, suggests astrocytes rather than neurons may be particularly vulnerable to oxidative stress.

Effects of an ethanol-gasoline mixture: results of a 4-week inhalation study in rats.

The inhalation toxicity of an ethanol-gasoline mixture was investigated in rats. Groups of 15 male and 15 female rats were exposed by inhalation to 6130 ppm ethanol, 500 ppm gasoline or a mixture of 85% ethanol and 15% gasoline (by volume, 6130 ppm ethanol and 500 ppm gasoline), 6 h a day, 5 days per week for 4 weeks. Control rats of both genders received HEPA/charcoal-filtered room air. Ten males and ten females from each group were killed after 4 weeks of treatment and the remaining rats were exposed to filtered room air for an additional 4 weeks to determine the reversibility of toxic injuries. Female rats treated with the mixture showed growth suppression, which was reversed after 4 weeks of recovery. Increased kidney weight and elevated liver microsomal ethoxyresorufin-O-deethylase (EROD) activity, urinary ascorbic acid, hippuric acid and blood lymphocytes were observed and most of the effects were associated with gasoline exposure. Combined exposure to ethanol and gasoline appeared to exert an additive effect on growth suppression. Inflammation of the upper respiratory tract was observed only in the ethanol-gasoline mixture groups, and exposure to either ethanol and gasoline had no effect on the organ, suggesting that an irritating effect was produced when the two liquids were mixed. Morphology in the adrenal gland was characterized by vacuolation of the cortical area. Although histological changes were generally mild in male and female rats and were reversed after 4 weeks, the changes tended to be more severe in male rats. Brain biogenic amine levels were altered in ethanol- and gasoline-treated groups; their levels varied with respect to gender and brain region. Although no general interactions were observed in the brain neurotransmitters, gasoline appeared to suppress dopamine concentrations in the nucleus accumbens region co-exposed to ethanol. It was concluded that treatment with ethanol and gasoline, at the levels studied, produced mild, reversible biochemical hematological and histological effects, with some indications of interactions when they were co-administered.

Early development of the serotonergic and dopaminergic nervous system in Spisula solidissima (surf clam) larvae.

We have defined the development of the serotonergic and dopaminergic components of the central nervous system in the early Spisula solidissima (surf clam) embryo using HPLC and immunocytochemistry. HPLC analysis reveals norepinephrine, dopamine, and serotonin are present at 24 h post-fertilization. Immunocytochemistry shows that the serotonergic nervous system emerges during the late trochophore stage with the development of a single serotonergic cell, C/A1, in the cerebral/apical ganglion. After 48 h, a second serotonergic cell forms, C/A2, which is connected to C/A1 by two serotonergic processes, and a single serotonergic cell emerges in the visceral ganglion, V1. At 72 h, a new serotonergic cell body develops in the cerebral/apical ganglion, C/A3. After 96 h, the cerebral/apical ganglion and visceral ganglion are connected by a serotonergic process. Expression of the dopamine receptor, D2, begins by 24 h with a generalized expression in the region of the developing gut. D2 expression in the gut ceases by 48 h. At 48 h, a network of fibers forms dorsolateral to the mouth. By 72 h, D2 expressing projections emerge from this network.

Spatial reversal learning in Aroclor 1254-exposed rats: sex-specific deficits in associative ability and inhibitory control.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants that have been associated with cognitive deficits in children exposed in utero. Cognitive deficits due to PCB exposure have also been documented in animal models, but the underlying behavioral mechanisms responsible for those deficits remain to be elucidated. The current study examined the effects of gestational and lactational exposure to PCBs on spatial discrimination-reversal learning (spatial RL) in rats using standard two-lever operant testing chambers. Pregnant Long-Evans rats (10/dose) received either 0 or 6 mg/kg Aroclor 1254 (A1254) po in corn oil from gestational day 6 to postnatal day 21. One male and one female from each litter were tested on spatial RL beginning at 190-220 days of age. Animals were reinforced with a 45-mg food pellet for pressing the lever associated with the correct spatial location (either left or right). After reaching 85% correct performance for 2 consecutive days, the opposite spatial location was reinforced. Five of these position reversals were given. Male rats exposed to A1254 made significantly more total errors (121.6 +/- 12.5) on the first reversal than controls (90.7 +/- 5.8). In contrast, female rats exposed to A1254 exhibited deficits on the fourth and fifth reversals (23.6 +/- 4.2, 17.0 +/- 2.8 and 36.7 +/- 4.7, 26.8 +/- 2.5 for control and exposed animals, respectively). Response-pattern analyses in the A1254-exposed male and female rats revealed fundamental differences in the underlying behavioral mechanisms responsible for the deficits. A1254-exposed males exhibited an increased tendency to incorrectly respond to the previously correct stimulus (i.e., perseverate) following a reversal while A1254-exposed females exhibited impairments in their ability to make new associations with a reinforced spatial location (i.e., associative deficit). These data provide new insights into the underlying behavioral mechanisms that may be responsible for the spatial learning deficits observed in PCB-exposed rodents and monkeys.

