Biomedical subjects

L G Costa

Publications and source records attributed to L G Costa.

At least 55 records · Page 3Linked to original sources

PubMed1998

Interaction of blood lead and delta-aminolevulinic acid dehydratase genotype on markers of heme synthesis and sperm production in lead smelter workers.

The gene that encodes gamma-aminolevulinic acid dehydratase (ALAD) has a polymorphism that may modify lead toxicokinetics and ultimately influence individual susceptibility to lead poisoning. To evaluate the effect of the ALAD polymorphism on lead-mediated outcomes, a cross-sectional study of male employees from a lead-zinc smelter compared associations between blood lead concentration and markers of heme synthesis and semen quality with respect to ALAD genotype. Male employees were recruited via postal questionnaire to donate blood and urine for analysis of blood lead, zinc protoporphyrin (ZPP), urinary coproporphyrin (CPU), and ALAD genotype, and semen samples for semen analysis. Of the 134 workers who had ALAD genotypes completed, 114 (85%) were ALAD1-1 (ALAD1) and 20 (15%) were ALAD1-2 (ALAD2). The mean blood lead concentrations for ALAD1 and ALAD2 were 23.1 and 28.4 microg/dl (p = 0.08), respectively. ZPP/heme ratios were higher in ALAD1 workers (68.6 vs. 57.8 micromol/ml; p = 0.14), and the slope of the blood lead ZPP linear relationship was greater for ALAD1 (2.83 vs. 1.50, p = 0.06). No linear relationship between CPU and blood lead concentration was observed for either ALAD1 or ALAD2. The associations of blood lead concentration with ZPP, CPU, sperm count, and sperm concentration were more evident in workers with the ALAD1 genotype and blood lead concentrations >/= 40 microg/dl. The ALAD genetic polymorphism appears to modify the association between blood lead concentration and ZPP. However, consistent modification of effects were not found for CPU, sperm count, or sperm concentration.

Adult↗

PubMed1998

Neurotoxicity testing: a discussion of in vitro alternatives.

A large number of chemicals may exert adverse effects on the central and/or peripheral nervous system. A commonly recommended strategy for neurotoxicity testing is that of a tiered approach aimed at identifying and characterizing the neurotoxicity of a compound. Guidelines exist in the United States and other countries that define the tests to be utilized in tier 1 testing. To address problems related to the increasing cost and time required for toxicity testing, the increasing number of chemicals being developed, and the concern of animal welfare activists, attention is currently being devoted to in vitro alternatives. This paper addresses the use of in vitro systems in neurotoxicology, and their potential role in a general strategy for neurotoxicity testing. The advantages and disadvantages of in vitro approaches for mechanistic studies and for screening of neurotoxicants are discussed. Suggestions for further validation studies are proposed.

Animal Testing Alternatives↗

PubMed1998

Fibroblast heterogeneity of signal transduction mechanisms to complement-C1q. Analyses of calcium mobilization, inositol phosphate accumulation, and protein kinases-C redistribution.

Fibroblasts of healthy and granulation gingiva are phenotypically heterogeneous with regard to binding C1q collagen-like (cC1qR) or C1q globular-heads (gC1qR) regions, respectively. Here, isolated fibroblast subsets, expressing either the cC1qR or the gC1qR phenotype, were stimulated with C1q, and assessed for changes in cytosolic free calcium [Ca2+]i, accumulation of inositol trisphosphate (IP3), and redistribution of Ca2+-dependent protein kinases-C (cPKCs) from cytosol to membranes. Changes in [Ca2+]i were determined using Indo-1 fluorescence in combination with adhering cell analysis and sorting (ACAS) cytometry. Accumulation of IP3 was quantified using a competitive radioreceptor binding assay. Redistribution of cPKCs was evaluated by immunoblotting with antibodies to PKCalpha/betaI-betaII/gamma. Subsets manifested different fluctuations in [Ca2+]i levels 20 seconds after C1q-stimulation in the presence of millimolar concentrations of external calcium. Whereas cC1qR fibroblasts responded with a 38% over baseline [Ca2+]i increase which was sustained for 20 to 30 minutes, gC1qR fibroblasts responded with a higher (264% over baseline) and more rapid (2 to 3 minutes) transient. Likewise, subsets exhibited different kinetics of IP3 accumulation. Whereas cC1qR fibroblasts responded with an IP3 increase of 32 +/- 3 pmol/10(4) cells over baseline after 5 seconds stimulation, gC1qR fibroblasts responded after 15 to 20 seconds with a lower increase (13 +/- 0.8 IP3 pmol/10(4) cells over baseline). Subsets differed in cPKCs redistribution which peaked in gC1qR-membranes 30 seconds after stimulation and remained sustained between 10 and 30 minutes. No cPKC redistribution was detectable in stimulated cC1qR-cells. We conclude that fibroblasts are heterogeneous in phosphoinositide-Ca2+ signaling and cPKC redistribution to C1q, and suggest that these differences may affect activities of normal and granulation gingiva.

