Abstract  Polychlorinated biphenyls (PCBs) and methylmercury (MeHg) are persistent organic pollutants accumulating in the food chain. Pre- and neonatal exposure to these neurotoxicants may affect brain development and lead to long-lasting alterations in cerebral function, which can result in motor alterations in youth and/or adulthood. Some neurotoxicants induce gender specific effects. The aims of the present work were to: (1) assess the effects of developmental exposure to MeHg, PCB 153 or PCB 126 on spontaneous locomotor and vertical activity and motor coordination when the rats are 2-month old; (2) assess whether perinatal exposure to combinations of MeHg with PCB153 or PCB126 alter the effects of the individual neurotoxicants; (3) follow the progression of motor alterations when the rats are 3-, 5- and 7-month old; (4) assess if the effects are similar or different in males and females. Pregnant rats were treated with MeHg (0.5mg/kgday); PCB126 (100ng/kgday) or PCB153 (1mg/kgday) or with combinations of MeHg with each PCB, administered in food from gestational day 7 until weaning at post-natal day 21. PCB 126 impaired motor coordination at 2 months in males but not in females. PCB 153 impaired coordination both in males and females. Combinations of MeHg with PCB153 or PCB126 did not affect motor coordination, indicating that MeHg counteracts the effects of the PBCs. The combination of MeHg and PCB153 induces hypolocomotion at 2 months but hyperactivity at 7 months while the individual compounds did not induce any effect. PCB126 induced gender selective effects, reducing locomotor activity at 2 months in females but not in males. The combination of MeHg and PCB126 behaves as PCB126 alone. All compounds and combinations tested induce gender-selective alterations in vertical activity. The effects on locomotor and vertical activity change with age in the same rats. At 2 months all compounds and combinations reduce vertical activity in females but not in males. At 7 months all treatments induced hyperactivity both in males and females, except MeHg+PCB126. In conclusion, the results show that: (a) many motor alterations induced by most compounds are different in males and females; (b) mixtures of MeHg with PCBs 153 or 126 induce different effects that the individual compounds; (c) different types of motor activity (spontaneous locomotion, vertical activity and motor coordination) are affected differently by the same neurotoxicant or mixture; and (d) the effects on locomotor and specially on vertical activity change with the age of the rat. Most compounds reduce activity at youth (2 months) and induce hyperactivity at adulthood (5-7 months). The change from hypo- to hyperactivity occurs earlier in males.

Abstract  Adult deer mice testes were subjected to routine histopathology following exposure to Aroclor 1254 supplemented diet (5 ppm), for 30 days. Body and testicular weight revealed no statistical significance between the control and treated animals. From a histological standpoint the testes of the controls were similar to normal murids and other animals. In contrast, the testes from treated animals displayed seminiferous tubules with significant degenerative alterations. These alterations included fewer layers of seminiferous epithelium exaggerated intercellular spaces and appearance of pyknotic nuclei. Most tubules displayed subluminal nuclei that morphologically could be identified as part of spermatozoa heads and these usually lacked tails, indicating that the treatment interfered with spermiogenesis. Therefore, we concluded that Aroclor 1254 as an environmental contaminant is highly destructive to seminiferous tubules, and that these histological alterations undoubtedly are responsible for the depressed fertility in Peromyscus following chronic exposure to PCBs, that has been reported in the literature.

Abstract  The development of second-generation nestling American kestrels (Falco sparverius) was altered by in ovo exposure of only one parent to polychlorinated biphenyls (PCBs). Polychlorinated biphenyls appear to alter nestling development through both maternally and paternally mediated effects. In 1998, F0 parent kestrels consumed approximately 5 to 7 microg total PCBs/g bird/d (Aroclors 1248:1254: 1260) for approximately 100 d prior to eggs hatching; these eggs, containing total PCB concentrations of 34.1 microg/g, produced 13 F1 offspring, which were then paired in 1999 with unexposed kestrels to examine developmental effects of maternal or paternal in ovo PCB exposure. Using a toxicokinetics model, eggs from the maternally exposed group had predicted PCB levels of 0.03 to 0.34 microg/g, with enriched higher chlorinated congeners. Polychlorinated biphenyl concentrations in eggs of all generations have recently been found in eggs and nestlings of free-ranging eagles. Consistent with the first generation, maternally exposed F2 females generally were larger, had altered growth rates, and delayed maximal growth and fledging compared with control females. Maternally exposed F2 males were heavier but had shorter bones, grew more quickly and earlier, and fledged 2 d later than control males. In the maternally exposed group, concentrations of plasma triiodothyronine were elevated in F2 females but suppressed in F2 males. Paternally exposed F2 hatchlings of both sexes were comparable in size to controls with the exception of having longer tarsi bones, but subsequently showed slower, delayed growth (both sexes) and fledging (females) and lower thyroxine concentrations (males). The alterations in thyroid hormones in the F2 generation are discussed in light of the enrichment of higher chlorinated PCB congeners and hydroxylated PCB congeners. The developmental changes in the kestrel nestlings are likely a function of several possible mechanisms involving maternal PCB deposition, parental behavior, and neurobehavioral and endocrine-thyroid function in nestlings.

