Neurobehavioral abnormalities induced by prenatal exposure to substances of abuse--stating the problems.
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Animals↗
Biomedical subjects
J Elsner
Publications and source records attributed to J Elsner.
Review of the multiple chemical exposure factors which may disturb human behavioral development.
Previous research both in humans and laboratory animals provides evidence that prenatal exposure to metals, pollutants and drugs may impair the neurobehavioral development of the offspring. This may induce mental and psychomotor disturbances as well as learning, behavioral and sensory disorders. However, proof for a strict causality between some low-level exposures to chemicals and behavioral developmental dysfunctions, is often considered still not to be established. The pertinent studies on neurobehavioral developmental toxicity of individual substances (lead, cadmium, organic solvents, PCBs, alcohol, nicotine, diazepam) are reviewed, and the methodologies and conclusions, the missing aspects and the existing problems which still need to be solved in further studies, are discussed. In addition, the necessity of undertaking a broad prospective cohort study on multifactorial influences on the behavioral development of children is emphasized.
Animals↗
Synthesis and surface expression of ICAM-1 in polymorphonuclear neutrophilic leukocytes in normal subjects and during inflammatory disease.
During bacterial peritonitis of patients on continuous ambulatory peritoneal dialysis (CAPD) leukocytes, particularly polymorphonuclear neutrophilic granulocytes (PMNs), migrate into the peritoneal cavity. However, at the site of inflammation PMNs are not sufficiently able to protect the host against micro-organisms. Adhesion molecules, such as ICAM-1 (CD54), are involved in the interaction between endothelial cells and PMNs leading to the accumulation of PMNs at the site of inflammation. As PMNs are the predominant cell type in the peritoneal cavity in peritonitis, the aim of this study was to find out whether PMNs from CAPD peritonitis patients were able to express ICAM-1. Flow cytometric analyses with the anti-CD54 monoclonal antibody demonstrated that normal PMNs constitutively express slight amounts of ICAM-1. In contrast to normal PMNs, peritoneal PMNs from patients with CAPD peritonitis expressed high amounts of ICAM-1 (p = 0.003). Furthermore, ICAM-1 expression on peripheral blood PMNs of these patients significantly differed from PMNs from healthy donor (p = 0.01). Furthermore, Northern blot analysis revealed a weak signal of ICAM-1 mRNA in normal PMNs. However, peritoneal PMNs from CAPD peritonitis patients expressed a strong signal for ICAM-1 mRNA, suggesting that ICAM-1 is newly synthesized when PMNs invade the peritoneal cavity. In summary, this study clearly demonstrates that peritoneal PMNs of CAPD peritonitis express high amounts of ICAM-1 receptor on the level of mRNA and on the surface. Therefore, it is tempting to speculate that peritoneal PMNs interact amongst each other between ICAM-1 and its counter receptors CD11a,b/CD18 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
CD11 Antigens↗
Activation of the respiratory burst in human eosinophils by chemotaxins requires intracellular calcium fluxes.
Eosinophils represent major effector cells in the allergic inflammatory response. Following activation, these cells are capable of mediating tissue damage, particularly by the release of reactive oxygen species. In this study, the role of extracellular and intracellular calcium in the induction of the respiratory burst of human eosinophils was investigated in healthy non-atopic individuals. Pre-incubation of Fura-2-loaded eosinophils with the intracellular calcium chelator 2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid prevented the increase of the [Ca++]i following stimulation by RANTES, C5a and PAF, in concentration-dependent fashion, whereas depletion of extracellular calcium in the test medium by ethyl=eneglycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid was ineffective. To investigate the potential role of extracellular and intracellular calcium on the production of reactive oxygen species, flow-cytometric measurement of H2O2 production by dihydrorhodamine 123 and lucigenin-dependent chemiluminescence were carried out. Chelation of both intracellular and extracellular calcium prevented production of reactive oxygen species after stimulation with C5a, PAF, or RANTES. However, production of reactive oxygen species after stimulation by phorbol myristate acetate, which bypasses post-receptor events by direct activation of protein kinase C, was prevented only after chelation of intracellular but not extracellular calcium. This suggested a Ca(++)-sensitive form of protein kinase C in the activation process of the respiratory burst. These data demonstrate that intracellular and extracellular calcium represent a prerequisite of chemotaxin-induced activation of the respiratory burst in human eosinophils. Thus, intracellular calcium seems to play a central role in the modulation of the respiratory burst in eosinophils and might therefore be an interesting target for drugs that interfere with calcium homeostasis and reduce the tissue destructive power of eosinophils.