Analysis of Variance↗

PubMed1997

The effects of ethanol on glial cell proliferation: relevance to the fetal alcohol syndrome.

Exposure to ethanol during pregnancy is detrimental to brain development. Individuals affected by the Fetal Alcohol Syndrome present a number of central nervous system dysfunctions including microencephaly and mental retardation. Studies on the mechanisms of ethanol's developmental neurotoxicity have focused on its interaction with neurons; however, emerging evidence is suggesting that ethanol can significantly affect glial cells as well. A number of in vitro studies have shown that ethanol can inhibit the proliferation of various glial cells (mostly primary astrocytes or astrocytoma cells) at relatively high concentrations (100-200 mM). On the other hand, proliferation induced by some, but not all mitogens, is inhibited by low concentrations (10-50 mM) of ethanol. These inhibitory effects of ethanol may contribute to its developmental neurotoxicity observed following in vivo exposure. Animal models have indeed shown that ethanol causes microencephaly when given during the brain growth spurt, a period of brain development characterized by astroglial proliferation and maturation.

Animals↗

PubMed1997

Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease.

Monoamine oxidase B (MAO-B) is an enzyme that has relevance for Parkinson disease (PD) because of its roles in catabolizing dopamine and potentially activating exogenous neurotoxicants. A polymorphism of the gene encoding MAO-B has been identified as a single base change (A or G) in intron 13 of the X chromosome. The A allele was previously associated with an approximately twofold risk of PD. The present study compared A and G allele frequencies between newly diagnosed idiopathic PD cases and a control group free of neurodegenerative diseases. All study subjects were Caucasian. Cases were 37 men and 25 women, age 37-80 years; controls were 50 men and 29 women, age 45-82 years. MAO-B genotype was determined by the allele-specific polymerase chain reaction on DNA extracted from peripheral lymphocytes. In complete contrast to previous studies, elevated risks were detected with the G allele. The age-adjusted odds ratio for the G allele in males was 1.87 ((95% confidence interval) 0.78-4.47). Among females the age-adjusted odds ratios were 5.00 ((95% confidence interval) 1.13-22.1) for the GA genotype and 5.60 ((95% confidence interval) 1.01-30.9) for the GG genotype. These findings, although of limited statistical precision, suggest that the G allele of this MAO-B polymorphism may relate to PD risk.

Adult↗

PubMed1997

Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-trisphosphate receptor.

Xestospongins (Xe's) A, C, D, araguspongine B, and demethylxestospongin B, a group of macrocyclic bis-1-oxaquinolizidines isolated from the Australian sponge, Xestospongia species, are shown to be potent blockers of IP3-mediated Ca2+ release from endoplasmic reticulum vesicles of rabbit cerebellum. XeC blocks IP3-induced Ca2+ release (IC50 = 358 nM) without interacting with the IP3-binding site, suggesting a mechanism that is independent of the IP3 effector site. Analysis of Pheochromocytoma cells and primary astrocytes loaded with Ca2+-sensitive dye reveals that XeC selectively blocks bradykinin- and carbamylcholine-induced Ca2+ efflux from endoplasmic reticulum stores. Xe's represent a new class of potent, membrane permeable IP3 receptor blockers exhibiting a high selectivity over ryanodine receptors. Xe's are a valuable tool for investigating the structure and function of IP3 receptors and Ca2+ signaling in neuronal and nonneuronal cells.