The neurotoxicological consequences of developmental exposure to PCBs.

The articles highlighted in this issue are three reports by Kevin Crofton and colleagues dealing with neuromodulatory effects of PCB (Gilbert, Mundy, and Crofton, pp. 102-111; Roegge et al., pp. 121-130; and Crofton et al., pp. 131-140).

Polychlorinated biphenyls and methylmercury alter intracellular calcium concentrations in rat cerebellar granule cells.

Assessments of the effects of exposure of human populations to complex environmental contaminants, such as those found in contaminated fish, necessitate the investigation of contaminant interactions. We have recently demonstrated that polychlorinated biphenyls (PCBs) and methylmercury (MeHg) synergistically reduce rat brain striatal slice dopamine (DA) and increase media DA concentrations in vitro. To better understand the mechanism(s) by which these effects occur we examined the effects of these two contaminants, either alone or in combination, on intracellular calcium concentrations ([Ca2+]) in rat cerebellar granule cells using flow cytometry. Exposure of granule cells to either 2,2'-dichlorobiphenyl (2,2'-DCB) or MeHg dose-dependently increased [Ca2+]i. Granule cells exposed to 1.5 microM MeHg and 2.5 or 5.0 microM 2,2'-DCB showed synergistic increases in [Ca2+]i which were greatest at exposure times of 5 and 10 min. Higher dose combinations, including 2.0 microM MeHg and 10 or 20 microM 2,2'-DCB, or longer duration of exposure to lower concentrations of contaminant mixtures, reduced [Ca2+]i in the granule cells compared to elevations seen following exposure to MeHg only, suggesting a dose-dependent antagonism between PCBs and MeHg. These data provide evidence for the synergistic and antagonistic interactions of PCBs and MeHg at the level of [Ca2+]i regulation that may ultimately lead to alterations in cellular function, including changes in dopamine regulation.

Polychlorinated biphenyls and methylmercury act synergistically to reduce rat brain dopamine content in vitro.

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 punches were simultaneously exposed to PCBs and MeHg, there were significantly greater decreases in tissue DA concentrations and elevations in media DA than those caused by PCBs only, in the absence of changes in media lactate dehydrogenase concentrations. Elevations in both tissue and media 3, 4-dihydroxyphenylacetic acid concentrations were also observed. We suggest that the significant interactions between these two toxicants may be due to a common site of action (i.e., toxicant-induced increases in intracellular calcium and changes in second messenger systems) that influences DA function. The synergism between these contaminants suggests that future revisions of fish-consumption guidelines should consider contaminant interactions.

Differential immune responses in mice with left- and right-turning preference.

Humoral and cell-mediated immune responses of inbred BALB/c male mice were assayed for differential reactivities associated with behavioral sidedness, which was evaluated by spontaneous rotational behavior in a circular cage model system. Mice with left-turning preference had lower in vivo primary IgM and IgG anti-Keyhole Limpet Hemocyanin (KLH) antibody responses, delayed-type hypersensitivity (DTH) responses, and host-resistance against the intracellular bacteria, Listeria monocytogenes, than mice with right-turning preference. The only immune parameter not shown to be associated with turning preference was the secondary humoral immune response to KLH. The weak innate immune response of left-turners for clearance of Listeria showed close intercorrelation with elevated serum IL-6 levels. Serum corticosterone and splenic norepinephrine levels were differentially increased and decreased by infection, respectively. We suggest that the observed differential immune reactivities of individual animals with same age, gender, and genetic background are associated with functional asymmetries within the brain, that the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic innervation are involved in the regulatory brain: immune interconnection after infection, and that the HPA axis and sympathetic nervous system are involved in the brain laterality effects on immune responses.

