The effect of lead exposure on expression of SIRT1 in the rat hippocampus

Based on how the silent information regulator 2 homolog 1 (SIRT1) regulates the cyclic AMP response element binding protein (CREB), which is the molecular switch of long-term memory that maintains cognitive function, it is postulated that the impact of lead (Pb) on SIRT1 is one of the mechanisms leading to Pb-induced cognitive and learning deficits. Hence, the purpose of this study was to investigate the effect of Pb exposure on the expression of SIRT1, and the reversion effect of resveratrol, which is an activator of SIRT1. We examined the effects of maternal rat ingestion of Pb in drinking water during gestation and lactation on the expression of SIRT1 and CREB in the hippocampus of their offspring at postnatal week 3 (PNW3) and 52 (PNW52), and then reexamined these effects in offspring after intragastric administration of resveratrol for 4 weeks. Pb exposure decreased SIRT1 and CREB phosphorylation in a dose-dependent manner in the rat hippocampus at both PNW3 and 52, and resveratrol reversed those losses. These results indicated that SIRT1 might be a novel target to prevent Pb neurotoxicity.     

Age-related impairment of long-term depression in area CA1 and dentate gyrus of rat hippocampus following developmental lead exposure in vitro

Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Impairment of the induction of long-term depression (LTD) has been reported in area CA1 and dentate gyrus (DG) of rat hippocampus following chronic lead exposure. The present study was carried out to investigate age-related alterations of LTD in area CA1 and DG of rat hippocampus following developmental lead exposure in vitro. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices at various postnatal ages: postnatal day (PND) 17-23, 27-33, and 57-63. Following low-frequency stimulation (LFS, 900 pulses/1 Hz), the average magnitude of LTD is age related. In the controls, LTD magnitude in area CA1 decreased with age, whereas in DG it increased with age. In the lead-exposed groups, the magnitude of LTD declined during development in both area CA1 and DG. The differences of LTD magnitude between the control and lead-exposed rats were 27.26 +/- 9.15% (PND 17-23), 21.59 +/- 12.93% (PND 27-33), and 16.96 +/- 9.33% (PND 57-63) in area CA1, and were 6.95 +/- 9.26%, 17.60 +/- 3.91%, and 33.63 +/- 10.47% in DG, respectively. These results demonstrated that the lead-induced impairment of LTD magnitude was an age-related decline in area CA1 and an age-related increase in area DG of rat hippocampus. Published by Elsevier Science Inc.     

Muscarinic cholinergic modulation of synaptic transmission and plasticity in rat hippocampus following chronic lead exposure

The cholinergic system is believed to be associated with learning and memory functions. Lead (Pb²⁺) is a well-known neurotoxic metal that causes irreversible damage to the central nervous system (CNS). To investigate whether Pb²⁺ interferes with cholinergic modulation, we examined the effects of carbachol (CCh), a muscarinic cholinergic agonist, on synaptic transmission and plasticity in the CA1 area of the hippocampus of developmentally Pb²⁺-exposed rats. The results showed that: (1) In both control and Pb²⁺-exposed rats, 0.1 μM CCh significantly enhanced tetanus-induced long-term potentiation (LTP), while 5 μM CCh induced a reversible depression of field excitatory postsynaptic potentials (fEPSPs). However, both the enhancement of LTP and depression of fEPSPs were significantly smaller in Pb²⁺-exposed rats than in controls, suggesting that the extent of the effect of CCh on the cholinergic system was depressed by Pb²⁺. (2) In Pb²⁺-exposed rats, the enhancement of LTP induced by 0.1 μM CCh was attenuated by pirenzepine, a M₁AChR antagonist, but was not affected by methoctramine tetrahydrochloride (M-105), a M_2/4AChR antagonist. The depression of fEPSPs induced by 5 μM CCh was reduced by either pirenzepine or M-105. (3) Furthermore, paired-pulse facilitation (PPF) was not affected by 0.1 μM CCh in control and Pb²⁺-exposed rats but was increased by 5 μM CCh in either group; the increase in PPF was less pronounced in Pb²⁺-treated when compared to control rats. These results suggested that cholinergic modulation could be impaired by Pb²⁺, and this kind of impairment might occur via different mAChR subtypes. Our study delineated the effects of Pb²⁺ on muscarinic modulation, and this might be one of the underlying mechanisms by which Pb²⁺ impairs learning and memory.     