Alkaloids↗

PubMed1997

Paraoxonase (PON1) gene in mice: sequencing, chromosomal localization and developmental expression.

Serum paraoxonase hydrolyses the toxic metabolites of several organophosphorus insecticides, as well as the nerve agents soman and sarin. We have previously shown that elevated serum paraoxonase levels protect mice against organophosphate toxicity. In the present study, we determined the cDNA sequence and chromosomal location of the mouse paraoxonase gene, as well as its developmental expression in mice and rats. The mouse cDNA encodes a protein of 355 amino acids and shows 81% identity with the human sequence. In situ hybridization demonstrated that the mouse paraoxonase gene maps to chromosome 6, a region conserved with the paraoxonase region of chromosome 7q21-22 in humans. Serum paraoxonase activities toward three substrates, paraoxon, chlorpyrifos-oxon and diazoxon, were very low at birth and increased with age reaching adult levels at 20 days in mice and 25 days in rats. The increase of serum paraoxonase activity in developing animals correlates well with the increased resistance to organophosphate poisoning that has been reported in previous studies.

Age Factors↗

PubMed1996

Acetylcholine as a mitogen: muscarinic receptor-mediated proliferation of rat astrocytes and human astrocytoma cells.

The mitogenic effect of muscarinic receptor agonists in glial cells has been characterized in rat cortical astrocytes and human 132 1N1 astrocytoma cells. The muscarinic receptor agonist carbachol caused a dose- and time-dependent increase in proliferation, as measured by [3H]thymidine incorporation. The mitogenic effect was mimicked by several muscarinic, but not nicotinic receptor agonists, and was blocked by muscarinic receptor antagonists. Reverse transcription-polymerase chain reaction (RT-PCR) experiments indicated the presence of m2, m3 and to a lesser degree, m5 muscarinic receptor mRNA in both astrocytes and astrocytoma cells. Proliferation experiments with subtype-specific muscarinic receptor antagonists suggest that carbachol-induced proliferation is due to activation of muscarinic M3 receptors. The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) also stimulated glial cell proliferation. Down-regulation of protein kinase C, or the protein kinase C antagonist 1,5-(isoquinolynsulfanyl)-2-methylpiperazine dihydrochloride (H7) blocked proliferation induced by either TPA or carbachol. Of other neurotransmitters tested, histamine caused glial cell proliferation, norepinephrine and gamma-aminobutyric acid were ineffective, while serotonin and glutamate inhibited basal or serum-stimulated proliferation.

Acetylcholine↗

PubMed1996

Effects of ethanol administration on cerebral non-protein sulfhydryl content in rats exposed to styrene vapour.

Glutathione (GSH) and other non-protein sulfhydryls (NPS) are known to protect cells from oxidative stress and from potentially toxic electrophiles formed by biotransformation of xenobiotics. This study examined the effect of a simultaneous administration of styrene and ethanol on NPS content and lipid peroxidation in rat liver and brain. Hepatic cytochrome P450 and cytochrome b5 content, aniline hydroxylase and aminopyrine N-demethylase activities as well as the two major urinary metabolites of styrene, mandelic and phenylglyoxylic acids were also measured. Groups of rats given ethanol for 3 weeks in a liquid diet were exposed, starting from the second week, to 326 ppm of styrene (6 h daily, 5 days a week, for 2 weeks). In control pair-fed animals, styrene produced about 30% depletion of brain NPS and 50% depletion of hepatic NPS. Subchronic ethanol treatment did not affect hepatic NPS levels, but caused 23% depletion of brain NPS. Concomitant administration of ethanol and styrene caused a NPS depletion in brain tissue in the order of 60%. These results suggest that in the rat, simultaneous exposure to ethanol and styrene may lead to considerable depletion of brain NPS. This effect is seen when both compounds are given on a subchronic basis, a situation which better resembles possible human exposure.

