In Vivo and in Vitro Exposure to PCB 153 Reduces Long-Term Potentiation.
We examined the effects of gestational and lactational exposure to polychlorinated biphenyl (PCB PCB: see polychlorinated biphenyl.
in full polychlorinated biphenyl
Any of a class of highly stable organic compounds prepared by the reaction of chlorine with biphenyl, a two-ring compound. ) 153 (2,4,5,2',4',5'-hexaCB) on the magnitude of long-term potentiation (LTP LTP Long Term Potentiation
LTP Local Transport Plan
LTP Linux Test Project
LTP Liturgy Training Publications
LTP Long Term Prediction
LTP Last Traded Price
LTP Learning Technologies Project (NASA)
LTP Long Term Plan ) observed in the CAI (1) (Computer-Assisted Instruction) Same as CBT.
(2) See CA.
CAI - Computer-Aided Instruction region of hippocampal brain slices prepared from rats at 30 days of age. We compared these actions to those observed when PCB 153 is dissolved in normal Krebs-Ringer solution and perfused on slices from control rats of the same age. In vivo exposure was at three dose levels (1.25, 5, and 20 mg/kg/day) from gestational day 3 through weaning weaning,
n the period of transition from breast feeding to eating solid foods.
the act of separating the young from the dam that it has been sucking, or receiving a milk diet provided by the dam or from artificial sources. at postnatal day 21. Although responses to low-frequency stimulation of the Schaffer collateral pathway in exposed animals were not different from controls, significantly reduced LTP was induced after tetanic stimulation, even at the lowest dose studied. We observed a comparable depression of LTP when control slices were perfused with Krebs-Ringer that had been equilibrated with PCB 153 in a generator column. Neither in vivo nor in vitro exposure significantly altered the input-output curves obtained before tetanic stimulation, but both suppressed the increase in response observed in controls after tetanic stimulation. Because LTP is thought to be correlated with learning ability, these observations may provide at least a partial mechanism to explain the reduction of intelligence quotient observed in humans exposed to PCBs early in development. Key words. CA1, generator column, gestational/lactational exposure, hippocampus hippocampus
fabulous marine creature; half fish, half horse. [Rom. Myth. and Art: Hall, 154]
See : Monsters , in vitro exposure, learning. Environ Health Perspect 108:827-831 (2000). [Online 27 July 2000]
Polychlorinated biphenyl (PCB) exposure is correlated with a reduction in intelligence quotient (IQ) in children exposed through gestation and/or lactation lactation
Production of milk by female mammals after giving birth. The milk is discharged by the mammary glands in the breasts. Hormones triggered by delivery of the placenta and by nursing stimulate milk production. in at least two populations. Chen et al. (1) studied children in Taiwan exposed in the Yu-Cheng incident (where PCB-contaminated rice oil was used for cooking for a period of time). Children born to exposed mothers, even if born years after the maternal exposure, showed a variety of effects including a downward shift in average IQ of approximately 5 IQ points. This effect appeared not to reverse with the age of the child, suggesting that the effect might be permanent. Because the PCBs were heated during cooking there was some formation of dibenzofurans and thus some uncertainty as to whether observed effects were due to the PCBs, the furans, or both.
The other study with the most convincing demonstration of IQ deficits after PCB exposure is that of Jacobson and Jacobson (2). They followed children born to mothers who consumed contaminated fish from Lake Michigan, and reported a 6.2-point IQ deficit in the highest exposure category when the children were studied at 11 years of age. In this study the deficit appeared to be related to prenatal, not postnatal, exposure. Although the fish were also contaminated with other potentially neurotoxic neurotoxic
pertaining to or emanating from a neurotoxin.
a case of poisoning by a neurotoxin.
neurotoxic adjective substances, especially methylmercury, the authors suggested that the effect on IQ is secondary to exposure to PCBs. Decrements in neurobehavioral function have also been reported in other exposed human populations (3,4) and in exposed monkeys (5) and rodents (6,7).
Long-term potentiation (LTP) is a prolonged increase in synaptic synaptic /syn·ap·tic/ (si-nap´tik)
1. pertaining to or affecting a synapse.