Abstract  Adult male rhesus monkeys (Macaca mulatta) were given oral treatment of either Aroclor 1242 or vehicle (corn oil and glycerol) at a dose of 200 microg/kg body wt/day for 6 months to investigate the effects of the pollutant on plasma testosterone and the morphology of testes and accessory glands. Aroclor 1242 treatment significantly decreased testicular size and testosterone levels in plasma and adversely affected spermatogenic activity by disrupting epithelial organization. All components of the germinal epithelium were greatly reduced. The spermatogonia were either hypertrophied or had shrunken vesiculated cytoplasm with distorted mitochondria and nuclear pyknosis. Changes were milder in the Sertoli cells, where nuclear infoldings were reduced. Characteristic features of treated Leydig cells were the presence of electron-dense and electron-opaque zones, appearing as plaques, cell membrane abnormalities, and high variability in nuclear shape and heterochromatin distribution. All the Aroclor 1242-treated accessory glands contained more connective tissue than their vehicle-treated counterparts. The epithelium contained many layers of irregularly shaped necrotic cells possessing stereocilia in the epididymides, either hypochromic and hypertrophied or hyperchromic and hypotrophied cells in the prostate and shrunken cuboidal cells with elongated nuclei in the seminal vesicles. In conclusion, Aroclor 1242 treatment causes severe structural alterations on gonads and accessory organs in adult male rhesus monkeys, and these effects could be mediated through both estrogen and Ah receptors.

Abstract  Previous studies have shown that oral exposure of rats to polychlorinated biphenyls (PCBs) results in reduced 5-hydroxytryptamine (5-HT) concentrations in certain brain regions. In the present study, we investigated whether the PCB mixture Aroclor 1254 (0.33 mg/g body weight as a single oral dose) can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in 5-HT synthesis, and reduce 5-HT concentrations in selected brain areas. In two separate experiments, Aroclor 1254 exposure consistently reduced TPH activity in the brainstem (7.2 and 8.7%), frontal cortex (17.4 and 14.8%), and hypothalamus (10.7 and 9.4%) without altering the rats' food intake or growth. Moreover, Aroclor 1254 accumulation in the frontal cortex demonstrated a negative correlation with TPH activity (correlation coefficient -0.82). In addition, 5-HT concentrations decreased in the brainstem and frontal cortex after Aroclor 1254 exposure by 9.1 and 19.7%, respectively. These results suggest that the Aroclor 1254-induced decreases in 5-HT concentrations in certain areas of the rat brain are due to inhibition of TPH activity, similar to our recent observations in Atlantic croaker, and that TPH is one of the targets of PCB neurotoxicity in both fish and mammals.

Abstract  Mature male Sprague-Dawley rats received a single IP injection of either 2,2',4,4',5,5'-hexachlorobiphenyl (HCB), 3,3',4,4'-tetrachlorobiphenyl (TCB) (300 microm/kg) in corn oil (10 ml/kg) or the corn oil vehicle alone, and were killed four days later after having been fasted overnight. The vehicle control group consisted of rats which were allowed free access to feed as well as pair-fed animals. Lipid analyses were conducted on liver, hepatic microsomes and serum. TCB- (but no HCB-) treatment resulted in a statistically significant increase in total liver lipids and triglycerides. Liver phospholipids remained unchanged. Both PCBs increased the cholesterol and phospholipids content of the liver microsomal fraction. Serum lipids measured were not statistically different from control values. While HCB had little effect on the fatty acid composition of liver lipids, TCB caused an increase in C 18:1 (n-9) and a decrease in C 20:4 (n-6). Both PCBs increased C 18:0 in the hepatic microsomal fraction, but TCB also decreased C 16:0. Neither PCB altered the fatty acid composition of serum total lipids. These data are consistent with the concept that specific alterations in lipid metabolism are dependent on the structure of the PCB.