兔动脉粥样硬化斑块的MR实验研究

目的应用MRI对兔动脉粥样硬化斑块进行成像。方法应用动脉内膜损伤和高胆固醇饮食建立兔动脉粥样硬化模型,采用多种序列对实验动物动脉血管进行成像,并与病理相对照。结果成功建立兔动脉粥样硬化模型;MR图像T1WI、T2WI、PDWI表现为兔动脉管壁增厚,斑块呈等信号、高信号或低信号,与病理切片检测结果符合率较高;MR能够发现动脉血管粥样硬化斑块,并可协助分析其成分。结论 MR可以检测兔动脉粥样硬化模型的斑块,亦可能对斑块定性分析有帮助。     

Comparison of the developmental milestones and preweaning neurobehavioral parameters in rat pups exposed to lead (Pb) during gestation,lactation and pregestation period

Studies in urban children exposed to low lead (Pb) have shown neurobehavioral deficits in the domains of intelligence, reaction time and attention. The structures – hippocampus (vital for learning and memory) and cerebellum (play a role in motor behavior and cognition) – which develop postnatally, are affected by developmental Pb exposure. The effect of low level of Pb exposure during specific periods of early brain development on early neurobehavioral outcomes in rat pups has not been studied. So in this study, pregnant albino Wistar strain rats were exposed to low levels of Pb in drinking water during gestation period (G group), lactation period (L group), both gestation and lactation period (GL group) and prior to pregnancy (a period of 1 month) (PG group). The rat pups born in each of these groups were assessed in preweaning neurobehavioral parameters including surface righting reflex, swimming development, negative geotaxis and ascending wire mesh test. The swimming development scores were low in the GL group of rats. The negative geotaxis score in GL and G groups were altered. The day of achievement of ascending wire mesh test was significantly delayed in GL, G and L groups of rats. To conclude, results show that (a) low level of Pb exposure during gestation and lactation period of brain development causes significant alterations in the early neurobehavioral and sensorimotor reflex development in the absence of concomitant weight loss and (b) gestation period only and lactation period only, Pb exposure causes alteration in some of the neurobehavioral outcomes.     

The combined effects of developmental lead and ethanol exposure on hippocampus dependent spatial learning and memory in rats: Role of oxidative stress

Either developmental lead or ethanol exposure can impair learning and memory via induction of oxidative stress, which results in neuronal damage. we examined the effect of combined exposure with lead and ethanol on spatial learning and memory in offspring and oxidative stress in hippocampus. Rats were exposed to lead (0.2% in drinking water) or ethanol (4 g/kg) either individually or in combination in 5th day gestation through weaning. On postnatal days (PD) 30, rats were trained with six trials per day for 6 consecutive days in the water maze. On day 37, a probe test was done. Also, oxidative stress markers in the hippocampus were also evaluated. Results demonstrated that lead + ethanol co-exposed rats exhibited higher escape latency during training trials and reduced time spent in target quadrant, higher escape location latency and average proximity in probe trial test. There was significant decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities and increase of malondialdehyde (MDA) levels in hippocampus of animals co-exposed to lead and ethanol compared with their individual exposures. We suggest that maternal consumption of ethanol during lead exposure has pronounced detrimental effects on memory, which may be mediated by oxidative stress.     

