PubMed Health⌕ Search

Biomedical subjects

G Winneke

Publications and source records attributed to G Winneke.

At least 19 recordsLinked to original sources
PubMed1999

Developmental exposure of rats to a reconstituted PCB mixture or aroclor 1254: effects on organ weights, aromatase activity, sex hormone levels, and sweet preference behavior.

Polychlorinated biphenyls (PCBs) are lipophilic industrial chemicals which are regularly detected in human breast milk, serum, and tissues. They possess hormone-modulating properties, and, when transferred transplacentally to the developing fetus, PCBs have been shown to induce persistent sex-specific neurobehavioral deficits. Interactions of PCBs with sex steroid-modulated neural differentiation could in part account for such effects. To test this hypothesis, female Long-Evans rats were exposed via food containing 40 mg/kg of either a reconstituted PCB mixture (RM), composed according to the congener-pattern in human breast milk, or the technical PCB mixture Aroclor 1254 (A1254). The exposure period started 50 days prior to mating and was terminated at birth (postnatal day 0: PND 0). Aromatase (CYP 19) activity was determined in hypothalamus/preoptic area (HPOA) brain-sections from newborn male pups. This enzyme converts testosterone (T) to 17beta-estradiol (E(2)) and plays a key role in sexual brain differentiation. Moreover, serum concentrations of T and E(2), physical development, organ weights, exposure levels, and sex-specific behavior were evaluated at different life stages. On PND 0, a reduced aromatase activity was detected in the HPOA of male RM-pups compared to controls. Female RM-weanlings exhibited significantly elevated uterine wet weights on PND 21, which is a marker for estrogenic activity. In the adult stage (PND 170), male offspring with maternal exposure to either PCB mixture showed markedly reduced testes weights and serum testosterone levels, thus demonstrating persistent antiandrogenic effects. On PND 180, male RM-rats exhibited a behavioral feminization in a sweet preference test, suggesting long-lasting changes in neuronal brain organization caused by the perinatally suppressed aromatase activity. The results suggest that maternal exposure to the RM, the pattern of which is similar to the PCB spectrum in human milk, results in more distinct effects on sex steroid-dependent processes and behavior than the technical PCB mixture A1254. PCB levels in brain and adipose tissue of the exposed offspring lay within 1-2 orders of magnitude above background concentrations in humans.

Aging↗
PubMed1999

Characterization of potential endocrine-related health effects at low-dose levels of exposure to PCBs.

This article addresses issues related to the characterization of endocrine-related health effects resulting from low-level exposures to polychlorinated biphenyls (PCBs). It is not intended to be a comprehensive review of the literature but reflects workshop discussions. "The Characterizing the Effects of Endocrine Disruptors on Human Health at Environmental Exposure Levels," workshop provided a forum to discuss the methods and data needed to improve risk assessments of endocrine disruptors. This article contains an overview of endocrine-related (estrogen and thyroid system) interactions and other low-dose effects of PCBs. The data set on endocrine effects includes results obtained from mechanistic methods/ and models (receptor based, metabolism based, and transport protein based), as well as from (italic)in vivo(/italic) models, including studies with experimental animals and wildlife species. Other low-dose effects induced by PCBs, such as neurodevelopmental and reproductive effects and endocrine-sensitive tumors, have been evaluated with respect to a possible causative linkage with PCB-induced alterations in endocrine systems. In addition, studies of low-dose exposure and effects in human populations are presented and critically evaluated. A list of conclusions and recommendations is included.

Animals↗
PubMed1998

Developmental neurotoxicity of polychlorinated biphenyls (PCBS): cognitive and psychomotor functions in 7-month old children.

Neurobehavioral effects of polychlorinated biphenyls (PCBs) at environmental levels of exposure have been reported in cross-sectional and prospective studies in infants and children. However, observations differ for effect spectrum, persistence and effective matrix (cord plasma, maternal plasma or milk). In order to improve risk assessment by clarifying some of these uncertainties, a European multicentric study was set up. Results from the German (Düsseldorf) cohort covering 171 healthy mother-infant pairs are given. The sum of PCB congeners 138, 153 and 180 (sigma PCB) in cord plasma and maternal milk was used to describe neonatal PCB exposure. Mean sigma PCB-concentrations were 0.55 ng/ml in cord plasma and 427 ng/g fat in breastmilk. This report covers the Bayley II mental (MDI) and psychomotor development index (PDI) as well as the Fagan Test of Infant Intelligence (Visual Recognition Memory) taken at 7 months of age in relation to neonatal sigma PCB. After confounder-adjustment significant negative associations were found between sigma PCB in milk and MDI (P < 0.05), whereas the other associations proved insignificant.