Abstract  One-day-old cockerels were fed: (J) 3,10,30,100, and 300 ppm of 3,4,5,3',4',5'-hexachlorobiphenvl (HCB); (II) 400 ppm of 2,3,4,2',3',4'-HCB; (III) 400 ppm of 2,4,5,2',4',5'-HCB; (IV) 400 ppm of 2,3,6,2',3',6'-HCB; and (V) 400 ppm of 2,4,6,2',4',6'-HCB. Surviving chicks were sacrificed at 21 days. Male mice were fed 10,30, 100 and 300 ppm of three of the above isomers (I, III, V), and survivors were sacrificed at 28 days, HCB's levels in adipose tissue and liver were determined. There were variations among the isomers as to dose and pathologic effects. Isomer (I) showed the greatest effect of those studied on mortality, body weight gain, liver, thymus, and spleen; it also attained the highest tissue concentration. It was the only isomer which produced porphyrin accumulation; and, in the chicks, produced hydropericardium, ascites, and edema. The decreasing order of overall toxicity was I >> V > II, III, I V. A general similarity of response was observed in both chicks and mice.

Abstract  The effects of differences in diet composition on polychlorinated biphenyl (PCB) poisoning was studied in four groups of male Wistar rats fed two different diets for 30 days. In rats fed a commercial diet, normal growth was observed, whereas rats fed this diet with PCB added had markedly depressed growth. The growth of rats fed a synthetic diet was lower than that of the group fed commerical diet. The weight of the liver increased significantly in PCB-treated rats. In rats given PCB and fed a commercial diet, the liver showed prominent dark brown pigmentation which was identified histochemically as ceroid. The liver of rats given PCB and fed a synthetic diet had a pale yellow color due to an accumulation of lipids. Serum cholesterol was increased in both PCB-fed groups; serum triglyceride concentrations were increased only in rats given PCB and fed commercial diet. Liver linoleic acid concentrations in rats given PCB and fed a commercial diet, and the oleic acid concentrations in rats given PCB and fed a synthetic diet were elevated. Thus, the toxic manifestations of PCB in rats differ significantly when different dietary regimens are used.

Abstract  Poorly metabolized polychlorinated biphenyl (PCB) congeners are bioaccumulated in the bodies of rodents and humans. Little is known about the continuing biological effects of these persistent chemicals. To determine whether a single high dose of a PCB mixture to mice would have long-term effects on liver enzymes, Aroclor 1254 was given at a single dose of 500 mg/kg to (C57BL/6 × DBA/2)F1 female mice. Paired controls received olive oil. Mice were killed at intervals of 0.5 to 55 weeks after treatment and liver assessed for aminopyrine demethylase activity. At selected time points, blood and homogenates of liver and of whole carcass were analyzed for content of PCBs by gas chromatography with electron capture detection. Hepatic aminopyrine demethylase activity was significantly elevated in Aroclor-treated mice, relative to controls, for 42 weeks after treatment. A three- to fourfold increase persisted for at least 14 weeks, with a convergence of treated and control values thereafter. Significant amounts of nine PCB congeners were detected in carcass, liver, and blood; total carcass PCB, estimated on the basis of these congeners, correlated significantly with liver aminopyrine demethylase elevation, and a similar trend was noted for liver. At 42 weeks after treatment, total PCB levels were 70 mg/kg for carcass, 2.4 mg/kg for liver and 0.28 mg/kg for blood. Congener profiles were similar in all three compartments, with the majority of the retained chemical being 2,3′,4,4′,5- and 2,3,3′,4,4′-pentachlorobiphenyl and 2,2′,4,4′,5,5′-and 2,2′,3,4,4′,5′-hexachlorobiphenyl. These results suggest that congeners bioaccumulated after a high PCB dose retain biological activity in the body for nearly a year after treatment.