Perinatal lead exposure and relapse to drug-seeking behavior in the rat: a cocaine reinstatement study

Rationale Intravenous self-administration of cocaine at low doses is increased by chronic low-level exposure to lead during gestation and lactation (perinatal lead exposure). Insofar as drug potency is increased by early lead exposure, it must be considered that cocaine-seeking and relapse after periods of withdrawal similarly may be enhanced by perinatal lead exposure. Objectives Employing an animal model, the present study examined the effects of lead exposure during gestation and lactation on cocaine-induced reinstatement of drug-seeking, when animals were tested as adults. Methods Adult female rats were gavaged once daily with 0 or 16 mg lead for 30 days prior to breeding with non-exposed males. This exposure regimen continued until offspring were weaned at postnatal day (PND) 21. At PND 120, male offspring were trained to self-administer cocaine intravenously (IV) [0.50 mg/kg cocaine per infusion on a fixed-ratio schedule where two lever presses resulted in drug delivery (FR-2 schedule)]. After steady-state responding was established, cocaine reinstatement responding was assessed for each group within an extinction paradigm. During the initial 1 h of reinstatement testing, the previous baseline contingencies were in place, i.e. animals operated under an FR-2 schedule for an infusion of 0.50 mg/kg cocaine. During the 2 h, 3 h, and 4 h of testing saline infusions were substituted for cocaine infusions. After responding extinguished during hour 4, reinstatement of responding was tested by administering an intraperitoneal (IP) priming injection of 0.00, 5.00, 10.00, or 20.00 mg/kg cocaine. Following these injections, lever responding for saline infusions was monitored during hour 5. Results The number of saline infusions self-administered during hour 5 increased in a dose-dependent fashion for both controls (group 0-mg) and lead-exposed (group 16-mg) animals. However, lead-exposed animals self-administered significantly more saline infusions than controls at the 5.00 mg/kg and 10.00 mg/kg doses. This apparent metal-related increase in sensitivity to cocaine was evident with blood lead in metal-exposed test animals returning to control levels. However, brain lead levels remained elevated in lead-exposed test animals, relative to controls. Conclusions The results of this investigation suggest that low-level lead exposure during gestation and lactation increases sensitivity to the relapse phase of drug abuse. It is further apparent that this increased sensitivity to the reinstatement of drug-seeking behavior is long-lasting.     

Evidence for altered hippocampal volume and brain metabolites in workers occupationally exposed to lead: a study by magnetic resonance imaging and (1)H magnetic resonance spectroscopy

Environmental and occupational exposure to lead (Pb) remains to be a major public health issue. The purpose of this cross-sectional study was to use non-invasive magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy ((1)H MRS) techniques to investigate whether chronic exposure to Pb in an occupational setting altered brain structure and function of Pb-exposed workers. The Pb-exposed group consisted of 15 workers recruited from either a Pb-smelting factory or a Pb-battery manufacturer. The control group had 19 healthy volunteers who had no history of Pb exposure in working environment or at home. The average airborne Pb concentrations in fume and dust were 0.43 and 0.44mg/m(3), respectively, in the smeltery, and 0.10 and 1.06mg/m(3), respectively, in the Pb battery workshop. The average blood Pb concentrations (BPb) in Pb-exposed and control workers were 63.5 and 8.7mug/dL, respectively. The MRI examination showed that brain hippocampal volume among Pb-exposed workers was significantly diminished in comparison to age-matched control subjects (p<0.01), although the extent of this reduction was relatively small (5-6% of the control values). Linear regression analyses revealed significant inverse associations between BPb and the decreased hippocampal volume on both sides of brain hemisphere. Among five brain metabolites investigated by MRS, i.e., N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho), inosine (mI), glutamate/glutamine (Glx) and lipids (Lip), a significant decrease in NAA/Cr ratio (7% of controls, p<0.05) and a remarkable increase in Lip/Cr ratio (40%, p<0.01) were observed in the brains of Pb-exposed workers as compared to controls. Furthermore, the increased Lip/Cr ratio was significantly associated with BPb (r=0.46, p<0.01). Taken together, this study suggests that occupational exposure to Pb may cause subtle structural and functional alteration in human brains. The MRI and MRS brain imaging techniques can be used as the non-invasive means to evaluate Pb-induced neurotoxicity.     

