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Recently, we reported that in utero and lactational exposure to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a task-specific reduction of errors on the radial arm maze (RAM), without similar improvements on other spatial learning tasks including the Morris water maze. The effect was more pronounced in males than in females. This study further investigated the effects of in utero and lactational exposure to TCDD on RAM performance by testing male and female TCDD-exposed rats on either an eight-arm RAM with all arms baited or a 12-arm RAM with 8 of the 12 arms baited. If the rats have improved spatial learning or memory on the RAM, then they should be improved on both RAM tasks; whereas, if they are using adjacent arm selection or some other response strategy to solve the task, they should not show enhanced performance on the 12-arm RAM where not all the arms are rewarded. Time-mated Sprague-Dawley dams were gavaged with corn oil vehicle or one of two doses of TCDD in vehicle (0.1 or 0.2 microg/kg body weight) on gestational days 10 to 16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and female from each litter was tested on the eight-arm RAM with all arms baited. As in our previous studies, the 0.1-microg/kg TCDD-exposed male rats showed a significant decrease in the number of errors. However, the 0.2-microg/kg males did not differ from the controls. Neither group of TCDD-exposed females differed from the controls. None of the TCDD-exposed rats differed from the controls in adjacent arm selection behavior. An additional male and female from each litter were tested on the 12-arm RAM with only 8 of the 12 arms baited. In this task, neither TCDD group differed from the controls. These results suggest that the reduction of errors on the eight-arm RAM may be due to increased response patterning or use of intramaze cues rather than to improved spatial learning or memory. Also, the reduction in errors was only present at the lower dose of TCDD suggesting that the improvement in performance is only present at very low, nonovertly toxic doses of TCDD.

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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.

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Recently we reported that in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or coplanar polychlorinated biphenyls (PCBs) resulted in a reduction of errors on a radial arm maze (RAM) working memory task. The effect was more pronounced in males than in females. In this study, we further investigated the effects of in utero and lactational exposure to TCDD on learning and memory by testing male and female TCDD-exposed rats on three different spatial learning and memory tasks: the RAM, the Morris water maze (MWM), and spatial discrimination-reversal learning (RL), as well as on a nonspatial learning task, visual RL. Time-mated Sprague-Dawley rats were gavaged with either TCDD (0.1 microg/kg/day) or corn oil vehicle on gestation days 10-16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on the same RAM working memory task used in the previous study. Again, the TCDD-exposed male rats displayed a pronounced decrease in errors relative to control males. Following the RAM testing, the same animals were tested on the MWM, but no differences between the exposed and control rats were observed. Another male and female from each litter were tested on spatial RL on a T-maze. There were no differences between the exposed and control rats on this task. Following spatial RL, the same rats were tested on visual RL on the same maze. The exposed animals did not differ from controls on original learning, but took more trials to reach criterion on the first and second reversals. These results demonstrate a reliable, but task-specific, facilitation of spatial learning and memory in male rats exposed to TCDD during gestation and lactation. In contrast, both male and female TCDD-exposed rats showed a deficit in learning on the visual RL task. This pattern is consistent with that seen in earlier monkey studies. Perinatally TCDD-exposed monkeys were facilitated on certain spatial tasks, but impaired on visual RL tasks.

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Halogenated arylhydrocarbons (HAHs) exert a wide range of effects on the developing brain. These effects result in altered patterns of neuroendocrine function and behavior in adulthood, as well as changes in cognitive function. The underlying mechanisms have not yet been clearly defined. This paper briefly reviews the effects of HAHs on brain development, and proposes the hypothesis that interactions between different hormone-sensitive systems may contribute to the broad spectrum of responses observed after fetal or early postnatal HAH exposure. Physiological interactions between the effects of sex steroids, corticosteroids, and thyroid hormone are known to influence the development of the central nervous system (CNS). Since the biosynthesis and/or action of each of these hormones is sensitive to developmental HAH exposure, it is suggested that convergent effects of HAHs on different endocrine pathways may underlie some of the disruptive effects of these chemicals on CNS differentiation. Data are presented indicating that the disruptive effects of low dose dioxin exposure on sexual differentiation of the rat brain are probably not mediated through blockade of estrogen responses, but may instead involve subtle developmental changes in other endocrine systems, perhaps also affecting the feedback control of adrenocortical function. The potential for interactive endocrine effects illustrates the need for a fuller understanding of the range of biological activities of HAHs in the brain, so that the potential risks of low dose developmental exposure to these environmental toxicants can be predicted with greater certainty.