Calcium↗
C3a activates the respiratory burst in human polymorphonuclear neutrophilic leukocytes via pertussis toxin-sensitive G-proteins.
In contrast to C5a, which represents a well-established potent activator of the respiratory burst in polymorphonuclear neutrophilic granulocytes (PMN), the functional role of C3a in the activation of PMN is, so far, poorly understood. Herein, the potential role of human C3a in the activation of the respiratory burst in human PMN was investigated. The release of reactive oxygen species (ROS) of PMN from healthy donors was measured by lucigenin-dependent chemiluminescence. C3a dose-dependently induced the production of ROS in human PMN in the range between 10 ng/mL and 1,000 ng/mL, whereas C3a-desArg was inactive. Flow cytometric measurement of H2O2 by dihydrorhodamine-123 labeling of anti-CD16-stained PMN showed that predominantly neutrophilic PMN are responsible for the C3a-induced activation of the respiratory burst. To exclude that C3a stimulation was caused by contamination with C5a, the specificity of C3a-induced activation of PMN was shown using monoclonal antibodies (MoAbs). Accordingly, the effect of C3a was completely abolished in the presence of Fab fragments of a blocking anti-C3a MoAb. In addition, blockade of the C5a receptor by the anti-C5a receptor (anti-C5aR) MoAb, S5/1, totally inhibited the C5a-induced production of ROS, whereas the C3a response in the presence of the anti-C5aR MoAb was unaffected. The specificity of the response was further confirmed by homologous desensitization after restimulation with C3a. In contrast, no cross-desensitization was observed upon stimulation with C5a. The C3a-induced ROS production by PMN was inhibited by pertussis toxin, indicating the involvement of guanine nucleotide-binding proteins (Gi proteins) in the signal transduction process initiated by C3a. In addition, stimulation of PMN by C3a resulted in a transient increase in the cytosolic free calcium concentration ([Ca2+]i) in a dose-dependent manner. In contrast to C3a-induced ROS production, C3a did not induce a chemotactic response in PMN, indicating functional qualitative differences as compared with C5a. In summary, these results show that C3a is a potent activator of the respiratory burst in human PMN. Therefore, these findings point to a novel role of C3a in the pathogenesis of inflammatory diseases associated with increased C3a levels and PMN activation.
Calcium↗
C3a activates reactive oxygen radical species production and intracellular calcium transients in human eosinophils.
Whereas C5a is a well-established potent activator of eosinophils, the functional role of C3a in the activation of eosinophils is, so far, poorly understood. Here, the activation of human eosinophils stimulated with C3a was analyzed and compared to C5a activation. Flow-cytometrical measurements revealed that stimulation of eosinophils by C3a resulted in a transient elevation of the intracellular calcium concentration ([Ca2+]i) in a dose-dependent manner. In addition, the production of reactive oxygen radical species (ROS) of eosinophils after C3a and C5a stimulation was measured by lucigenin-dependent chemiluminescence and quantified by superoxide dismutase-inhibitable reduction of ferricytochrome C. Half maximal and maximal ROS production in response to C3a was observed at 50 ng/ml and 1000 ng/ml, respectively, whereas C3a-desArg was inactive. To ensure that C3a stimulation was not caused by contamination with C5a, monoclonal antibodies were used to demonstrate the specificity of C3a. The effect of C3a was completely abolished in the presence of monovalent antigen-binding fragments of a functionally blocking anti-C3a monoclonal antibody. In addition, blockade of the C5a receptor by the monoclonal anti-C5a receptor antibody S5/1 totally inhibited the C5a-evoked ROS production, whereas the C3a response in the presence of S5/1 was unaffected. Finally, desensitization experiments revealed a homologous desensitization of C3a after restimulation with C3a. In contrast, no cross-desensitization was observed upon stimulation with C5a. Furthermore, the C3a- and C5a-induced production of ROS of eosinophils was totally inhibited by pertussis toxin, indicating the involvement of guanine nucleotide-binding proteins (Gi-proteins). In summary, these results demonstrate that C3a is a potent activator for eosinophils initiating transient [Ca2+]i changes and production of reactive oxygen species. C3a therefore may play a part in the pathophysiology of diseases with eosinophil and complement activation.
Calcium↗
[Ca2+]i-transients and actin polymerization in human neutrophils under stimulation with GRO alpha and complement fragment C5a.