2. pertaining to synapsis.
Of or relating to synapsis or a synapse. responses that can be induced in certain neural pathways by a brief tetanic stimulation (8). LTP is believed to be at least a component of learning and memory (9). LTP is reduced in aged animals (10) and is reduced or absent in various mutants that show reduced learning capacity (11,12). When LTP in animals is saturated, further learning is impaired (13). LTP is blocked by lead (14,15), an environmental contaminant contaminant /con·tam·i·nant/ (kon-tam´in-int) something that causes contamination.
something that causes contamination. that also causes a reduction in IQ. We previously showed (16) that acute exposure of hippocampal brain slices of normal rats to PCB mixtures results in a reduction of LTP with exposures that did not significantly alter other aspects of synaptic transmission.
PCB 153 (2,4,5,2',4',5'-hexaCB) is a di-ortho, nondioxin-like congener congener /con·ge·ner/ (kon´je-ner) something closely related to another thing, as a member of the same genus, a muscle having the same function as another, or a chemical compound closely related to another in composition and exerting that is persistent in both the environment and in the human body. PCB 153 is present in almost every person in significant amounts because of its resistance to degradation. It is one of the three dominant PCB congeners in human adipose tissue (17) and is the congener with the highest concentration in breast milk (18). Because it is a poor activator of the aryl ar·yl
An organic radical derived from an aromatic compound by the removal of one hydrogen atom. hydrocarbon (Ah) receptor (19) it has generally not been considered particularly hazardous.
We determined the effects of gestational and lactational exposure to PCB 153 at three concentrations and compared those to effects of acute exposure of control rat hippocampal area CA1 slices.
Timed-pregnant Sprague-Dawley rats (Taconic Farms, Inc., Germantown, NY) were exposed by ingestion ingestion /in·ges·tion/ (-chun) the taking of food, drugs, etc., into the body by mouth.
1. The act of taking food and drink into the body by the mouth.
2. to PCB 153 mixed in corn oil and applied daily on a sweet wafer. The rats were dosed from gestational day 7 through postnatal day 21, when the pups were weaned. We synthesized the PCB 153 in our laboratories, and purity was [is less than] 99% with no other congeners detected. The possible presence of contaminating furans was tested in the laboratory of Patrick O'Keefe (Wadsworth Laboratories, Albany, NY), and total tetra-, penta-, and hexachlorodibenzofurans (sum of 2,3,7,8- and non-2,3,7,8-substituted congeners) were present at 418, 177, and 15 ppb, respectively. 2,3,7,8-Tetra and 1,2,3,4,7,8-hexachlorodibenzofuran were present at 1.49 and 0.37 ppb, respectively. Chlorinated chlorinated /chlo·ri·nat·ed/ (klor´i-nat?ed) treated or charged with chlorine.
charged with chlorine.
some, e.g. dibenzodioxins were not present above detection limits of 0.3-1.3 ppb. We exposed dams at four dose levels (0, 1.25, 5.0, and 20.0 mg/kg/day). At birth, litters were culled to eight pups (five males and three females). There were no significant dose-related effects on fertility, birth number, and postnatal growth at these doses. Body weights of PCB-exposed dams were not different from controls. We ran the experiment over a period of 5 weeks in blocks of four dams: one control and one at each exposure level. One male pup (30 [+ or -] 3 days of age) from each litter was used in these experiments, and the investigator was blinded to exposure category until the end of the full experimental period. On average we studied three slices of hippocampus per animal. Results were averaged and reported on the basis of per-litter exposure. Thus five animals were used for recording LTP at each dose level in these studies.
We determined LTP in the CA1 region of hippocampal brain slices as previously described (15,16). In brief, animals were euthanized by cervical dislocation, the brain quickly removed into ice-cold Krebs-Ringer solution [normally containing (in mM) NaCl, 125; KCl, 3.5; [KH.sub.2][PO.sub.4], 1.2; Mg[Cl.sub.2], 1.3; Ca[Cl.sub.2], 2.4, Na[HCO HCO Harvard College Observatory
HCO Hubbard Communications Office (Scientology)
HCO Hearing Carry-Over
HCO Health Care Organization
HCO Helicopter Control Officer
HCO Human Capital Office .sub.3], 26; and glucose, 10, pH 7.3] in which all NaCl was replaced with isosmotic isosmotic /isos·mot·ic/ (i?soz-mot´ik) having the same osmotic pressure.