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Polychlorinated diphenyl ethers (PCDEs) are industrial byproducts and widespread environmental contaminants. Their structural similarity to PCBs suggests that they may exhibit subtle effects on both adult and juvenile mammals. We examined the effects of 3 PCDEs (2,2',4,5,6'-pentachlorodiphenyl ether, 2',3,4,6'-tetrachlorodiphenyl ether, and 2,2',4,4',5,5'-hexachlorodiphenyl ether) on maternal rat thyroid levels shortly after exposure, and on the thyroid levels of 16 day old juvenile rats that had been prenatally exposed. Both 2,2',4,5, 6'-pentachlorodiphenyl ether and 2',3,4,6'-tetrachlorodiphenyl ether depressed thyroxine (T4) levels in the maternal females as well as in both sexes of juvenile rats. 2,2',4,4',5,5'-hexachlorodiphenyl ether did not alter T4 levels in the pregnant females, but depressed juvenile T4 levels. None of the congeners studied significantly altered T3 levels. Effects on thyroid hormones did not correlate with the congeners' induction of cytochrome P450.

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There is mounting evidence that perinatal exposure to ortho-substituted PCB congeners causes neurobehavioral and neurochemical alterations. The molecular mechanism for these effects is not understood, but certain ortho-substituted PCBs have been found to interact specifically with ryanodine-sensitive Ca2+ channels in vitro. These channels are widely expressed in brain and are thought to be responsible for Ca(2+)-induced Ca2+ release. Thus, the ryanodine receptor may represent a selective molecular target through which ortho-substituted PCBs disrupt calcium signaling in neurons, and produce neurochemical and neurobehavioral alterations. Of the PCBs evaluated, 2,2',3,5',6-pentachlorobiphenyl (PCB 95) exhibits the highest potency and efficacy towards the ryanodine receptor in vitro. Therefore, we conducted an in vivo study to investigate the effects of developmental exposure to PCB 95 on neurobehavioral functional and regional brain ryanodine binding. Time-mated Sprague-Dawley rats were dosed with PCB 95 (8 or 32 mg/kg/day) or corn oil vehicle via gavage on gestation days 10-16. One male and one female from each litter were evaluated for neurobehavioral effects. Locomotor activity was evaluated in an automated open field at 35 and 100 days of age. Spatial learning and memory was assessed using an eight arm radial maze working memory task at 60 days of age and a T-maze delayed spatial alternation task at 140 days of age. The animals were then euthanized and [3H] ryanodine binding was assayed in homogenates of cerebral cortex, hippocampus and cerebellum. Rats exposed to PCB 95 showed normal levels of activity as juveniles, but were hypoactive in adulthood. They also showed a faster acquisition of the working memory task on the radial arm maze, but did not differ from controls on the T-maze delayed spatial alteration task. Region-specific changes in ryanodine binding to Ca2+ channels were also observed, with decreased binding in the hippocampus, increased binding in the cerebral cortex and a biphasic effect in the cerebellum. How these changes in ryanodine receptor function are related to the alterations in behavior will be a challenging problem to elucidate.

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Recently we reported that in utero and lactational exposure to specific ortho-substituted polychlorinated biphenyl (PCB) congeners resulted in a learning deficit on a delayed spatial alternation (DSA) task in female rats. In this study, spatial learning and memory was assessed following in utero and lactational exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Time-mated Sprague-Dawley rats were dosed with PCB 77 (3,3',4,4'-tetrachlorobiphenyl), 2 or 8 mg/kg/day; PCB 126 (3,3',4,4',5-pentachlorobiphenyl), 0.25 or 1.0 micrograms/kg/day; TCDD, 0.025 or 0.1 micrograms/kg/day; or corn oil vehicle via gavage on gestation days 10-16. Litters were culled to eight on day 2 and weaned on day 21. Beginning on day 80, one male and one female from each litter were tested on an eight-arm radial maze working memory task. The TCDD-exposed rats displayed pronounced decreases in errors relative to controls. PCB 77- and PCB 126-exposed rats showed similar, but less pronounced, decreases in errors. The same animals were later tested on a T-maze DSA task, but no differences among groups were observed. In conclusion, perinatal exposure to low doses of TCDD or structurally related coplanar PCBs appeared to facilitate acquisition of a working memory task on the radial arm maze. This effect was very different from that previously observed in rats exposed to ortho-substituted PCB congeners. The rats exposed to ortho-substituted PCBs did not differ from controls on the radial arm maze and were impaired on the T-maze DSA task. Together these findings suggest that coplanar and ortho-substituted PCBs may have different mechanisms of action on the CNS.

