Herbert Wiegand

Impairment of long-term potentiation and learning following chronic lead exposure

Chronic lead exposure during brain development is known to affect functions of the central nervous system. We exposed rats chronically to low levels of lead at different developmental stages in order to determine the most sensitive periods of exposure. Active avoidance learning and hippocampal long-term potentiation were tested in the same animals. If the exposure period comprised the prenatal and the early postnatal phase and was continued into adulthood, learning as well as long-term potentiation were impaired. Starting the exposure not before 16 days postnatally, however, neither affected learning nor hippocampal potentiation. These results reflect the higher vulnerability of the immature as compared to the mature hippocampus to lead-induced functional deficits.

LONG-TERM POTENTIATION IN RAT HIPPOCAMPAL SLICES IS IMPAIRED FOLLOWING ACUTE LEAD PERFUSION

Orthodromically evoked field potentials were recorded in the CA1 region of hippocampal slices while perfusing the slices with media containing lead acetate. High-frequency stimulation (HFS) was applied to the stratum radiatum during lead perfusion. In half of the slices investigated, HFS resulted in an initial increase of the evoked responses which decayed again after about 10 min. In the other half the evoked responses increased only after the washout of lead and this potentiation was comparable to untreated controls. The lead-induced depression of the long-term potentiation might be related to the behavioral deficits observed in chronically lead-exposed mammals.

Neurophysiological and psychophysical measurements reveal effects of acute low-level organic solvent exposure in humans

SummaryThe organic solvent tetrachloroethylene (Per) is proposed to be a human neurotoxicant. In order to evaluate whether the sensory system is affected by Per at low concentrations, two groups of male volunteers were exposed in an inhalation chamber to 10 and 50 ppm Per, respectively. During the inhalation exposure, which lasted for 4 h per day on four consecutive days, visually evoked potentials (VEPs) and brainstem auditory evoked potentials (BAEPs) were measured. In addition, in some of these volunteers, the visual contrast sensitivity was determined psychophysically. In the group exposed to 50 ppm Per, the VEP peak latencies N75, P100 and N150 increased in the course of the inhalation period. A comparison of the two groups revealed statistically significant differences of these latency changes during Per exposure. In contrast, the BAEPs of the two groups did not differ significantly during the whole exposure period. The contrast sensitivity functions showed a tendency of increased threshold contrasts at low and intermediate spatial frequencies during exposure to 50 ppm Per. The results indicate visual system dysfunctions in terms of delayed neuronal processing time and altered contrast perception due to acute Per exposure.

Visual Functions in 6-Year-Old Children in Relation to Lead and Mercury Levels

Within a larger comparative environmental health screening program in East and West Germany we investigated functions of the developing visual system in field experiments in a total of 384 children living in three different areas. Visual functions were assessed neurophysiologically by visual-evoked potentials (VEPs) and psychophysically by measuring the contrast sensitivity (CS). Blood lead concentrations and urinary mercury levels were used as markers of environmental and/or amalgam-derived exposure, respectively. The relationships among lead and mercury concentrations and the neurophysiological and psychophysical outcomes were investigated by means of linear regression analysis. After adjusting for confounding effects, statistically significant lead-related changes were found only for some of the VEP interpeak latencies, while some of the CS values were significantly reduced with increasing mercury concentrations. All other outcome variables were not significantly related to lead or mercury levels. It is concluded that even at blood lead levels in the range of 14 to 174 micrograms/l and at very low urinary mercury levels subtle changes in visual system functions can be measured.

Chronic prenatal and postnatal Pb2+ exposure increases [3H]MK801 binding sites in adult rat forebrain

We have measured the binding of [3H]MK801 to the N-methyl-D-aspartate (NMDA) receptor-ion channel in membrane preparations from adult rat forebrain exposed to lead (Pb2+) during gestation, lactation, and postweaning. Our results indicate a 30.9% increase in the number of [3H]MK801 binding sites in Pb2+ exposed animals relative to controls. No significant changes in the affinity constant were observed. The level of blood Pb2+ for which such changes were measured was 13.9 +/- 2.8 micrograms/dl. These results indicate that alterations in the NMDA receptor-ion channel complex are present at blood Pb2+ levels which are environmentally relevant and suggest that chronic Pb2+ exposure during development can influence the NMDA receptor complex in the adult rat brain.

Glial fibrillary acidic protein and RNA expression in adult rat hippocampus following low-level lead exposure during development

The astroglial cytoskeletal element, glial fibrillary acidie protein (GFAP), is a generally accepted sensitive indicator for neurotoxic effects in the mature brain. We used GFAP as a marker for structural changes in rat hippocampus related to chronic low level lead exposure during different developmental periods. Four groups of rats were investigated: a control group, a perinatal group, which was exposed during brain development (EO-P16), a permanent group, exposed during and after brain development (E0-P100), and a postweaning group, exposed after brain development (P16–P100). Sections were processed for light microscopy (hematoxylin-eosin, Nissl, periodic acid Schiff (PAS) and GFAP-specific immunohistology), for electron microscopy, and for in-situ hybridization (GFAP). Sections were prepared from animals tested for active avoidance learning (AAL) and long-term potentiation (LTP). Chronic lead exposure did not affect glial and neuronal functions, as assessed by LTP and AAL, when lead exposure started after brain development (postweaning group). In this group, astrocytes displayed increased GFAP and GFAP gene transcript levels. However, lead exposure affected neuronal and glial function when the intoxication fell into the developmental period of the brain (perinatal and permanent groups). In these groups, LTP and AAL were impaired, and astrocytes failed to react to the toxic exposure with an adequate increase of GFAP and GFAP gene transcripts. Although GFAP is an accepted marker for neurotoxicity, our data suggest the marker function of GFAP to be restricted to postnatal toxic insult.