Of or exhibiting equal osmotic pressure.
having the same osmotic pressure. sucrose, blocked, and mounted on a vibratome with tissue-binding glue (Konishi, Osaka, Japan). Slices (450-[micro]m thick) were cut and incubated in normal Krebs-Ringer solution for at least 1 hr before being mounted in the recording chamber, submerged, and constantly perfused with Krebs-Ringer. We stimulated the Schaffer collateral pathway at a frequency of 0.033 Hz at a stimulation intensity [is less than] 10 V, which gave a response that was approximately 50% maximal and had an amplitude of between 0.7 and 1 mV. After stability of the recording had been obtained [recording for at least 30 min after mounting and a population field excitatory postsynaptic potential ex·ci·ta·to·ry postsynaptic potential
A local change in the depolarization produced in the postsynaptic neuronal membrane in response to an excitatory impulse; summation of these depolarizations can lead to discharge of an impulse by the neuron. (fEPSP) of constant amplitude], we recorded control responses and applied tetanic tetanic /te·tan·ic/ (te-tan´ik) pertaining to tetanus.
1. Of or causing tetanus or tetany.
2. Marked by sustained muscular contractions.
n. stimuli consisting of two separate 1-sec stimulations, each at the test intensity at 100 Hz with the two stimulations separated by 5 sec. Input-output curves were obtained before and after tetanic stimulation in slices from animals after in vivo exposure by monitoring the amplitude of the fEPSP, reflecting the monosynaptic monosynaptic /mono·syn·ap·tic/ (-si-nap´tik) pertaining to or passing through a single synapse.
Having a single neural synapse. response generated in many different neurons recorded from the apical apical /ap·i·cal/ (ap´i-k'l) pertaining to an apex.
1. Relating to the apex of a pyramidal or pointed structure.
2. dendritic dendritic /den·drit·ic/ (den-drit´ik)
1. branched like a tree.
2. pertaining to or possessing dendrites.
Relating to the dendrites of nerve cells. layer as a function of stimulation intensity. We prepared five to six slices per animal, of which it was usually possible to record from three. The LTP amplitude was measured as the percent increase in amplitude at 60 min compared to control and the post-LTP input-output relations were also determined 60 min or more after tetanus.
In animals with in vivo exposure the exposure code was broken only after all experiments were completed. For in vitro exposure to PCB 153, we prepared a generator column by depositing 200 mg PCB 153 in 50 mL hexane hexane /hex·ane/ (hek´san) a saturated hydrogen obtained by distillation from petroleum.
n. onto glass beads and evaporating it to dryness (20). Distilled water was slowly circulated over the beads for a period of not less than 4 days; the beads were then used to make a Krebs-Ringer solution that contained PCB 153 at the limit of its aqueous solubility (reported as 0.91 ppb) (21), which is approximately 3 nM. We prepared slices from unexposed male rat pups at 30 days of age as described above and perfused the slices with normal Krebs-Ringer solution. After recording stability was achieved the perfusing solution was changed to the KrebsRinger containing PCB 153. This solution was perfused for 15 min before tetanic stimulation to determine effects on baseline synaptic responses, then tetanic stimulation was applied and the PCB solution perfusion continued for an additional 20 min. Normal Krebs-Ringer was then perfused for an additional 40 min and LTP and input-output curves were determined again 60 min or more after tetanic stimulation.
We performed analysis of PCB 153 concentrations by dual capillary column gas chromatography with electron capture detection and sample clean-up on a Florisil column (22). Serum PCB levels were measured from dams at the time of weaning and from samples of the Krebs-Ringer made from the generator column for the in vitro exposure.
Figure 1 shows averaged raw data traces of the fEPSP before and after tetanic stimulation. The data were recorded from the CA1 region in control slices and slices from animals gestationally and lactationally exposed to PCB 153 at 1.25 mg/kg/day. There was no obvious effect of the PCB exposure on baseline synaptic responses before tetanic stimulation or on the process of posttetanic potentiation potentiation /po·ten·ti·a·tion/ (po-ten?she-a´shun)
1. enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone.