Administration, Inhalation↗

PubMed1996

Urinary mercapturic acid diastereoisomers in rats subchronically exposed to styrene and ethanol.

Styrene is stereoselectively oxidized by cytochrome P450 to its reactive metabolite, styrene oxide. The (R)- and (S)-enantiomers of styrene oxide can be conjugated with glutathione (GSH) to both (R)- and (S)-diastereoisomers of the specific mercapturic acids, N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (M2). Several investigations have indicated different toxic potential of the (R)- and (S)-configurations of styrene oxide and its GSH- and N-acetyl-conjugates. In this study the mercapturic acid diastereoisomers were measured in the urine of rats exposed to styrene in combination with ethanol, a good inducer of styrene metabolism. Male Sprague-Dawley rats were given an isocaloric liquid diet containing ethanol (5% w/v) for 3 weeks. Starting from the 2nd week, the animals were also exposed to styrene vapours (300 ppm, 6 h/day, 5 days/week) in a dynamic exposure chamber. Both the (R)- and (S)-diastereoisomers of the M1 and M2 as well as the conventional biomarkers, mandelic acid (MA) and phenylglyoxylic acid (PGA) were measured in urinary samples. Approximately 30 and 25% reduction of the levels of brain non-protein sulfhydryls (NPS) was observed in the animals given styrene and ethanol, respectively, while the combined ethanol and styrene treatment resulted in a 60% decrease. Ethanol consumption also resulted in higher urinary levels of the M1-R, M1-S and M2 metabolites associated with increased M1-R/S ratio and higher urinary MA excretion compared to animals treated with styrene. These results suggest that the urinary mercapturic acid diastereoisomers may be used as a noninvasive tool to examine stereoselective patterns of styrene metabolism in vivo, as well as their alterations caused by ethanol. These compound-specific mercapturic acids may also be valuable indicators of styrene-induced disorders of GSH homeostasis in nonaccessible organs.

Acetylcysteine↗

PubMed1996

Inhibition of muscarinic receptor-stimulated glial cell proliferation by ethanol.

Acetylcholine and other muscarinic agonists stimulate the proliferation of rat cortical astrocytes and 132 1N1 human astrocytoma cells by activating muscarinic m3 cholinergic receptors. Ethanol was a potent inhibitor of carbachol-stimulated proliferation, measured by [3H]thymidine incorporation, with an IC50 of 10 mM. On the other hand, basal and serum-stimulated proliferation of astrocytes and astrocytoma cells was inhibited by ethanol with lower potency (IC50 = 200-250 mM). Concentration-response experiments with carbachol, in the presence of 10 mM ethanol, suggested that inhibition of proliferation by the alcohol was of the noncompetitive type. Experiments with acetaldehyde and with the alcohol dehydrogenase inhibitor 4-methylpyrazole suggested that the inhibitory effect of alcohol was due to ethanol itself and not to its metabolite acetaldehyde. Proliferation of astrocytoma cells induced by carbachol and the inhibitory effects of ethanol were also confirmed by flow cytometry using the 5-bromodeoxyuridine-Hoechst 33258 method. Ethanol (10 mM) had no effect on proliferation induced by 50 micrograms/ml insulin and 100 ng/ml platelet-derived growth factor BB; on the other hand, the mitogenic effect of 1 mM histamine, 100 U/ml interleukin-1, and 100 ng/ml 12-O-tetradecanoylphorbol 13-acetate were inhibited by approximately 50%. These results indicate that proliferation of glial cells induced by muscarinic agonists is especially sensitive to the inhibitory effect of ethanol. This action of ethanol may be relevant to its developmental neurotoxicity, particularly microencephaly, which is one of the common features of the fetal alcohol syndrome.

Acetaldehyde↗

PubMed1996

Biomarker research in neurotoxicology: the role of mechanistic studies to bridge the gap between the laboratory and epidemiological investigations.