The neutrophil chemotaxins, complement fragment C5a (C5a) and GRO alpha, induced the mobilization of Ca2+ from intracellular stores and the polymerization of actin in human neutrophils as assayed by flow cytometric measurements. [Ca2+]i-transients developed as an "all-or-none" response. Individual neutrophils required different threshold concentrations of added ligand to induce [Ca2+]i-transients which were then always maximal. In contrast, chemotaxin-induced formation of actin filaments in single neutrophils occurred in a dose-dependent manner. Pertussis toxin blocked chemotaxin-induced actin polymerization and [Ca2+]i-transients indicating that both cell responses shared initial activation steps such as ligand binding and activation of guanine nucleotide-binding proteins (G-proteins).
Actins↗
Altered surface marker expression and function of G-CSF-induced neutrophils from test subjects and patients under chemotherapy.
We have previously reported an altered surface marker expression and chemotaxis of G-CSF-induced neutrophils from patients with severe congenital neutropenia. However, effects of G-CSF and influence of the underlying disease on neutrophils could not be discerned. In this study we have evaluated the effects of G-CSF on neutrophil phenotype and function in patients under chemotherapy and in healthy test subjects. We found a significantly enhanced expression of Fc gamma RI, CD14 and CD54 and a decrease in the level of Fc gamma RIII during G-CSF treatment. In addition, motility of G-CSF-induced neutrophils was significantly decreased. The effects were seen in patients under cytotoxic chemotherapy and in healthy test subjects. Surface marker alterations and neutrophil motility were affected by G-CSF administration in a dose-dependent manner. Kinetic studies on neutrophils from healthy test subjects demonstrated that all effects could be seen after a single administration of 300 micrograms G-CSF and began to appear within 4 h. Release of partially immature neutrophils from the bone marrow and indirect activation of these cells by G-CSF are discussed as possible reasons for the findings presented. They demonstrate that G-CSF has profound effects on neutrophil phenotype and function in vivo which might have clinical implications.
Antigens, Surface↗
Changes in light-scatter profile, membrane depolarization and calcium mobilization of neutrophils induced by G-CSF in vivo.
To extend our studies about phenotypical and functional alterations of G-CSF-induced neutrophils we have evaluated their light-scatter profile, mobilization of intracellular calcium ([Ca2+]i) and membrane depolarization after stimulation. A significant increase in the forward scatter signals could be demonstrated in such neutrophils from patients with neutropenias of various origin and from healthy test subjects. This increase began 4 h and returned to normal 96 h after G-CSF injection in the latter group. We found an impairment of [Ca2+]i mobilization in neutrophils from patients with glycogen storage disease type IB after stimulation of these cells with fMLP. It was even more pronounced than in severe congenital neutropenia (SCN). However, [Ca2+]i fluxes were normal when ionomycin was used. Neutrophils from patients with cyclic neutropenia (cyNP) and chemotherapy-induced neutropenia (chNP) mobilized [Ca2+]i similar to those from healthy donors. Furthermore, we found a decreased percentage of neutrophils depolarizing after stimulation with fMLP and PMA in patients with SCN, whereas membrane depolarization was normal in patients with chNP and cyNP. All the alterations found here are suggested to be caused by a partial immaturity of the neutrophils, although in vivo activation and a direct effect of G-CSF on myeloid precursors might be involved.
Calcium↗
Single-step purification of recombinant melanoma growth-stimulating activity by anion-exchange high-performance liquid chromatography.
The cytokine melanoma growth-stimulating activity (MGSA) is a growth factor for melanoma cells and a chemotaxin for neutrophils. Known purification procedures of MGSA from human sources or expression systems give a low yield and require multiple chromatography steps. Here, a fast and high-yield method for the purification of recombinant MGSA is described. Approximately 500 micrograms MGSA were recovered from the bacterial lysate of a 10 liter culture within a day. For this purpose, total mRNA of Hs294T melanoma cells was isolated and cDNA of MGSA was obtained by reverse transcription and polymerase chain reaction. The cDNA of MGSA was subcloned into the expression vector pGEX-2T, generating a fusion with the Schistosoma japonicum glutathione S-transferase gene. The fusion protein was expressed in E. coli DH5a and purified from the bacterial lysate using glutathione-sepharose beads. MGSA was cleaved from the complex of fusion protein and glutathione-sepharose beads with thrombin and purified to homogeneity by anion-exchange high-performance liquid chromatography with a Mono-S-column. The bioactivity of the recombinant MGSA was assessed by chemotactic migration and triggered [Ca2+]i-transients in human neutrophils. In addition, [125I]MGSA bound specifically to undifferentiated human leukemia cells HL-60 transfected with the cDNA of the interleukin-8 (IL-8) receptor beta with similar properties as [125I]IL-8. Thus, this described method might be a powerful tool to generate large amounts of cytokines in a short time.