Ascorbic acid ameliorates oxidative damage induced by maternal low-level lead exposure in the hippocampus of rat pups during gestation and lactation

This study was to investigate the effects of ascorbic acid on the hippocampus of suckling rats in the presence of lead (Pb)-induced oxidative stress. Pregnant Sprague-Dawley rats received treatment with drinking water, divided into three groups, as follows: (1) distilled water; (2) 0.2% Pb; (3) 0.2% Pb+ascorbic acid (100mg/kg/day). Rat pups were euthanized at the age of 21days and their brain tissue was examined using light microscopy. Protein levels of Cu/Zn superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD), and catalase (CAT) in the hippocampus were determined by Western blotting. We found a significant decrease in levels of Cu/Zn SOD and Mn SOD among Pb-exposed pups. Ascorbic acid supplementation appeared to negate the decrease in protein levels for Cu/Zn SOD and Mn SOD. In the case of CAT, there was no effect from Pb administration alone and Pb plus ascorbic acid appeared to increase the levels. In histopathology, ascorbic acid decreased the number of damaged cells in cornu ammonis areas CA1, CA3, and the dentate gyrus (DG) in hippocampus. Our results showed that administration of ascorbic acid during pregnancy and lactation could ameliorate some of the oxidative damage induced by Pb exposure in the developing rat hippocampus.     

Girl or boy? Prenatal lead,cadmium and mercury exposure and the secondary sex ratio in the ALSPAC study

The aim of this study was to evaluate the effect of prenatal exposure to lead, cadmium and mercury levels on the secondary sex ratio. Whole blood samples were collected from pregnant women enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study at a median gestational age of 11 weeks and were analyzed for lead, cadmium and mercury. Regression analysis was used to identify associations between maternal lead, cadmium and mercury levels and the secondary sex ratio with adjustment for confounders. There was no evidence for associations between maternal lead, cadmium or mercury levels and the secondary sex ratio in this sample. It appears unlikely that alterations in the secondary sex ratio are influenced by exposure to heavy metals, but further work should be done in large cohorts in other countries to confirm these findings.     

纵隔型肺癌X线、CT及MRI的表现及诊断灵敏度比较

目的 探讨纵隔型肺癌X线、CT及MRI的表现及诊断灵敏度.方法 回顾性分析经手术确诊的31例纵隔型肺癌患者的临床资料,31例均行胸部正侧位X线和CT平扫,其中7例行增强CT扫描,21例行MRI平扫,其中3例增强扫描.分析纵隔型肺癌MRI、X线及CT影像学表现特征及诊断灵敏性.结果 31例患者手术证实中央型肺癌18例,周围型肺癌13例.纵隔型肺癌胸部X片的共同表现为纵隔明显增宽,气管受压移位变形;CT显示肿块边缘不规则,外缘呈分叶、毛刺状,纵隔淋巴结肿大,伴有阻塞性肺炎和肺不张;MRI的影像学特征除了CT表现外则可较准确显示肿块侵及胸膜、胸壁和胸椎.X线临床诊断诊断灵敏度为88％,MRI为100％,CT为100％;MRI和CT的诊断灵敏度明显高于X线(x2=12.251,P＜0.05).结论 纵隔型肺癌临床诊断极易出现误诊,将临床症状与影像学表现结合可增加临床诊断的准确性.     

Testicular toxicity following short-term exposure to tri- and hexavalent chromium: an experimental study in the rat

The effect of tri- and hexavalent chromium after intraperitoneal administration for 5 consecutive days on testicular histopathology and epididymal sperm number was assessed. Treatment with hexavalent chromium induced testicular atrophy and a reduction in epididymal sperm number after 60 days. No effect was seen after treatment with trivalent chromium.     