Abstract  Polychlorinated biphenyls (PCBs) are complex mixtures of congeners that exhibit carcinogenic and toxicant activities in a variety of mammalian tissues. Here, we studied the acute in vivo and in vitro effects of a commercially used PCB product, Aroclor 1248 (A1248), a mixture of tri-, tetra-, and pentachloro congeners. Single intraperitoneal (i.p.) or bilateral intratesticular (i.t.) injections of A1248 decreased serum androgen levels in both groups 24 h after injection. Chorionic gonadotropin-stimulated androgen production by acute testicular cultures from both groups was also reduced, and progesterone production was attenuated in cultures from i.t.-treated animals. The capacity of the postmitochondrial fractions from testes of i.t.-treated animals to convert pregnenolone to progesterone and progesterone to testosterone was reduced as well. In vitro studies revealed that a 10- to 15-min exposure of postmitochondrial testicular fractions and intact interstitial cells from normal animals to A1248 in a subnanomolar concentration range was sufficient to attenuate the conversion of pregnenolone to progesterone and progesterone to testosterone. At micromolar concentrations, A1248 added in vitro also inhibited the conversion of Delta(4)-androstendione to testosterone without affecting the viability of interstitial cells. These results indicate that A1248 down-regulates the testicular androgenesis by an acute inhibition of 3beta-hydroxysteroid dehydrogenase, 17alpha-hydroxylase/lyase, and 17beta-hydroxysteroid dehydrogenase activities.

Abstract  The frequent observation of intra-individual variability (IIV) in the expression of ADHD symptoms suggest that IIV is an integral component of the disorder. We tested IIV in ADHD-like phenotype from five different studies of rodent models of ADHD, including studies with Spontaneous Hypertensive Rats (SHR/NCrl and SHR/N), Wistar-Kyoto Hyperactive Rats (WKHA/N), Wistar-Kyoto Hypertensive rat (WKHT), PCB-126 and -153-treated Lewis rats and behaviorally normal Wistar/Mol, Wistar-Kyoto (WKY/N and WKY/NMol), and untreated Lewis rats. Averages of the absolute residual deviation of ADHD-like behavior from individual means ("individual phenotypic dispersion," PD(i)) were used to represent IIV in the fixed-interval (FI) and extinction (EXT) phases of operant behavioral activity. Across all studies, SHR rats had higher PD(i) than WKY rats (P < 0.0001) for all ADHD-like traits, and higher PD(i) for hyperactivity than WKHT and WKHA/N rats. Male SHR rats in particular had higher PD(i) for hyperactivity than male or female WKYs, SHR females for EXT hyperactivity, and higher dispersion for inattention than WKY females. These findings strongly suggest the genetic control of IIV, and suggest that the SHR may be a useful model for the identification of genes for IIV in human ADHD. These findings also obliquely support the SHR as a useful model for ADHD overall.

Abstract  Metabolic changes in lipids, ascorbic acid, and hepatic microsomal cytochrome P-450 by feeding polychlorinated biphenyls (PCB) were investigated in streptozotocin-induced diabetic rats. Streptozotocin (STZ, 60 mg/kg body weight) was injected in Wistar male rats intraperitoneally. Diabetic and non-diabetic rats were fed ad libitum a 20% casein-based control diet or a PCB-containing diet (200 mg/kg diet) for 9 days. Body weight decreased significantly in STZ-induced diabetic rats with or without PCB (groups PD and D, respectively). In rats of group D, urinary ascorbic acid excretion was 15 times higher than that in non-diabetic rats fed a control diet (group C). Dietary PCB caused 30-fold higher urinary ascorbic acid excretion in non-diabetic rats (group P) than that in group C. In group PD, urinary ascorbic acid was nearly 60 times higher than that in group C. Ascorbic acid in liver and kidney was significantly lower in group D than in group C, and it was significantly lower in group PD than in group P. Liver microsomal cytochrome P-450 and b5 were both increased by dietary PCB in group P. Addition increase in these enzymes was observed in diabetic rats by PCB. Serum total cholesterol was 1.8 times higher in group P than in group C. Further increase in serum total cholesterol was observed in group PD. These data suggest that metabolic changes in lipids and ascorbic acid induced by the dietary xenobiotic were magnified in STZ-induced diabetic rats.

Abstract  The effect of the endocrine-disrupting chemical 3,3',4,4',5-pentachlorobiphyenl (PCB 126) on intestinal microbiota after oral administration, and the improvement of intestinal microbiota and feces quantity by the subsequent administration of Lactobacillus acidophilus or Lactobacillus reuteri was investigated. All the rats were given 100 mu g/kg bodyweight of PCB 126. The changes in bacterial counts were confirmed using a culture method. The administration of PCB 126 tended to decrease the bacterial counts of lactobacilli (10(9.6)-10(10.2) to 10(8.8)-10(9.2)) and bifidobacteria (10(5.3)-10(6.1) to 10(3.6)-10(4.2)), and to increase those of Enterobacteriaceae (10(8.2)-10(9.1) to 10(9.4)-10(10.3)) and staphylococci (10(6.6)-10(7.4) to 10(7.2)-10(8.4)) compared to no PCB 126 administration. After administration of PCB 126, L. acidophilus or L. reuteri orally administered to rats caused Enterobacteriaceae and staphylococci counts to decrease, suggesting that the intestinal microbiota was improved by the lactobacilli. The administration of L. acidophilus and L. reuteri improved the balance of intestinal microbiota, and defecation volume returned to its normal level. L. acidophilus and L. reuteri have a remedial effect on intestinal microbiota affected by PCB 126 and can function to lessen accumulated PCB 126 volume.