Amino Acid Sequence↗
Bicarbonate-based dialysis solution preserves granulocyte functions.
OBJECTIVE: Intraperitoneal phagocytes play an important role in local defense in preventing continuous ambulatory peritoneal dialysis (CAPD) peritonitis. This study therefore investigates the effect of the conventional lactate-based dialysis solution-pH 5.2 (LBDS-pH 5.2) and a bicarbonate-based dialysis solution (BBDS) on various cell functions. DESIGN: We studied C5a-induced actin polymerization (AP) as a measure of the cytoskeletal alteration, phagocytosis of zymosan particles, and chemotaxis in neutrophils incubated in either LBDS-pH 5.2, LBDS-pH 7.4, or BBDS-pH 7.4, comparing the data with cells treated with phosphate-buffered saline-pH 7.4 (PBS-pH 7.4) as a control. SUBJECTS: Polymorphonuclear neutrophils (PMNs) were isolated from the blood of healthy donors and incubated with dialysis solution prior to the experiment. RESULTS: C5a-induced AP was dramatically inhibited in PMNs incubated in LBDS-pH 5.2, paralleled by a complete inhibition of phagocytosis and C5a-induced chemotaxis. In comparison, BBDS improved AP to values above the control and also nearly normalized phagocytosis. Chemotaxis markedly improved in cells treated with the low glucose-containing BBDS (Bic 20), containing high glucose concentrations (Bic 30). CONCLUSION: In comparison with conventional lactate-based dialysis solution-pH 5.2, bicarbonate-based dialysis solution at low osmolality better preserves neutrophil functions that involve the cytoskeleton.
Actins↗
Flow cytometry reveals different lag times in rapid cytoplasmic calcium elevations in human neutrophils in response to N-formyl peptide.
Flow cytometric analyses were performed to study intracellular single-cell calcium transients ([Ca2+]i) in suspended human neutrophils during the initial phase of N-formyl peptide stimulation. Thereby, two neutrophil populations became apparent. Early maximally Ca(2+)-responding (high fluorescence) neutrophils and not-yet Ca(2+)-responding (low fluorescence) neutrophils, but no neutrophils with intermediate levels of [Ca2+]i were detected. Within 7 s the number of low fluorescence neutrophils decreased and the number of high fluorescence neutrophils increased maximally. This suggests that [Ca2+]i transients occurred abruptly in individual neutrophils within a time interval below 1 s. At lower N-formyl peptide concentrations the lag times of individual neutrophils and the interval time of maximal activation of the [Ca2+]i-responding neutrophil population increased, however the percentage of [Ca2+]i-responding cells decreased. Surprisingly, no influence of the N-formyl peptide concentration on the [Ca2+]i-induced fluorescence signal of the individual cell was observed: it was always in an almost maximal range or not responding. In parallel, binding studies performed with fluorescein-labeled N-formyl peptide revealed that the heterogeneity of [Ca2+]i-responding cells cannot be explained by different receptor occupancy. In summary, this study demonstrates that [Ca2+]i transients induced by N-formyl peptides in suspended individual human neutrophils occur very rapidly in an almost "all-or-none manner" and that the mean increasing fluorescence signal of a calcium indicator within a whole neutrophil population results from varying lag times of the individual cells, rather than from the mean simultaneous progress of many cells.
Calcium↗
Production of oxygen radicals by fibroblasts and neutrophils from a patient with x-linked chronic granulomatous disease.
Recently, a superoxide-generating NADPH-oxidase system in human fibroblasts has been described. Therefore, we reassessed the possible use of this cell type for prenatal diagnosis of CGD patients comparing normal and CGD peripheral blood neutrophils (PMN) and skin fibroblasts in their reactive oxygen intermediate (ROI)-producing capacity. While PMN of the CGD patient showed a clearly reduced respiratory burst activity, which correlated well with the measured content of cytochrome b558, fibroblasts of the same individual showed no impaired production of superoxide anion or H2O2 upon stimulation by cytokines (TNF and IL-1) or other agents (Ca2+ ionophores and PAF, unpublished results). Furthermore, fibroblasts of the CGD patient or of normal donors could be inhibited in ROI production by diphenylene iodonium (DPI) and 2-iodobiphenyl. In contrast to PMN, no inhibition of the fibroblast NADPH-oxidase system was observed using staurosporin, an inhibitor of proteinkinase C. These data demonstrate, in contrast to previous studies, that fibroblasts are able to produce ROI. Nevertheless, since fibroblasts obtained from a CGD patient exhibited no difference in ROI production compared with fibroblasts obtained from healthy donors, they are not suitable for prenatal diagnosis of CGD.