There is an increasing interest in the development and validation of biomarkers for use in biochemical/molecular epidemiological studies. Though the area of neurotoxicology has received much attention in the past several years, it still lags behind with regard to the development of biomarkers, particularly those of health effects and susceptibility. This review discusses several aspects of biomarker research as it relates to neurotoxic compounds and focuses on selected agents (organophosphorus insecticides, styrene, n-hexane, carbon disulfide, acrylamide), which have been the subject of a number of investigations in animals and humans. While traditional biomonitoring approaches and novel techniques (e.g., hemoglobin adducts) provide several measurements for monitoring exposure to neurotoxic chemicals, potential markers of genetic susceptibility have been seldom investigated in a neurotoxicology context. Furthermore, the complexity of the nervous system, together with the multiplicity of end points and the limited knowledge of the exact mechanism(s) of action of neurotoxicants, has led to only limited advancements in the development of biomarkers for neurotoxic effects. Significant progress in this area will depend upon an increased understanding of the cellular, biochemical, and molecular targets directly involved in neurotoxicity.

Acrylamide↗

PubMed1996

Effects of organophosphate exposure on muscarinic acetylcholine receptor subtype mRNA levels in the adult rat.

Repeated exposure to organophosphorus (OP) insecticides results in a decrease of muscarinic acetylcholine receptors (MRs) in the central nervous system. OP-induced MR down-regulation in vivo is modeled by chronic in vitro exposure to muscarinic agonists. Many studies, both in vivo and in vitro, indicate that the treatment-induced decrease in MR number is accompanied by a decrease in the mRNA levels of specific MR subtypes. In this study, the in vivo effects of OP exposure on the mRNA levels of three MR subtypes (m1, m2, and m3) were examined in brain tissue and in peripheral mononuclear cells, which express the m3 subtype. Adult male Sprague-Dawley rats were orally administered disulfoton (2 mg/kg/day) for 14 days, and a subset of exposed animals was allowed to recover for 28 days. This treatment caused a 28% and 81% decrease, respectively, in [3H]-QNB binding and acetylcholinesterase activity in the cortex, similar to that observed in previous studies; after recovery, these levels had returned to 99% and 90%, respectively, of controls. There was a significant decrease in m1 mRNA levels in hippocampus (23%) after disulfoton treatment, while no change was observed in the cortex, corpus striatum, medulla, or cerebellum. The m2 subtype mRNA was significantly decreased in both hippocampus (24%) and medulla (19%), but not in cortex, striatum, or cerebellum. m3 mRNA levels were significantly decreased in cortex (10%), but no change was observed in hippocampus, medulla, cerebellum, or lymphocytes. After recovery, no differences in m1 or m3 mRNA levels were observed in any tissue examined, whereas the decrease in m2 mRNA in the hippocampus remained significant (29%). These results indicate that OP exposure can differentially regulate mRNA levels for MR subtypes in different brain areas, and suggest that m2 muscarinic receptors in the hippocampus are most affected by this treatment.

Animals↗

PubMed1996

Biochemical markers of neurotoxicity. A review of mechanistic studies and applications.

Neurotoxicology presents major challenges to the development of biological markers in accordance to conventional research strategies. Because of the inaccessibility of the nervous system, one of the proposed alternatives is the study of biochemical signals in peripheral tissues which can easily and ethically be obtained in humans, and which could represent surrogate indicators of equivalent parameters in the nervous tissue. Considerable scientific support to this approach is provided by the results of recent investigations in major areas of pharmacology and psychobiology. Studies examining parameters of neurotransmission and second messenger systems in peripheral blood cells, and variations in the peripheral body fluid content of endogenous substances reflecting nervous tissue dysfunction or damage are presented in this paper as examples of efforts toward rational development and validation of novel indicators of nervous system toxicity. Cholinergic muscarinic receptors and calcium signalling in peripheral blood lymphocytes, myelin basic protein in cerebrospinal fluid, and blood polyamines are discussed as potential surrogate indicators based on the results of in vitro or in vivo animal studies of neurotoxic metals (mercury, triethyltin), pesticides (disulfoton), drugs of abuse (d-fenfluramine) and model epileptogenic compounds (kainic acid). Data from investigations examining serum prolactin, type B monoamine oxidase (MAO-B) and dopamine beta-hydroxylase (DBH) in workers occupationally exposed to manganese, lead or styrene are also presented. Although research in this field is still at its very early stage, current evidence suggests that (i) certain neurochemical markers may be valuably used in animal studies as a complement to conventional laboratory tests to augment their sensitivity or predictivity; (ii) a mechanistic research approach is required to establish which markers offer the greatest promise for application in human biomonitoring.