Abstract  Polychlorinated biphenyls are persistent environmental pollutants that elicit a wide range of effects in humans and wildlife, mediated by the aryl hydrocarbon receptor. 3,3',4,4',5-pentachlorobiphenyl (PCB126) is the most potent congener with relative effect potencies ranging from 0.0026 to 0.857, and a toxic equivalency factor (TEF) of 0.1 set by an expert panel of the World Health Organization. In this study, the hepatic effects elicited by 300 microg/kg PCB126 were compared with 30 microg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in immature, ovariectomized female C57BL/6 mice. Comprehensive hepatic gene expression analyses with complementary histopathology, high-resolution gas chromatograph/high-resolution mass spectrometer tissue analysis, and clinical chemistry were examined. For temporal analysis, mice were orally gavaged with PCB126 or sesame oil vehicle and sacrificed after 2, 4, 8, 12, 18, 24, 72, 120, or 168 h. In the dose-response study, mice were gavaged with 0.3, 1, 3, 10, 30, 100, 300, 1000 microg/kg PCB126, 30 or 100 microg/kg TCDD and sacrificed after 72 h. 251 and 367 genes were differentially expressed by PCB126 at one or more time points or doses, respectively, significantly less than elicited by TCDD. In addition, there was less vacuolization and necrosis, and no immune cell infiltration, despite comparable or higher TEF-adjusted hepatic PCB126 levels. The functional annotation of differentially expressed genes was consistent with the observed histopathology. Collectively, the data indicate that 300 microg/kg PCB126 elicited a subset of weaker effects compared with 30 microg/kg TCDD in immature, ovariectomized C57BL/6 mice.

Abstract  The present study has compared the neurobehavioral effects of two structurally different PCB congeners or their combination in rats. Time-mated Long-Evans rats received daily injections of the coplanar PCB 77 (3,4 3',4'-TCB: 0.5 or 1.5 mg/kg), the di-ortho-chlorinated PCB 47 (2,4,2',4'-TCB: 1.5 mg/kg) or a congener mixture (0.5 mg/kg PCB 77 + 1.0 mg/kg PCB 47) from day 7 to 18 of gestation. The PCB exposure levels in brain and perirenal fat of dams and offspring were determined by GC/ECD on gestational day 19 (GD 19), postnatal day 21 (PND 21), and PND 45. PCB 77 was accumulated to a smaller degree than PCB 47. On GD 19, PCB 77 was found to a greater extent in the brains of the offspring than in the brains of the dams, whereas the level of PCB 47 was almost the same in dams and offspring. The testing of open-field behavior in male rats on PND 18 and PND 70 revealed an altered distribution of activity with enhanced activity in the inner zone in PCB 77-treated rats compared to all other groups, while the overall activity was not changed. Distance traveled and rearing behavior on PND 340 were elevated relative to controls in all PCB-treated groups, indicating age-related effects of maternal exposure. A step-down passive avoidance task revealed decreased latencies in the PCB 77 and combined exposure groups on PND 80. Only PCB 77-treated animals showed increased latencies on PND 100 on the haloperidol-induced catalepsy test. These results indicate long-term effects of maternal exposure to PCB 77 on emotional and motor functions. At the dose levels used in the present experiments, the two congeners given in combination did not cause additive or synergistic effects. Instead, concurrent exposure to PCB 47 seemed to counteract PCB 77-induced changes in the pattern of activity.