Are PCBs the major neurotoxicant in Great Lakes salmon?

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.

2,2',6,6'-Tetrachlorobiphenyl is estrogenic in vitro and in vivo.

Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants whose effects on biological systems depend on the number of and the positions of the chlorine substitutions. In the present study we examined the estrogenicity of the fully ortho-substituted PCB, 2,2',6,6'-tetrachlorobiphenyl (2,2',6,6'-TeCB). This PCB was chosen as the prototypical ortho-substituted PCB to test the hypothesis that ortho-substitution of a PCB with no para- or meta-chlorine-substitutions results in enhanced estrogenic activity. The results indicate that 2,2',6,6'-TeCB is estrogenic both in vitro, in the MCF-7 cell focus assay, and in vivo, in the rat uterotropic assay. The estrogenic activity elicited by the addition of 5 microM 2,2',6,6'-TeCB to the medium of MCF-7 cultures was inhibited by the estrogen receptor (ER) antagonist, LY156758, suggesting that 2,2',6,6'-TeCB or a metabolite is acting through an ER-dependent mechanism. Results from competitive binding assays using recombinant human (rh) ER indicate that 2,2',6,6'-TeCB does not bind rhERalpha or rhERbeta. A metabolite of 2,2',6,6'-TeCB, 2,2',6,6'-tetrachloro-4-biphenylol (4-OH-2,6,2',6'-TCB), does bind rhERalpha and rhERbeta and is also 10-fold more estrogenic than 2,2',6,6'-TeCB in the MCF-7 focus assay; however, this metabolite is not detected in the medium of MCF-7 cultures exposed to 2,2',6,6'-TeCB. Taken together, the results suggest that the estrogenicity observed in human breast cancer cells and the rat uterus may be due to 1) an undetected metabolite of 2,2',6,6'-TeCB binding to the ER, 2) 2,2',6,6'-TeCB binding directly to a novel form of the ER, or 3) an unknown mechanism involving the ER.

Subchronic toxicity of PCB 105 (2,3,3',4,4'-pentachlorobiphenyl) in rats.

The toxicity of 2,3,3',4,4'-pentachlorobiphenyl (PCB 105) was investigated in Sprague-Dawley rats following dietary exposure to this substance at levels of 0, 0.05, 0.5, 5 or 50 ppm for 13 weeks. Growth rate and food consumption were not affected and no clinical signs of toxicity were observed. Increased incidences of enlarged, fatty liver and decreased thymic weight were observed in the highest-dose groups of both genders; these groups also had elevated hepatic microsomal ethoxyresorufin deethylase activity and uroporphyrin. Significant increases in serum cholesterol and hepatic pentoxyresorufin dealkylase activity were observed in the highest-dose males and two highest-dose females. By contrast, liver UDP-glucuronosyl transferase activity was elevated in the two highest-dose males and the highest-dose females. Urinary ascorbic acid excretion was increased in the highest-dose males. While the amount of vitamin A was decreased dose-dependently, starting at 0.5 ppm in the liver of both sexes and in the lung of the females, the level in the kidney of the highest-dose group was increased. Administration of PCB 105 resulted in decreased dopamine in the caudate nucleus region of the brain in males and homovanillic acid in caudate nucleus and nucleus accumbens of females. Increased 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in the substantia nigra region of both sexes, with most of the increases being seen in highest-dose females. Anemia, characterized by decreased hemoglobin, hematocrit and red cell indices, occurred in the highest-dose group, as did eosinophilia. Treatment with PCB 105 caused dose-dependent histopathological changes in the liver and thyroid. Thymic changes were observed in the highest-dose males and two highest-dose females. Tissue residue data showed a dose-dependent accumulation of this congener in fat, liver and spleen, kidney and brain. Based on these data the no-observable-effect level of PCB 105 was judged to be 0.05 ppm or 3.9 microg kg(-1) body wt. day(-1) in males and 4.2 microg kg(-1) body wt. day(-1) in females.

Neurobehavioral effects of chronic ingestion of Great Lakes chinook salmon.