2. posttetanic p. (PTP (1) See peer-to-peer.
(2) (Picture Transfer Protocol) An ISO standard for transferring photos from a digital camera to a computer or photo printer. ), which is the rapid increase in response amplitude that occurs immediately after tetanic stimulation and results from increased transmitter release due to presynaptic presynaptic /pre·syn·ap·tic/ (-si-nap´tik) situated or occurring proximal to a synapse.
Relating to the area on the proximal side of a synaptic gap. accumulation of calcium. However, the slices from exposed animals show reduced LTP compared to control animals.
[Figure 1 ILLUSTRATION OMITTED]
Figure 2 shows results from all of the in vivo exposure experiments. The bars represent the percent increase above the pretetanus baseline response of the response recorded 60 min or more after the tetanic stimulation. Even the lowest dose of PCB 153 resulted in significant reduction in LTP. Although the reduction at 5.0 mg/kg/day did not reach statistical significance because of a large standard error, there was a trend toward a dose-dependent decrease in LTP over these ranges.
[Figure 2 ILLUSTRATION OMITTED]
Figure 3 shows the effect of in vitro application of PCB 153 (indicated by the heavy line in Figure 3C) on fEPSP amplitude, PTP, and LTP. Figure 3A shows an individual fEPSP before and 60 min after induction of LTP from a control slice, whereas Figure 3B is a similar pair of responses from a slice perfused with Krebs-Ringer solution containing PCB. Figure 3C shows pooled data from studies with 11 control and 8 exposed slices prepared from different animals. Perfusion of the PCB-containing solution resulted in a relatively immediate increase (approximately 20%) in the amplitude of the fEPSP, which reversed with washing. This is shown more clearly in Figure 4 in records from one experiment. Although the fEPSP transiently increased somewhat in amplitude, LTP was not maintained in slices perfused with the PCB-containing solution. Figure 5 shows plots of the LTP, expressed as the increase in fEPSP amplitude recorded 60 or more min after tetanic stimulation, obtained from control slices and slices exposed to PCB 153 in vitro from 30-day-old animals. Both showed a degree of LTP suppression similar to that observed with the in vitro exposures.
[Figures 3-5 ILLUSTRATION OMITTED]
Figure 6 shows input--output curves for the in vivo exposures before and after induction of LTP and demonstrates that PCB 153-exposed animals show a reduced response over the full range of the input-output curve. We did not detect any significant effect on the input-output curve before tetanic stimulation in either the in vivo or in vitro (not illustrated) exposure.
[Figure 6 ILLUSTRATION OMITTED]
Serum levels of PCB 153 in dams at the end of exposure were 11 [+ or -] 2 ppb in controls; 270 [+ or -] 92 ppb in the 1.25-mg/kg/day group; 1,125 [+ or -] 490 ppb in the 5-mg/kg/day group; and 2,019 [+ or -] 1,911 ppb in the 20-mg/kg/day group. Three determinations of PCB 153 concentration in Krebs-Ringer solution made from distilled water circulated for at least 4 days over the generator column gave concentrations between 0.5 and 1.3 ppb, which is consistent with the conclusion that the concentration would be near the limit of solubility of this congener.
These studies add significantly to the accumulating body of evidence that PCB exposure results in decrements in nervous system plasticity without disruption of normal synaptic transmission. These studies also provide a possible experimental basis for the observation that children developmentally exposed to PCBs suffer from reduced IQ.