Abstract  This study investigated the effects of consumption of Great Lakes fish on progressive ratio performance, and on the pattern and concentrations of brain polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethene (DDE), and mirex in the rat. Adult, male Sprague-Dawley rats were fed a 30% diet of either Lake Ontario salmon (LAKE), Pacific Ocean salmon, or lab chow control for 20 or 65 days. Following the treatment regimen, half the rats from each group were sacrificed immediately for gas chromatographic analysis of organochlorine contaminants, and the other half were tested on a multiple fixed-ratio-progressive-ratio reinforcement schedule and then sacrificed for analysis. Consumption of Lake Ontario fish resulted in significantly higher levels of brain PCBs, DDE, and mirex relative to controls, but still well within human exposure ranges (<1 microg/g fat). Consumption of Lake Ontario fish for 20 or 65 days produced an average brain PCB concentration of 457 and 934 ng/g fat, respectively. Consumption of laboratory rat chow or Pacific Ocean salmon for 20 or 65 days produced an average brain PCB concentration of 240, 464, and 441 ng/g fat, respectively. Moreover, both LAKE-fed groups showed a much more heavily chlorinated pattern of brain PCBs than all control groups, as evidenced by both significant increases in the most heavily chlorinated PCB congeners and significant increases in the average chlorine biphenyl. All LAKE brains contained significant concentrations of DDE and mirex, whereas no control brains contained any detectable quantities. Analysis of progressive-ratio performance indicated that LAKE rats responded normally during fixed-ratio schedules but quit significantly sooner than control rats on a progressive-ratio 5 (PR5) schedule, indicating reduced persistence on progressively leaner reinforcement schedules. Analysis of brain PCBs indicated that total PCBs were most strongly related to PR5 performance. These data indicate that consumption by rats of contaminated Lake Ontario fish produces (1) increased concentrations of PCBs, DDE, and mirex in the brain, (2) a more heavily chlorinated distribution of PCBs in the brain, and (3) reduced persistence of progressive-ratio reinforcement schedules. While these behavioral changes are related to brain PCB level, more work is necessary before the effects can be directly attributed to PCBs.

Abstract  Toxic equivalency factor (TEF) has been proposed to estimate the risk of polychlorinated biphenyl (PCB) congeners. However, ortho chlorine substitution in the two phenyl rings gives each PCB its own pattern of toxicity which is different from the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin. The present study evaluated the effect of prenatal and postnatal exposure to a low dose of the mono-ortho pentachlorobiphenyl PCB 118 on thyroid hormone concentrations and EROD activity in rats. Moreover, the tissue distribution of PCB 118 following one oral dose was evaluated. Sprague-Dawley rats were treated by gavage on GD 6 with 375 microg of PCB 118/kg b.w. Decreases in thyroxine and TSH levels were observed in dams at the end of lactation. Perinatal exposure to a low dose of PCB 118 permanently disrupted the hypothalamo-pituitary-thyroid (HPT) axis leading to a significant increase in thyroxine levels in offspring, as a 'thyroid resistance syndrome'. It is noteworthy that no changes in hepatic EROD activity were detected in dams at the end of lactation, even in the presence of high amounts of PCB in liver. Based on hepatic EROD activity (as a biomarker for aryl hydrocarbon receptor (AhR) induction), the mechanism of thyroid homeostasis disruption seems to be AhR-independent. Additionally, the 'thyroid resistance syndrome' observed in our study indicates the need for further detailed investigations on the HPT axis. We conclude that not only TEF, but also AhR-independent responses should be taken into account for risk assessment of mono-ortho PCB congeners.

Abstract  The objective of the present study was to investigate whether neonatal exposure to single PCB congeners 3,3',4,4',5-pentachlorobiphenyl (IUPAC 126) (co-planar) and 2,3,3',4,4?-pentachlorobiphenyl (IUPAC 105) (mono-ortho co-planar like') when given as one single dose (0.14?14 mol/kg body weight per os) to 10 day old male NMRI mice could induce neurotoxic effects in the adult animal, as earlier seen for some ortho-substituted PCBs. Furthermore, to ascertain whether behavioural aberrations, both in spontaneous behaviour and in learning and memory function, were followed by changes in the cholinergic and/or the dopaminergic system, and whether behavioural changes could worsen with age. It was found that neonatal exposure to 3,3',4,4',5-pentachlorobiphenyl can induce persistent aberrations in spontaneous behaviour and that this derangement can grow worse with age. Furthermore, this exposure affected also learning and memory functions in the adult animal and in the animals showing this deficit, the cholinergic nicotinic receptors in the hippocampus were affected. Exposure to 2,3,3',4,4'-pentachlorobiphenyl, at the same dose or higher, did not cause any significant change in the investigated behavioural variables, spontaneous and swim-maze behaviour.