Calcimycin↗
Severe infectious complications in a girl suffering from atopic dermatitis were found to be due to chronic granulomatous disease.
Recently, the diagnosis of a variant form of chronic granulomatous disease (CGD) could be established in an 11-year-old girl who had been treated for atopic dermatitis for many years. In addition to severe superinfections of lesions of the skin, the following symptoms were found currently or in her history: an episode of chronic diarrhoea (suspected as lactose intolerance), an endomyocarditis, a paranephritic abscess and recurrent lymph node abscesses. This case is demonstrated to underline the importance of extensive immunologic diagnostics in situations of recurrent severe infections of the skin, especially if other organs are involved. Diagnosis and type of CGD were strongly indicated by flow cytometrical measurement of H2O2 and cytochrome b558-expression by neutrophils and confirmed by a Western blot test. No immunoreactive p47phox could be found in the patient's cells. In this autosomal recessive variant of CGD some retained ability of phagocytes to produce reactive oxygen intermediates was present. Special management of patients with CGD is necessary to prevent serious infectious complications. Genetic counselling is another important consequence of the correct diagnosis.
Child↗
Abnormal regulation in the signal transduction in neutrophils from patients with severe congenital neutropenia: relation of impaired mobilization of cytosolic free calcium to altered chemotaxis, superoxide anion generation and F-actin content.
Severe congenital neutropenia (SCN) can be corrected in vivo by treatment with pharmacological dosages of recombinant human granulocyte colony-stimulating factor (rhG-CSF). In order to analyze the decreased chemotaxis of neutrophils from SCN patients receiving rhG-CSF, neutrophil functions essential for chemotaxis were investigated. The mobilization of cytosolic calcium ([Ca2+]i) and the functional state of cytoskeletal proteins in neutrophils from SCN patients were compared with either neutrophils from healthy donors (or, in selected experiments, from patients with cyclic neutropenia) and neutrophils from patients with chemotherapy-induced neutropenia also receiving rhG-CSF. Using flow cytometric analysis, two neutrophil subpopulations were detected in SCN patients in response to N-formylmethionine leucyl-phenylalanine (FMLP) (10(-9) M to 10(-7) M), one of which was unable to respond to this stimulus with an increase in [Ca2+]i. Whereas a homogeneous increase in [Ca2+]i in normal neutrophils occurred at 10(-9) M FMLP, neutrophils from SCN patients required 10(-6) M FMLP to respond homogeneously with an increase in [Ca2+]i. In contrast, G-CSF induced neutrophils from patients with cyclic neutropenia and from patients with chemotherapy-induced neutropenia showed a normal increase in [Ca2+]i after stimulation. The [Ca2+]i-dependent superoxide anion (O2-) generation in response to FMLP was also significantly diminished in neutrophils from SCN patients compared to normal neutrophils. However, O2- generation elicited by phorbolester (PMA), which directly activates protein kinase C (PKC), was not affected in SCN neutrophils. The total immunoreactive actin content and basal F-actin content in neutrophils from SCN patients were elevated as compared to normal neutrophils and neutrophils from patients with chemotherapy-induced neutropenia. The increase in F-actin content following FMLP activation was much lower in neutrophils from SCN patients as compared with normal neutrophils. These data suggest a defect in the signal transduction pathway in neutrophils from SCN patients between FMLP ligand-receptor interaction and Ca2+ mobilization, whereas upstream of PKC, triggered events seem to be unaffected. Therefore, [Ca2+]i-dependent neutrophil function in response to FMLP, such as actin disassembly, chemotaxis and O2- generation are diminished in SCN neutrophils. The pathomechanism responsible for the defective [Ca2+]i increase might be an initial step in understanding the underlying pathophysiology of SCN.
Actins↗
Heterogeneity in the mobilization of cytoplasmic calcium by human polymorphonuclear leukocytes in response to fMLP, C5a and IL-8/NAP-1.