There is considerable evidence from animal studies that PCB exposure causes altered behavior and reduced learning ability, where exposure can be quantitated, and that human investigations are consistent with the conclusion that PCB exposure early in life causes neurobehavioral decrements (1-4). A number of early studies with PCB mixtures demonstrated neurobehavioral effects in rodents (23-25). In more recent studies with single congeners, Schantz et al. (6) investigated effects of gestational exposure on days 10-66 of rats to PCB 28 (2,4,4'-triCB; 8 or 32 mg/kg/day), 118 (2,3',4,4',5-pentaCB; 4 or 16 mg/kg/day), and 153 (16 or 64 mg/kg/day) on adult rat behavior. The authors reported that at higher doses of all three congeners there were delays in acquisition of a working/reference memory task and a T-maze delayed spatial alternation alternation /al·ter·na·tion/ (awl?ter-na´shun) the regular succession of two opposing or different events in turn.
alternation of generations metagenesis. task in females but not males. We used smaller doses of PCB 153 in the present experiments but we used greater exposure time. We studied only males at 30 days of age; Schantz et al. (6) studied males and females [is greater than] 90 days of age. The observations of Schantz et al. (6) suggest the possibility that the decrement To subtract a number from another number. Decrementing a counter means to subtract 1 or some other number from its current value. in LTP might be even greater in females. Alterations of behavior with PCB 153 have also been reported by Holene et al. (26). The authors exposed nursing dams to PCB 153 at 5 mg/kg on alternate days between postnatal day 3 and 13 and observed hyperactivity in males.
Several other PCB congeners also reportedly cause changes in learning behavior. Eriksson and Fredriksson (7) reported that neonatal exposure of mice to PCB 52 (2,2'5,5'-tetraCB) affected learning and memory functions in adult animals, although they did not see similar effects of three other congeners [PCBs 28, 118, and 156 (2,3,3',4,4',5-hexaCB)] in the same dose range. However, the authors reported changes in spontaneous behavior observed with PCB 28. In a later study the same authors (27) demonstrated reduced learning in a swim maze after a single oral dose of PCB 126 (0.46 mg/kg) but no effect of a similar dose of PCB 105 (2,3,3',4,4'-pentaCB). However, Rice and Hayward (28) saw no effect of gestational and lactational exposure of rats to PCB 126 at levels of up to 1 [micro]g/kg/day on multiple fixed interval--fixed ratio and DLR DLR Dollar(s)
DLR Deutsches Zentrum für Luft- und Raumfahrt (German Aerospace Center)
DLR Docklands Light Railway (London, UK)
DLR Dynamic Language Runtime performance. Weinand-Harer et al. (29) exposed pregnant rats to 1 mg/kg/day PCB 77 (3,4,3',4'-tetraCB) or 47 (2,4,2',4'-tetraCB) for 11 days during gestation; they reported significant differences in the PCB 77-exposed animals from controls in haloperiodol-induced catalepsy catalepsy (kăt`əlĕp'sē), pathological condition characterized by a loss of consciousness accompanied by rigidity of muscles that keeps limbs in any position in which they are placed. and passive avoidance behavior when tested as adults. In monkeys there have not been long-term studies with single congeners, but upon exposure to mixtures several groups demonstrated behavioral effects, including impaired performance on discrimination, delayed spatial alternation, fixed interval, and differential reinforcement of low rate performance (5,30-32). Although the relevance of LTP to some of these behavioral alterations is still unclear and different PCB congeners clearly have different effects, our observations at minimum provide a possible cellular substrate for some of these alterations.
PCBs cause several neurotoxic effects. Shain et al. (33) showed that some ortho-substituted congeners inhibit tyrosine hydroxylase, the rate-limiting enzyme in synthesis of the important neurotransmitter dopamine. Seegal et al. (34) demonstrated reductions in dopamine concentration in monkeys exposed to Aroclor mixtures. A number of ortho-substituted congeners cause acute neuronal cell death in cerebellar cerebellar /cer·e·bel·lar/ (ser?e-bel´ar) pertaining to the cerebellum.