Abstract  Environmental pollutants that disrupt endocrine system might also affect the modeling and remodeling of bone. Environmental factors, irrespective of age and sex contribute for the development of secondary osteoporosis. Polychlorinated biphenyls have adverse effects on various organs including bone. The present study was designed to investigate the effects of PCB (Aroclor 1254) on femur bone and the ameliorative role of vitamin C or E. In this regard, four groups of adult male albino rats were used as control, PCB (2mg/kgb.wt.), PCB+vitamin C (100mg/kgb.wt.) and PCB+vitamin E (50mg/kgb.wt.). The bone formation markers (ALP, Collagen), bone resorption marker (TRAP), antioxidant enzymes (SOD, GPX and GST) and lipid peroxidation in the femur were studied. Aroclor 1254 treatment decreased the ALP activity and collagen, but increased the TRAP activity and lipid peroxidation. While it decreased the SOD and GPX activity, GST was unaltered. Interestingly, simultaneous administration of vitamin C or E prevented the adverse effects of Aroclor 1254 in the femur. In conclusion, the present investigation suggests that Aroclor 1254 induced oxidative stress affects femoral bone metabolism. However, vitamin C or vitamin E protected the femur from the oxidative stress.

Abstract  Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in children. The current study assessed effects of gestational and lactational exposure to a commercial PCB mixture, Aroclor 1254 (A1254), on spatial learning and memory in rats, using the radial-arm maze (RAM). Pregnant Long-Evans females (10/dose group) were exposed to 0 or 6-mg/kg/day A1254 (po in corn oil) from gestation day (GD) 6 to weaning at postnatal day (PND) 21. After they reached adulthood, 1 male and 1 female from each litter were tested on a working/reference memory task using a 12-arm RAM. Eight of the 12 arms were baited, with the pattern of baited arms remaining the same on every trial for each rat. Compared to control males, the A1254-exposed males made significantly more working memory errors (2.15 +/- 0.13 and 3.20 +/- 0.18 errors +/- SEM for control and A1254 males, respectively) and reference memory errors (3.17 +/- 0.10 and 4.13+/-0.14 errors +/- SEM for control and A1254 males, respectively) on the RAM. In contrast, A1254-exposed females were not impaired relative to control females on the RAM. Drug challenges with dizocilpine (MK-801) and scopolamine did not differentially affect working or reference memory of control and exposed rats. These data suggest that perinatal exposure to A1254 may cause sex-specific deficits in spatial learning and memory, and that NMDA-mediated and muscarinic neurotransmission, as assessed with the drug challenges, were not markedly impaired in the A1254-exposed animals.

Abstract  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.

Abstract  Polychlorinated biphenyls (PCBs) are ubiquitous man-made toxicants capable of endocrine disruption. Studies in several species have shown that exposure to PCBs and their hydroxylated metabolites reduces fecundity and decreases circulating concentrations of thyroid hormones, causing serious reproductive and developmental defects. Thyroid hormones modulate both follicular development and steroidogenesis, and affect estrogen metabolism and the regulation of estrogen receptor. This study was designed (1). to determine whether exposure to a commercially prepared PCB mixture (Aroclor 1016) exerts detrimental effects on follicle maturation in the Long-Evans hooded rat; and (2). to determine whether the modulatory effects of Aroclor can be attenuated by levo-thyroxine sodium (T(4)) supplementation. Animals were treated on gestation days 7-13 with a single daily intraperitoneal injection (2.5 mg/kg per day) of Aroclor. Half of the Aroclor-treated dams were also given T(4) supplements (2.89 microg/kg per day) via drinking water. Female pups were sacrificed on postnatal days 24/25, and the ovaries were excised, fixed for histology and analyzed. The analysis included a count, measurement and classification of healthy and atretic preantral and antral follicles in the greatest cross-sectional area. The results indicated that treatment with Aroclor significantly reduced the number of preantral follicles <50000 microm(2) and the total number of antral follicles in the 50-100000 and >100000 microm(2) size classes. T(4) circumvented the Aroclor effect on the number of preantral follicles <50000 microm(2); however, a significant reduction in the antral follicle number persisted in the 50-100000 and >100000 microm(2) size classes. In addition, we observed a significant increase in atresia in the Aroclor-treated ovaries in the antral <50000 microm(2) size class, which was not present in ovaries exposed to both Aroclor and T(4). These data support the hypothesis that Aroclor reduces the number of preantral and antral follicles of certain size classes in rats exposed during the critical period of development, and that supplementation with T(4) can attenuate the effects of Aroclor on small, but not medium or large antral follicles. Atresia of small, antral follicles may constitute one of the underlying mechanisms by which folliculogenesis is modulated by Aroclor 1016.