The visible excitation and emission wave-lengths of the recently developed fluorescent Ca2+ indicator fluo-3 permit analysis of the intracellular Ca2+ concentration, [Ca2+]i, in flow cytometry with a 488-nm argon laser. The role of [Ca2+]i in human polymorphonuclear leukocyte heterogeneity was investigated in response to formyl-methionyl-leucyl-phenylalanine (fMLP), C5a, and interleukin 8/neutrophil attractant/activation protein 1 (IL-8/NAP-1) by flow cytometry. The [Ca2+]i changes in different subpopulations within a heterogeneous cell suspension were resolved upon stimulation with fMLP. Using an anti-CD16 phycoerythrin-conjugated antibody and fluo-3 simultaneously, neutrophils affected and nonaffected in Ca2+ mobilization were distinguished in two patients suffering from glycogen storage disease type 1b. In normal neutrophils, a different time course of Ca2+ mobilization of neutrophil subpopulations immediately after stimulation with fMLP was detected. In addition, after stimulation with a low concentration of IL-8/NAP-1 (10(-10) M) two subsets of neutrophils appeared; one of them showed an increase in [Ca2+]i, while the other did not. These results indicate heterogeneity in the neutrophil signal transduction process involved in Ca2+ mobilization. Therefore, flow cytometric analyses can resolve changes in single-cell [Ca2+]i distribution patterns, which is important for the understanding of [Ca2+]i in neutrophil heterogeneous activation processes.
Aniline Compounds↗
Altered function and surface marker expression of neutrophils induced by rhG-CSF treatment in severe congenital neutropenia.
Neutrophils from patients suffering from severe congenital neutropenia (SCN), who were receiving recombinant human granulocyte colony-stimulating factor (rhG-CSF), were investigated in order to analyze the previously described decrease in chemotaxis. This study demonstrated the decreased chemotaxis to five well-known chemoattractants, FMLP, C5a, IL-8, LTB4 and PAF. To further investigate this impairment of patients' neutrophils, receptors and receptor turnover for chemoattractants were examined using flow cytometry. We found 1) increased FMLP receptor and decreased C5a receptor expression, 2) a normal expression of intracellular FMLP receptors after incubation with PMA, 3) increased loss and decreased re-expression of FMLP receptors after incubation with this peptide, 4) normal expression of adhesion glycoproteins CR3 (CD11b/CD18) and LFA1 (CD11a/CD18), 5) further signs of in vivo preactivation: high expression of Fc gamma-RI (CD64) and Fc gamma-RII (CD32), decreased expression of Fc gamma-RIII (CD16), increased expression of CD14, and low expression of HLA-DR. These data demonstrate that the decrease of chemotaxis of neutrophils from SCN patients is not due: a) to a decrease in the number of intra- or extracellular FMLP receptors; b) to a decrease of adhesion molecules. However, the decreased chemotaxis could result from an altered FMLP receptor turnover. The relevance of the altered Fc gamma-receptor pattern for the in vivo occurrence of side-effects, e.g. the necrotic vasculitis, of G-CSF treatment is discussed.
Antibodies, Monoclonal↗
Animal models for human behavioral deficiencies during development.
Often considered to be a subdiscipline of neurotoxicology, experimental behavioral teratology has difficulties to be acknowledged by its own right. Results obtained in the laboratory concerning purely behavioral effects induced by low level prenatal exposure to substances are often doubted to contain any relevance with respect to humans. This doubt is based on many debates going on in the numerous extrapolation steps between observed effects on animal behavior and human psychopathology. Taking the inverse path, extrapolation from a typical human behavioral syndrome (minimal brain dysfunction) to observations which can be made on laboratory animals, the following main debates are discussed: the psychology debate (behaviorism--perceptionism--cognitivism); the psychopathology debate (hyperactivity--attention deficit--tactile-kinesthetic perception deficiency--sensory integration deficits); the relevance debate (behavior is reprogrammable software--behavioral deficits may reflect undetectable hardware defects); the interpretation debate (behavioral teratogenicity is chemical imprinting--behavioral disturbances due to chemicals reflect neurotoxicity); the intelligence debate (IQ decrements--attention deficits); the developmental delay debate (the relevance of a delay in the behavioral development); the sensitivity debate (behavior is the most sensitive measure in toxicology--the brain redundancy and plasticity compensates subtle deficiencies); the statistics debate (gather as many behavioral variables as possible--stay simple and measure only one aspect of behavior); the regulation debate (behavioral teratology should be regulated in detail--tests should not be prescribed). It is attempted to find rational solutions for these debates which menace to jeopardize the very existence of behavioral teratology.
Behavior↗