Involving the part of the brain (cerebellum), which controls walking, balance, and coordination. granule cells (35,36), perhaps via interference with calcium homeostasis homeostasis
Any self-regulating process by which a biological or mechanical system maintains stability while adjusting to changing conditions. Systems in dynamic equilibrium reach a balance in which internal change continuously compensates for external change in a feedback (37). Pessah and colleagues [summarized in Fischer et al. (38)] showed that several ortho-substituted congeners alter calcium transport across microsomal microsomal
pertaining to or emanating from microsome. membranes by a ryanodine receptor-mediated pathway, and suggested that this is a common mechanism of ortho-substituted PCB toxic actions. Wong et al. (39) also explored effects of the tri-ortho-substituted PCB 95 (2,2',3,5',6-pentaCB) on fEPSPs from hippocampal CA1 slices, and reported that PCB 95 but not PCB 66 (2,3',4,4'-tetraCB) reduced fEPSP amplitude. They attributed this action to effects of ryanodine receptors. Although there has not been much study of PCBs and LTP, Altmann et al. (40) reported that developmental exposure to PCB 77 blocked LTP in visual cortex but not hippocampus. However, PCB 77 should not act at ryanodine receptors. The results of Altmann et al. (40) are also inconsistent with our previous observation that PCB 77 blocks LTP in CA1, although our studies were with acute exposure (16). We found that all of the major Aroclor mixtures blocked LTP, as did PCB 28 and 77. Further studies are necessary, although it seems unlikely that the effects of PCBs causing neuronal cell death and alterations of dopamine concentrations are due to the same mechanisms that alter LTP. The concentrations of PCBs required for these actions are generally reported to be somewhat greater than those causing a reduction of LTP, and dopamine is not known to have a critical role in LTP in CA1. Gilbert and Crofton (41) recently reported that in vivo exposure to Aroclor 1254 results in decrements of LTP in the dentate gyrus, which is consistent with our observations in a different hippocampal area.
The mechanism(s) whereby PCBs block LTP are presently unknown. Whereas the demonstration that both PCB 153 and the mixtures and single congeners previously studied by Niemi et al. (16) are effective on acute in vitro exposure is consistent with a direct action of PCBs, it is also possible that with in vivo exposure they might act indirectly through disruption of thyroid function. Ness et al. (42) showed that different congeners have different potencies in reducing total thyroxine levels in rats, with PCB 153 of intermediate potency. However, Desaulniers et al. (43), and others reported that PCB 153 exposure results in an increase, not a decrease, in serum thyroid hormone levels. Niemi et al. (44) previously showed that hypothyroid Hypothyroid
Having too little thyroxin stimulation.
Mentioned in: Goiter
hypothyroid adjective Referring to hypothyroidism, see there animals show reduced LTP.
The rapid and reversible increase in fEPSP amplitude on acute perfusion of PCB 153 was unexpected. It is noteworthy that this effect was transient and was reduced with time even in the continued presence of PCB 153. Somewhat similar effects on hippocampal population responses have been reported by Hong et al. (45) and Gilbert and Liang (46). It is possible that this action reflects a PCB-induced increase in intracellular calcium concentration in the presynaptic terminal, similar to that which can be induced in isolated cells (35,36) and would increase transmitter release. The mechanisms responsible for this action will require additional study, but the transient increase did not prevent acute application of PCB 153 from causing a reduction in LTP as measured 40 min after washing with control Krebs-Ringers.
PCB 153 is one of the most persistent congeners; it is widely distributed in humans and the environment. Because it is a poor activator of the Ah receptor it has widely been considered lacking in significant toxicity. Our results suggest that this may not be the case, if indeed LTP is a valid indicator of substances that alter learning ability.
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Rifat J. Hussain,(1) Janos Gyori,(1),(2) Anthony P. DeCaprio,(1) and David O. Carpenter(1)
(1) Department of Environmental Health and Toxicology, School of Public Health, University at Albany, Rensselaer, New York Rensselaer is a city in Rensselaer County, New York, U.S., located on the Hudson River, directly opposite Albany. As of the 2000 census, the city population was 7,761; in 1920, it was 10,832. , USA; (2) Balaton Limnological lim·nol·o·gy
The scientific study of the life and phenomena of fresh water, especially lakes and ponds.
[Greek limn Research Institute of the Hungarian Academy of Science, Tihany, Hungary
Address correspondence to D.O. Carpenter, School of Public Health, University at Albany, One University Place, B242, Rensselaer, NY 12144. Telephone: (518) 525-2660. Fax: (518) 525-2665. E-mail: email@example.com
Supported by NIEHS P42 ES04913, NIH D43 TW00636, and the U.S.-Hungarian Joint Fund (D. Carpenter).
Received 23 December 1999; accepted 17 April 2000.