The effects of early life lead exposure on the expression of insulin-like growth factor 1 and 2 (IGF1, IGF2) in the hippocampus of mouse pups

The present study was undertaken to investigate the effects of maternal lead exposure on expression of IGF1 and IGF2 in the hippocampus of mice offspring. Lead exposure initiated from beginning of gestation to weaning. Lead acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.5% and 1% groups respectively. On the 21st postnatal day, the learning and memory ability was tested by Water Maze test and the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of IGF1 and IGF2 in hippocampus was examined by immunohistochemistry and western blotting. The lead levels in blood and hippocampus of all lead exposure groups were significantly higher than that of the control group (P < 0.05). In Water Maze test, the performances of 0.5% and 1% lead exposure groupswere worse than that of the control group (P < 0.05). The expression of IGF1 and IGF2 was decreased in lead exposed groups than that of the control group (P < 0.05). The low expression of IGF1 and IGF2 in the hippocampus of pups may contribute to the impairment of learning and memory associated with maternal Pb exposure.     

K(+) depolarization evokes ATP, adenosine and glutamate release from glia in rat hippocampus: a microelectrode biosensor study

BACKGROUND AND PURPOSE

This study was undertaken to characterize the ATP, adenosine and glutamate outflow evoked by depolarization with high K⁺ concentrations, in slices of rat hippocampus.

EXPERIMENTAL APPROACH

We utilized the microelectrode biosensor technique and extracellular electrophysiological recording for the real-time monitoring of the efflux of ATP, adenosine and glutamate.

KEY RESULTS

ATP, adenosine and glutamate sensors exhibited transient and reversible current during depolarization with 25 mM K⁺, with distinct kinetics. The ecto-ATPase inhibitor {"type":"entrez-protein","attrs":{"text":"ARL67156","term_id":"1186396857","term_text":"ARL67156"}}ARL67156 enhanced the extracellular level of ATP and inhibited the prolonged adenosine efflux, suggesting that generation of adenosine may derive from the extracellular breakdown of ATP. Stimulation-evoked ATP, adenosine and glutamate efflux was inhibited by tetrodotoxin, while exposure to Ca²⁺-free medium abolished ATP and adenosine efflux from hippocampal slices. Extracellular elevation of ATP and adenosine were decreased in the presence of NMDA receptor antagonists, D-AP-5 and ifenprodil, whereas non-NMDA receptor blockade by CNQX inhibited glutamate but not ATP and adenosine efflux. The gliotoxin fluoroacetate and P2X7 receptor antagonists inhibited the K⁺-evoked ATP, adenosine and glutamate efflux, while carbenoxolone in low concentration and probenecid decreased only the adenosine efflux.

CONCLUSIONS AND IMPLICATIONS

Our results demonstrated activity-dependent gliotransmitter release in the hippocampus in response to ongoing neuronal activity. ATP and glutamate were released by P2X7 receptor activation into extracellular space. Although the increased extracellular levels of adenosine did derive from released ATP, adenosine might also be released directly via pannexin hemichannels.

LINKED ARTICLE

This article is commented on by Sershen, pp. 1000–1002 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02072.x     

Behavioral and morphological endpoints: as an early response to sublethal malathion intoxication in the freshwater fish,Labeo rohita

A short-term definitive test by the static renewal bioassay method was conducted to determine the acute toxicity (LC₅₀) of commercial-grade organophosphate insecticide, malathion (50% EC) on the freshwater fish, Labeo rohita. Carp fingerlings were exposed to different concentrations of malathion for 96 hours. The acute toxicity (LC₅₀) of malathion was found to be 4.5?µg/L. One tenth (1/10, 0.45?µg/L) of the acute toxicity value was selected as the sublethal concentration for subacute studies. The fish were exposed to sublethal concentration for 1, 5, 10, and 15 days and allowed to recover in toxicant-free medium for 15 days. Behavioral responses and morphological deformities were studied in the experimental tenures. Fish in toxic media exhibited irregular, random, circular swimming movements, hyperexcitability, loss of equilibrium, and sinking to the bottom. Caudal bending was the prime morphological malformation. The behavioral and morphological deformities were due to inhibition of acetylcholinesterase (AChE) activity. Inhibition of AChE activity results in excess accumulation of acetylcholine in cholinergic synapses, leading to hyperstimulation and cessation of neuronal transmission (i.e., paralysis). The carp were found under stress, but mortality was insignificant at the sublethal concentration tested. Impaired behavioral responses and morphological deformities were observed during recovery. This may be a consequence due to inhibition of brain and muscular AChE by malaoxon, via the biotransformation of sequestered malathion.     