Abstract  Previous studies have revealed that one of the major metabolites of PCBs detected in human blood, 4-OH-2,3,3',4',5-pentaCB (4-OH-CB107), accumulated in fetal liver, brain, and plasma and reduced maternal and fetal thyroid hormone levels after prenatal exposure to pregnant rats from gestational days (GD) 10-16. In the present study, the effects of 4-OH-CB-107 on developmental landmarks, steroid hormone levels, and estrous cyclicity of rat offspring after in utero exposure to 4-OH-CB107 was investigated. Pregnant rats were exposed to 0, 0.5, and 5.0 mg 4-OH-CB107 per kg bw from GD 10 to GD 16. Another group of rats was exposed to Aroclor 1254 (25 mg/kg bw) to study the differences between effects caused by parent PCB congeners and the 4-OH-CB107 alone. A significant, dose-dependent prolongation of the estrous cycle was observed in 75% and 82% of female offspring exposed to 0.5 and 5.0 mg 4-OH-PCB107, respectively, compared to 64% of Aroclor 1254 (25 mg/kg) exposed offspring. The diestrous stage of the estrous cycle was prolonged, resembling a state of pseudopregnancy, which might reflect early signs of reproductive senescence. Plasma estradiol concentrations in female rat offspring were significantly increased (50%) in the proestrous stage after exposure to 5 mg 4-OH-CB107 per kg bw. No effects on estradiol levels were observed in Aroclor 1254 treated animals. These results indicate that in utero exposure to 4-OH-CB107 leads to endocrine-disrupting effects, especially in female offspring. The possible impact on neurobehavior following exposure to 4-OH-CB107 will be reported elsewhere.

Abstract  Polychlorinated biphenyls (PCB), which are tumor promoters, have been found in human tissues for decades. Their contribution to cancer risk may only now start to appear, due to long human cancer latency and the nature of tumor promotion. Epidemiological associations have been seen between PCB exposure or tissue content and cancer at several sites. In rodents, tumor promotion by PCBs has been little studied in tissues other than liver. Previously, in an experiment modeling infant carcinogen exposure following PCBs received in milk, lung and liver tumors, initiated neonatally in mice by the environmental nitrosamine N-nitrosodimethylamine (NDMA), were promoted by later treatment with Aroclor 1254. The present study was undertaken to confirm and characterize the effects of Aroclor 1254 on tumor number, latency, size and malignancy. Male Swiss mice were given NDMA on postnatal day 4 and Aroclor 1254 (250 mg/kg) on day 8, and killed at intervals. Eight PCB congeners were quantified in the carcasses. Incidences of mice with NDMA-initiated lung tumors at 28 weeks of age were increased 2.5-fold by PCBs. Multiplicities of lung tumors were enhanced four-fold by PCBs at 28 and 52 weeks. By 72 weeks tumor numbers were similar in the NDMA-only and NDMA-PCB groups. Liver tumors first occurred in significant numbers at 52 weeks and only in mice receiving both NDMA and PCBs. As for the lung, at 72 weeks the incidence was high in both the NDMA-only and NDMA-PCB groups. Sizes of tumors and liver carcinoma incidence were not altered by PCB treatment. Carcass analysis revealed a significant positive association between lung tumor numbers at 28 weeks and relative percentage of 2,2',4,4',5-pentachlorobiphenyl, with no other correlations. The results confirm that PCBs promote lung as well as liver tumors, by triggering the early appearance of latent initiated tumors otherwise presenting in old age.

Abstract  Previous studies indicate that repeated exposure of weanling male Fischer 344 rats to Aroclor can cause immune system alterations but the pattern of effects suggested the release of corticosteroids may have played a role. Rats were exposed daily by gastric intubation to the polychlorinated biphenyl (PCB) Aroclor 1254 at 0.1, 1.0, 10, or 25 mg/kg for exposure durations of 5, 10 or 15 weeks. By the 15th week of dosing all groups displayed an elevation in the basal level of serum corticosterone but no change in adrenal weight. Further, rats exposed to Aroclor 1254 for 15 weeks and subjected to stress prior to serum collection displayed elevations in corticosterone levels equivalent to stressed control rats. The failure to observe altered adrenal structure indicative of hyperactivity in the presence of increased serum levels of corticosterone suggest these basal increases may be indirect rather than direct effects of Aroclor 1254.