Cognition↗
PubMed1997

Assessment of neurophysiologic and neurobehavioral effects of environmental pollutants in 5- and 6-year-old children.

To investigate the effects of environmental pollutants on neuronal functions in residents of different areas in Germany, a mobile laboratory was developed. The equipment permits the assessment of neurophysiologic as well as neurobehavioral parameters in epidemiologic studies. In two sets of field experiments in 1991 and 1994, more than 700 children, 5 and 6 years old, were tested in three different towns in East and West Germany. Visual functions were measured neurophysiologically by visually evoked potentials, using pattern reversal stimulation. By means of psychophysical methods, the contrast sensitivity was tested and the visual acuity assessed. Finger tapping, simple reaction time, vigilance, pattern comparison, pattern memory, and memory of geometric figures were measured using the Neurobehavioral Evaluation System (NES1 and NES2). In a preliminary analysis, the outcomes of the tests were related to the children's blood lead levels. The experiences with the field studies showed that all tests could be successfully performed even in pre-school-age children. The mobile laboratory has proven to be a useful tool for the detection of neurotoxic effects of environmental pollutants in larger populations, providing the opportunity for flexible operation at different locations.

Child↗
PubMed1997

Effects of maternal exposure to 3,3',4,4'-tetrachlorobiphenyl or propylthiouracil in rats trained to discriminate apomorphine from saline.

In the present experiment drug discrimination was examined in rats after maternal exposure to 3,3',4,4'-tetrachlorobiphenyl (PCB 77) using apomorphine (APO) as the training drug at a dose reported to act on dopamine D2 receptors. A group with maternal exposure to 6n-propyl-2-thiouracil (PTU) was included as a positive control for effects induced by PCB 77 on thyroid hormones. On gestational day (GD) 19 reduced levels of free and total thyroxine (FT4, TT4) and free triiodothyronine (FT3) were detected in dams exposed to PCB 77 or PTU. In the offspring decreases in levels of FT4 and TT4 were found in both treated groups on postnatal day (PND) 21, while reductions of FT3 were observed only in the PTU group. PTU-treated rats needed more daily sessions for successful discrimination between apomorphine and saline. There were no differences between groups in generalization tests and sessions with the D2/D3 agonist quinpirole, the D2 antagonist haloperidol plus APO, or with the GABAergic drug pentobarbital and only minor differences in sessions with the D1 agonist SKF-38393. Differences between controls and groups exposed to PCB 77 or PTU were detected in a blocking test using the mixed serotonin 5-HT1A agonist and partial D2 antagonist buspirone. This outcome suggests long-lasting effects by developmental exposure to PCB 77 on the interaction between dopaminergic and serotonergic processes which may be mediated by effects on thyroid hormone levels.

Animals↗
PubMed1997

Neurobehavioral aspects of lead neurotoxicity in children.

Neurobehavioural toxicity in occupational lead-exposure has typically not been observed at blood lead-concentrations (PbB) below 400 micrograms/l (e.g. 1, 2), whereas in environmentally exposed children such deficit has been reported to occur down to PbB of 100-150 micrograms/l and, perhaps, even below this range (4). Both cross-sectional and prospective studies have arrived at similar conclusions in this respect. The preferred endpoint in most such studies has been the IQ-measure, which has good psychometric qualities, is sufficiently well standardized to be comparable across studies, and exhibits attractive simplicity for the regulator in a public health context. Metaanalyses on both cross sectional and prospective studies in lead exposed children have concluded that a typical doubling of PbB from 100 to 200 micrograms/l is associated with an average loss of IQ of 1-3 points (3, 4). It should also be pointed out, however, that the IQ-focus has also interfered with systematic efforts to identify more specific lead-induced functional deficits by means of more detailed neurobehavioral analyses (5). Some neuropsychological findings in lead exposed children suggest that part of the impairment resembles performance deficit found to be characteristic for children presenting with signs and symptoms of attention deficit disorder.

Child↗
PubMed1997

Persistent decrease of the dopamine-synthesizing enzyme tyrosine hydroxylase in the rhesus monkey retina after chronic lead exposure.