Ambient Particulate Matter Affects Cardiac Recovery in a Langendorff Ischemia Model

Exposure to ambient particulate matter (PM) is associated with increased mortality and morbidity among subjects with cardiovascular impairment. We hypothesized that exposure of spontaneously hypertensive (SH) rats to PM impairs the recovery of cardiovascular performance after coronary occlusion and reperfusion-ischemia. SH rats were exposed by intratracheal instillation to saline, standard urban PM (Ottawa dust EHC-93, 10 mg/kg body weight) or endotoxin (lipopolysaccharides LPS, 350 EU/animal) to induce a similar pulmonary inflammation. At 4 h postexposure, hearts were isolated and retrograde perfused in a Langendorff model. The experimental protocol included 35 min of coronary occlusion followed by 120 min of reperfusion, during which left ventricular developing pressure (LDVP), coronary flow (CF), and heart rate (HR) were measured. Baseline LVDP in particle-instilled SH rats was significantly decreased compared to saline-instilled animals. In addition, after ischemia the recovery of LDVP was much slower in rats pretreated with PM or LPS compared to saline instilled rats. The direct effects of the soluble PM fraction and the role of Zn2+ were also tested cardiomyocytes (H9C2 cells). Both particle-free filtrate and Zn2+ inhibited ATP or ionophore-stimulated calcium influx in cardiomyocytes. This inhibitory effect was related to an effect on calcium channels, as shown with Nifedipine. This study provides evidence that exposure to instillation of PM has reversible acute effects on the recovery of cardiac physiological parameters after ischemia. The effect may be caused by a direct action of soluble metals on calcium homeostasis in heart, but pulmonary inflammation may also play a significant role.

Inhibition of long-term potentiation in developing rat visual cortex but not hippocampus by in utero exposure to polychlorinated biphenyls

The neurotoxic potential of polychlorinated biphenyls (PCBs) depends on the structure of the congener as well as on the age of the exposure. We exposed rats prenatally to a coplanar congener (PCB-77) or to a non-coplanar congener (PCB-47) and measured the amount of long-term potentiation (LTP) at postnatal days 11-19 in the visual cortex and hippocampus. While PCB-77 exposure affected LTP statistically significantly in cortical but not hippocampal slices, the exposure to PCB-47 was much less effective.

Synaptic plasticity in the CA1 and CA3 hippocampal region of pre- and postnatally lead-exposed rats.

The effects of low level lead exposure on synaptic plasticity in hippocampal regions CA1 and CA3 were determined in adult rats in vitro. In the CA3 region the NMDA (N-methyl-D-aspartate)-independent mossy fiber-CA3 synapse potentiation was not influenced by chronic pre- and postnatal lead exposure, while in the same rats, in the CA1 region the NMDA-dependent long-term potentiation was slightly reduced as compared to controls. Paired-pulse facilitation was neither impaired in CA1 nor in CA3 region in the lead-exposed rats. These findings suggest that NMDA-dependent forms of synaptic plasticity are more susceptible to chronic low level lead exposure than NMDA-independent forms of potentiation or paired-pulse facilitation.

Congener specific effects by polychlorinated biphenyls on catecholamine content and release in chromaffin cells

Abstract The effects of the non-planar polychlorinated biphenyl (PCB) congener 2,2′,4,4′-tetrachlorobiphenyl (2,4-TCB) and of the coplanar PCB congener 3,3′,4,4′-tetrachlorobiphenyl (3,4-TCB) were investigated on the catecholamine content and release from bovine adrenal chromaffin cells in culture. Each congener was tested at three concentrations (20, 50 and 100 μM) and two exposure periods (24 h and 5 days). Catecholamine release induced by K+-stimulation as well as catecholamine content of Triton X-100 treated cell cultures were examined using high-performance liquid chromatography (HPLC). 2,4-TCB showed dose- and time-dependent effects. 2,4-TCB at 100 μM reduced the K+-stimulated catecholamine release after 24 h of exposure. After 5 days of exposure, 2,4 TCB at 50 and 100 μM drastically reduced the K+-stimulated catecholamine release. 3,4-TCB even at a concentration of 100 μM over exposure of either 24 h or 5 days had no effects on the K+-stimulated secretion. When chromaffin cells, exposed to 2,4-TCB, were lysed with 0.5% Triton X-100, a dose- and time-dependent reduction of the catecholamine content appeared. The 3,4-TCB did not reduce the catecholamine content. Conversely there seemed to be a trend towards an increase in catecholamine content. Spontaneous release of catecholamines was strongly increased by the non-planar 2,4 TCB, while the coplanar 3,4 TCB showed no effects on this parameter. Furthermore, the effects of 2,4 TCB appeared to be reversible after replacing the highest concentration (100 μM) of the TCB-solution with culture-medium at the end of the 24-h exposure. Thus, K+-stimulated catecholamine release and the catecholamine content of bovine adrenal chromaffin cells was effectively reduced by the non-planar PCB congener whereas spontaneous catecholamine release was strongly increased. The coplanar PCB congener was ineffective at the same conditions.