Cholinergic activity in the rat hippocampus, cortex and striatum correlates with locomotor activity: an in vivo microdialysis study

The possible relationship between behavioral arousal and acetylcholine release in the striatum, hippocampus and frontal cortex was investigated in rats. In vivo microdialysate concentrations of acetylcholine and choline from these brain structures, and photocell beam interruptions (as a measure of behavioral arousal), were measured simultaneously under three conditions: after injections of 1) vehicle or 2) scopolamine (0.4 mg/kg), and 3) before and after the beginning of the rats' night cycle. Dialysate concentrations of ACh in all 3 brain structures and locomotor activity were increased after scopolamine and the onset of the lights out condition. Vehicle injections transiently increased ACh in the hippocampus and cortex and caused short-lasting increases in locomotor activity. Under all conditions, the release of ACh from each of the 3 brain structures correlated with the level of locomotor activity.     

Neuroprotection by aminoguanidine after lateral fluid-percussive brain injury in rats: a combined magnetic resonance imaging,histopathologic and functional study

The present study examined the effects of a selective inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG), on neuronal cell survival and post-traumatic recovery in rats following a lateral fluid percussive brain injury. Daily treatment of AG at the dosage of 100 mg/kg or normal saline was given intraperitoneally into rats starting 2 h before or 30 min after brain injury. Treatment with AG significantly reduced lesion volumes in the brains of rats after injury, as evaluated by high-resolution magnetic resonance imaging (MRI). Immunohistochemical analysis showed a marked induction of iNOS expression in brain macrophages ipsilateral to the injury. Apoptotic neurons were observed in the ipsilateral cerebral cortex by in situ terminal transferase d-UTP nick-end labelling (TUNEL) and caspase-3 immunohistochemistry. In rats receiving prophylactic or post-injury treatment of AG, the number of degenerating neurons was markedly reduced in the cerebrum compared to those receiving saline injection. The location and extent of these pathologic changes correlated with MRI findings. Neurobehavioral studies showed that rotametric performance, grip-strength score, total and ambulatory locomotor responses and acoustic startle response were reduced in rats subjected to the injury but were significantly improved in AG-treated rats. It is suggested that inhibition of iNOS by AG may represent a potential therapeutic strategy for the treatment of traumatic brain injury.     

Effect of prolonged administration of tianeptine on 5-HT neurotransmission: an electrophysiological study in the rat hippocampus and dorsal raphe

Extracellular unitary recordings of dorsal hippocampus CA₃ pyramidal neurons and of dorsal raphe 5-hydroxytryptamine (5-HT) neurons were used to assess the effect of tianeptine, a putative antidepressant, on the efficacy of 5-HT neurotransmission. Sustained tianeptine administration (20 mg/kg/day, s.c. × 14 days) did not modify the firing activity of 5-HT neurons in the dorsal raphe. Their responsiveness to the intravenous injection of LSD, an agonist of the somatodendritic 5-HT autoreceptor, and of 8-OH-DPAT, a selective 5-HT_1A agonist, was also unaffected by this treatment. The responsiveness of CA₃ pyramidal neurons to microiontophoretic application of 5-HT remained unchanged after sustained tianeptine administration, but it was markedly enhanced in rats treated with repeated electroconvulsive shocks. Finally, the duration of suppression of firing activity of CA₃ pyramidal neurons produced by electrical stimulation of the ascending 5-HT pathway, delivered at 1 Hz and 5 Hz, was not modified in rats treated with tianeptine. Methiothepin, an antagonist of the terminal autoreceptor enhanced the effectiveness of 5-HT pathway stimulation to the same extent in control and tianeptinetreated rats. The present results indicate that, administered at a dose known to stimulate 5-HT reuptake (20 mg/kg/day, s.c.; by minipump), and for a period of time (14 days) for which other antidepressant treatments have been shown to enhance 5-HT function, tianeptine does not modify the efficacy of 5-HT synaptic transmission in the rat hippocampus.     