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Perinatal exposure to polychlorinated biphenyl (PCB) mixtures or to certain ortho-substituted PCB congeners dramatically reduces circulating thyroxine (T4) concentrations. It is not clear whether perinatal exposure to coplanar PCBs or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a similar effect. In this study, time-mated Sprague-Dawley rats were dosed with 2 or 8 mg/kg/day PCB 77 (3,3',4,4'-tetrachlorobiphenyl), 0.25 or 1.00 micrograms/kg/day PCB 126 (3,3',4,4',5-pentachlorobiphenyl), 0.025 or 0.10 microgram/kg/day TCDD, or corn oil vehicle orally on gestation days 10-16. At weaning, plasma total T4 concentrations in PCB 77 and TCDD high-dose female pups were significantly depressed, but the changes were modest (84.4 and 79.6% of control, respectively). T4 concentrations in PCB 126 high-dose females and all high-dose males were also depressed slightly, but the changes were not statistically significant. UDP-Glucuronosyl transferase (UDP-GT) activity towards 4-nitrophenol was increased in all high-dose groups. Thus, the modest decreases in T4 could be due in part to increased T4 glucuronidation by UDP-GT. Triiodothyronine (T3) and thyroid stimulating hormone (TSH) concentrations were unchanged in all groups. In contrast to the minor changes in thyroid hormone status, liver microsomal ethoxyresorufin-O-deethylase (EROD) was markedly induced in all exposure groups and thymus weights were depressed in the high-dose groups. Because doses of coplanar PCBs or TCDD that caused marked induction of EROD activity had only minor effects on T4, we conclude that changes in thyroid hormone status at weaning are not among the more sensitive effects of perinatal exposure to these compounds.

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OBJECTIVE: To define the occurrence rate, time course, and potential etiologic factors of hyponatremia in patients with acute spinal cord injury. DESIGN: Analysis of data obtained from a retrospective review of medical records and from a systematized, prospective database pertaining to patients with spinal cord injury. SETTING: A university hospital with a federally funded regional spinal cord injury center and a dedicated spinal cord injury intensive care unit. PATIENTS: Two hundred eighty-two patients admitted between January 1, 1988 and December 31, 1989 with acute (< 24-hr duration) spinal cord or vertebral column injury. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean age of patients was 36.7 +/- 17.6 (SD) yrs; 225 (80%) of the patients were male and 57 (20%) were female. Hyponatremia, when it occurred, developed at a mean time of 6.4 +/- 6.7 days postadmission, reached its nadir at 8.7 +/- 8.8 days, and occurred in 28% of those patients with cervical injuries, 34% with thoracic injuries, and 27% with lumbar injuries (p = NS). Logistic regression analysis demonstrated that the type of spinal cord injury (Frankel class: range is A = complete neurologic lesion to E = no neurologic lesion) was the strongest predictor of hyponatremia. The occurrence rate of hyponatremia was as follows: Frankel class-A 62%; Frankel class-B 48%; Frankel class-C 41%; Frankel class-D 23%; Frankel class-E 16% (p < .0001). CONCLUSIONS: The prevalence of hyponatremia in acute spinal cord injury is much higher than in the general medical or surgical patient population. This abnormality usually occurs within the first week postinjury. The most significant predictor of hyponatremia is the type rather than the level of spinal cord injury. The potential etiological factors are many and these factors are probably interrelated. The pathophysiological mechanisms that result in hyponatremia must be explored so that this occurrence and its consequences can be prevented.

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