One of the toxic effects of lead in the CNS is an altered functional state of the catecholamine system, especially a reduction in the activity of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine synthesis. Here we report on a lead-induced decrease in TH-content in neurones of the rhesus monkey retina. Rhesus monkeys were pre- and postnatally exposed to 0, 350, or 600 ppm of lead acetate (Pb) in the diet over 9 years. Lead exposure was followed by a 35-month period of lead-free diet. During this period, blood lead levels of the treated animals declined to nearly those of the untreated controls. Subsequently the animals were sacrificed and the retinas processed for TH immunocytochemistry. The fluorescent dye FITC was used to visualise the antibody reaction. Photometric measurements of the fluorescence intensity of stained neurones were made with a laser scanning microscope. In the rhesus monkey retina two types of TH-immunoreactive neurones are present. In the bright fluorescent type, lead exposure resulted in decreased fluorescence intensity and altered the intensity profile of the TH-immunoreactive cells in a dose-dependent manner. In these cells, fluorescence intensity was 0.53 and 0.22 for 350 ppm Pb and 600 ppm Pb respectively when the fluorescence intensity of the untreated controls (0 ppm Pb) is taken as 1. Both lead doses also reduced the number of ascending fibres in the inner nuclear layer and the dense staining of fibres in sublayer 1 of the inner plexiform layer. The weakly fluorescent cell type disappeared to a large extent under 350 ppm Pb treatment and was not detectable in the 600 ppm Pb group. The results demonstrate that lead exposure affects the dopaminergic retinal amacrine cells by reducing the TH-content in these neurones and that this neurotoxic effect persists beyond the end of exposure.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening. I. Background and genesis.

Numerous events over several years culminated in recognition of the need to explicitly evaluate the nervous system as a potential target for environmental chemicals. Based on recommendations from several international expert panels, the International Programme on Chemical Safety (IPCS) sponsored the Collaborative Study on Neurobehavioral Screening Methods. A Steering Committee was created to oversee the project, develop the testing protocol, recruit participating laboratories and review and analyze the data. The protocol specified the tests, the chemicals (supplied from a common source) and the exposure conditions (acute and repeated dosing). Test methods were based upon existing practices in toxicological screening as well as recent advances in neurotoxicity screening. Chemicals were selected to produce different profiles of neurobehavioral effects. Considerable latitude was afforded the participating laboratories in the choice of several key variables (e.g., strain of rat, testing device for motor activity assessment) that could potentially affect the results of the experiments. The approach therefore provided a standardized yet flexible protocol for evaluating the reproducibility of neurobehavioral screening data in diverse laboratory settings.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: II. Protocol design and testing procedures.

This paper describes the development of the protocol for the International Programme on Chemical Safety (IPCS)-sponsored Collaborative Study on Neurobehavioral Screening Methods, including background on the methods and chemicals selected, as well as details concerning the conduct of the collaborative study, including proficiency testing, range-finding and main study. Participating laboratories in the collaborative study received training in the conduct and scoring of the behavioral tests and each laboratory received a video training film to train additional personnel as needed. Each of the eight laboratories that chose to participate in the study completed proficiency testing and assessed seven representative chemicals using a functional observational battery and automated motor activity assessment. The seven chemicals studied were acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples of the chemicals from a common source. Each laboratory derived doses for single and repeated administration based on the determination of a within-laboratory acute "top dose." Animal strains were not standardized and laboratory conditions were standardized to a limited degree in order to judge the general utility and robustness of these procedures in a diversity of testing situations.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: VII. Summary and conclusions.

In the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods, eight participating laboratories used a standard battery of behavioral tests to determine, in rats, the effects of seven representative chemicals following acute and repeated dosing. The results of the collaborative study indicate good agreement across laboratories with regard to the data collected in vehicle controls. It was clear, however, that some behavioral measures had significantly more variability than other tests. The laboratories also demonstrated the ability to detect known neurotoxic chemicals and identify profiles of effects that differed from non-neurotoxic agents. The results of the study suggest that appropriate training of personnel is crucial to ensure the reliability of the test battery. The results also underscore the importance of dose selection in behavioral screening studies, since it is sometimes difficult to determine the specificity of behavioral changes in animals receiving high doses of some chemicals. The collaborative study also emphasizes the need to utilize a battery of tests in screening a wide range of potential neurotoxic agents. Analysis of data from such studies poses unique challenges due to the large number of tests and test times, and the consequent possibility of false positives. Some statistical concerns may be alleviated by grouping the results from tests that measure similar functions into neurobiological domains. Although this approach improves confidence in the biological relevance of chemical-induced changes in behavior, it may also lead to false negatives. The exploration of other statistical approaches to analyze data from experiments using a test battery is encouraged. Nevertheless, results of the collaborative study strongly support the use of behavioral tests in hazard identification.

Animals↗
PubMed1996

Determination of polychlorinated biphenyls and chlorinated pesticides in human body fluids and tissues.