Evidence for cortical dysfunction and widespread manganese accumulation in the nonhuman primate brain following chronic manganese exposure: a 1H-MRS and MRI study.

Exposure to high levels of manganese (Mn) is known to produce a complex neurological syndrome with psychiatric disturbances, cognitive impairment, and parkinsonian features. However, the neurobiological basis of chronic low-level Mn exposure is not well defined. We now provide evidence that exposure to levels of Mn that results in blood Mn concentrations in the upper range of environmental and occupational exposures and in certain medical conditions produces widespread Mn accumulation in the nonhuman primate brain as visualized by T1-weighted magnetic resonance imaging. Analysis of regional brain Mn distribution using a "pallidal index equivalent" indicates that this approach is not sensitive to changing levels of brain Mn measured in postmortem tissue. Evaluation of longitudinal 1H-magnetic resonance spectroscopy data revealed a significant decrease (p = 0.028) in the N-acetylaspartate (NAA)/creatine (Cr) ratio in the parietal cortex and a near significant decrease (p = 0.055) in frontal white matter (WM) at the end of the Mn exposure period relative to baseline. Choline/Cr or myo-Inositol/Cr ratios did not change at any time during Mn exposure. This indicates that the changes in the NAA/Cr ratio in the parietal cortex are not due to changes in Cr but in NAA levels. In summary, these findings suggest that during chronic Mn exposure a significant amount of the metal accumulates not only in the basal ganglia but also in WM and in cortical structures where it is likely to produce toxic effects. This is supported by a significantly decreased, in the parietal cortex, NAA/Cr ratio suggestive of ongoing neuronal degeneration or dysfunction.     

Harmonisation of rat fetal skeletal terminology and classification. report of the third workshop on the terminology in developmental toxicology: Berlin, 14–16 September 2000

The initial efforts of the Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) and the Free University of Berlin to standardise terminology in the field of developmental toxicology began in 1995. Procedures were undertaken to harmonise the terminology used by the International Federation of Teratology Societies (IFTS) and the International Programme on Chemical Safety (IPCS). This article reflects these activities and is a report on the Third Workshop on the Terminology in Developmental Toxicology held in September 2000. This Workshop served as a forum to discuss the results of a survey on the classification of skeletal anomalies that had been previously sent to scientists active in the field. Although high agreement was reached among the evaluators for several terms, the use of a number of terms was rather variable. Therefore, the discussions at the workshop among the experts from research institutions, regulatory agencies, and industry were mainly focussed on those terms for which there was disagreement and/or uncertainties and the possible reasons. Pictures provided by the participants for the illustration of “grey zone” anomalies constituted the basis for detailed discussions. In many of the cases with lower agreement, decisions were facilitated by the provision of the corresponding picture. The main reasons for lower agreement were imprecise terms, insufficient knowledge on postnatal consequences, theoretical terms that are unlikely to occur in isolation, and the possibility of observing a range of severity that might be decisive for the classification of either a malformation or variation. The attendees concluded that “grey-zone” anomalies will never disappear completely and that for the assessment, the grade of severity and/or the frequency of the observation can be decisive for the terminology chosen. A Joint IPCS/IFTS Project was proposed to further consensus of terminology and classification and to link these anomalies to pictures at different skeletal sites. In order to support the harmonisation of regulatory decisions, it was proposed to establish a “Clearinghouse” System under the umbrella of the IPCS. The Clearinghouse could be contacted either by the regulatory authorities or by any company to clarify their queries, particularly with regard to registration or authorisation processes. Finally, it was recommended to also carry out a similar survey on “soft tissue anomalies” and “external findings.” The results of this survey will be discussed at a Joint IPCS/IFTS Workshop in Berlin in 2002.