Cross-generational chronic feeding of either a 5 or a 20% lyophilized Lake Huron (LH) or Lake Ontario (LO) chinook salmon diet to rats caused no observable effects on many behavioral dimensions including activity, exploration, sensorimotor function, and stereotypy. As assessed by the Morris water maze and the radial arm maze, there was no diet-induced impairment of spatial learning or long-term memory. There was no evidence that the fish diets caused an exaggerated response to food reward reduction as had been observed previously for rats fed Oswego area Lake Ontario salmon. Effects of the fish diets with the exception of one statistically significant but probably meaningless effect on the Morris water maze for females were found only for male rats and only for males who ate the 20% diet. F1 male rats were reluctant to traverse a runway for a single pellet reward. Performance of the reference/working memory version of the radial arm maze was affected for the F1 LO-20 rats and for the F2 LH-20 rats. Until further research is conducted it would be unwise to ignore indications that male rats may show some effect of chronic consumption of the highest concentration of these diets, particularly on tasks that require intact frontocortical dopamine function.

Neurochemical effects of consumption of Great Lakes salmon by rats.

This study, part of a larger project to determine the health consequences of both perinatal and adult exposure to contaminated salmon from the Great Lakes, determined the neurochemical effects of exposure of rats to chow adulterated with lyophilized salmon fillets. Concentrations of biogenic amines, their metabolites, and choline acetyltransferase (ChAT) were determined in the frontal cortex (FC), nucleus accumbens, caudate nucleus (CN), hippocampus (HC), and substantia nigra (SN) of adult rats who had been exposed, both perinatally and as adults, to standard rat chow adulterated with either 5 or 20% (w/w) lyophilized fillets from either Lake Huron (LH) or Lake Ontario (LO) salmon. Dopamine (DA) concentrations in the FC were significantly decreased following exposure to both 20% fish diets. CN DA concentrations were significantly reduced in rats exposed to all diets, while SN DA was decreased only in the LO20-fed animals. SN norepinephrine concentrations were reduced in all groups except for the LO5-fed rats. 3,4-Dihydroxyphenylacetic acid (DOPAC) concentrations in the FC were significantly increased in the LH20 and LO5 groups, while CN DOPAC concentrations were reduced in LH20, LO5, and LO20 animals. 5-Hydroxyindoleacetic acid concentrations were reduced in the FC and CN of all animals exposed to diets adulterated with Great Lakes salmon. ChAT concentrations were unaffected in rats exposed to any of the adulterated diets. The significant reductions in DA, particularly in the FC and CN, suggest that either fish-borne contaminants or consumption of fish, per se, may affect behaviors that require inhibition of normal responding. We conclude that consumption of contaminated fish from the Great Lakes may result in sufficient reductions in biogenic amine function to result in significant deficits in important behavioral functions in the rat and, by inference, in the perinatally exposed human.

Symposium overview: toxicity of non-coplanar PCBs.

Research into the mechanism of toxicity of PCBs has focused on the Ah receptor. However, it is becoming increasingly clear that certain ortho-chlorine-substituted, non-coplanar PCB congeners having low affinity for the Ah receptor exhibit important biological activities. Actions of non-coplanar PCB congeners in a variety of biological systems have been discovered and the mechanisms for these effects are being elucidated. The objectives of this symposium are to examine the state of knowledge concerning the mechanisms of toxic action of non-coplanar PCBs and to identify similarities and differences using a variety of biological systems. Effects to be considered will include: neurotoxicity, estrogenicity, insulin release, neutrophil function, calcium regulation, and relevant signal transduction systems. Finally, the symposium addresses the need to consider non-coplanar congeners within the context of risk assessment. The use of Ah-receptor binding and its associated biological effects to assess the total toxicity of PCBs may no longer be defensible because of the actions produced by non-coplanar congeners. This symposium provides documentation for that conclusion and focuses attention on emerging mechanisms of PCB action that have received relatively little attention to date. The topics presented should be of interest to toxicologists interested in mechanisms of action, in PCB risk assessment, and in regulatory toxicology.

Effects of in utero and lactational exposure of the laboratory rat to 2,4,2',4'- and 3,4,3',4'-tetrachlorobiphenyl on dopamine function.

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.