A fast and reliable method for the determination of polychlorinated biphenyls (PCBs) and chlorinated pesticides in human body fluids and tissues is presented. Sample clean-up and selective enrichment of analytes are carried out by liquid column chromatography without a prior solvent extraction step. Analytes are determined either by high-resolution capillary gas chromatography with mass spectrometric detection, or by dual-column GC followed by electron-capture detection. A procedure is described for the simultaneous determination of environmental levels of the PCB congeners 28, 52, 101, 138, 153 and 180 in human cord serum. The method allows the simultaneous determination of chlorinated pesticides such as aldrin, DDT, DDE, BHC and HCB and is also applicable to other biological matrices, such as bone marrow or tissues.

Bone Marrow↗
PubMed1996

The neurobehavioural toxicology and teratology of lead.

When comparing neurobehavioural observations from occupational lead-exposure of adults on the one hand, and environmental lead exposure of children on the other, it appears that the developing relative to the mature brain is more at risk. Neurobehavioural toxicity in occupational lead-exposure has typically not been observed at blood lead-concentrations (PbBs) below 400 micrograms/l, whereas ih environmentally exposed children such deficit has been reported to occur down to PbB of 100-150 micrograms/l and, perhaps, even below this range. Both cross-sectional and prospective studies have arrived at similar conclusions in this respect. The preferred endpoint in most such studies has been the IQ-measure, which has good psychometric qualities, is sufficiently well standardized to be comparable across studies, and exhibits attractive simplicity for the regulator in a public health context. At the same time, however, this IQ-focus has also interfered with systematic efforts to identify more specific lead-induced functional deficits by means of more detailed neurobehavioural analyses (Bellinger 1995). Metanalyses on both cross sectional and prospective studies in lead-exposed children have concluded that a typical doubling of PbB from 100 to 200 micrograms/l is associated with an average IQ-loss of 1-3 points (Pocock et al. 1994; WHO 1995), and no threshold has as yet been identified. Since, however, cause-effect contingencies necessarily remain doubtful in epidemiological studies if the observed effects are as subtle as these, experimental studies in animals have become helpful in supporting the causative role of lead to produce neurobehavioural deficit at steady-state PbB down to about 150 to 200 micrograms/l. Such deficit has been demonstrated by means of a variety of learning/memory models with positive and negative reinforcement contingencies in the rat--and in primates as well. It has also been shown in such studies that neurobehavioural deficit subsequent to early developmental exposure extends long into adulthood after cessation of exposure at weaning. It, therefore, appears that the neurobehavioural teratology of lead has more convincingly been demonstrated in animal models than in human exposure conditions, so far. A coherent theory to explain the particular vulnerability to lead of the developing brain is still lacking. Recent data do suggest, however, that Pb-induced disruption of calcium homeostasis in the immature brain might interfere with normal brain development.

Abnormalities, Drug-Induced↗
PubMed1996

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

The astroglial cytoskeletal element, glial fibrillary acidic 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 (E0-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.

Animals↗
PubMed1996

Impairment of schedule-controlled behavior by pre- and postnatal exposure to hexachlorobenzene in rats.

Hexachlorobenzene (HCB) is still frequently found at elevated levels in human adipose tissue and breast milk. As intoxication with HCB causes neurological disturbance in human beings, the purpose of the present study was to examine neurobehavioral functions in rats after pre- and postnatal exposure. Female rats were fed diets with 0, 4, 8, or 16 mg HCB/kg diet. Exposure started 90 days prior to mating and was continued throughout mating, gestation, and lactation. Thereafter, the offspring were given the same diets as their respective mothers. HCB levels were determined in the brain, the liver, and in the adipose tissue from virgin rats, dams, and the offspring. Concentrations on a lipid basis were found to decline in the order adipose > liver > brain. The exposure levels chosen did not cause gross toxic effects in dams or offspring. There were dose-related increases in liver-to-body-weight ratios in exposed dams, but not in unmated females treated alike. Behavioral testing was conducted in the offspring. Examination of open-field activity on PND 21, and of active avoidance learning on PND 90 failed to reveal significant differences between groups. Training of operant behavior started at the age of 150 days in the offspring from the control, the 8-mg group, and the 16-mg group. Animals were trained on a fixed interval schedule of 1 min (FI-1). On this schedule, responses were reinforced by a food pellet every time 1 min had elapsed after the preceding reinforcement. There were dose-dependent reductions in the post-reinforcement pause, e.g. the time between each reinforcement and the first reaction emitted after it. In addition, the index of curvature, which describes the efficiency of performance on the FI-1 schedule, was decreased in a dose-dependent fashion.

Adipose Tissue↗