Animals↗

PubMed1995

Heterogeneity of cholinergic muscarinic receptors coupled to phosphoinositide metabolism in immature rat brain.

The effects of muscarinic agonists and antagonists on phosphoinositide (PtdIns) metabolism were examined in the cerebral cortex and brainstem of 7-day-old rats, in order to evaluate the role of muscarinic receptor subtypes in this process. Additionally, comparative experiments were performed in cortices from adult animals. Accumulation of [3H]inositol phosphates ([3H]InsPs) in [3H]inositol pre-labeled brain slices was taken as an index of PtdIns hydrolysis. In neonatal cortex, maximal stimulation induced by the full agonists acetylcholine, carbachol and methacholine was 8-10 fold over basal [3H]InsPs accumulation. The effect of the partial agonists bethanechol, pilocarpine and oxotremorine varied from 3 to 4 fold over basal. Smaller responses to cholinergic stimulation were found in the brainstem and in the adult cortex. In neonatal cortex, muscarinic antagonists inhibited the stimulatory responses with the following order of potency: 4-DAMP > pirenzepine > AF-DX 116 approximately p-F-HHSiD. Pirenzepine inhibition of full agonist-induced [3H]InsPs accumulation showed biphasic curves, with two thirds of the response being inhibited with high affinity. When partial agonists were used, the resulting pirenzepine curves were better described by interaction at one high affinity site. No differences were found between immature and adult rats in the effect of pirenzepine on [3H]InsPs accumulation induced by carbachol, methacholine, or bethanechol. Inhibition by pirenzepine of PtdIns hydrolysis induced by carbachol or methacholine showed biphasic curves also in the brainstem. In this area, only one third of the response was inhibited with high affinity, and p-F-HHSiD was more potent as an antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1995

Postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism in mouse cerebral cortex: sensitivity to ethanol.

An enhanced coupling of cholinergic muscarinic receptors to phosphoinositide metabolism had been previously observed in brain from immature rat. This study reports that the postnatal development of muscarinic receptor-stimulated phosphoinositide metabolism is also enhanced in cerebral cortex slices from immature Swiss-Webster and Balb-c mice, as compared to adults. Response to the agonist carbachol was lower on postnatal day 3, peaked between days 5 and 12 and then declined to adult levels. Density of muscarinic binding sites, measured with the M1 ligand [3H]telenzepine on postnatal day 7, was, on the other hand, only half of the adult value. Phosphoinositide hydrolysis stimulated by glutamate decreased with age, while that elicited by norepinephrine increased. These results are also similar to those previously reported in the rat. Ethanol has been found to inhibit muscarinic receptor-stimulated phosphoinositide metabolism in rat brain in an age-dependent manner. This was confirmed in mouse brain, where ethanol inhibited this response in cerebral cortex of immature but not adult animals. These results indicate that the enhanced muscarinic receptor-stimulated phosphoinositide metabolism, which coincides with the brain growth spurt, is similar in rats and mice. Mice may be a useful species in which to genetically manipulate muscarinic receptors to gain a better understanding of their potential role in brain development.

Aging↗

PubMed1995

Evaluation of the neurotoxicity of glycidamide, an epoxide metabolite of acrylamide: behavioral, neurochemical and morphological studies.

Acrylamide is an important chemical used in the synthesis of polyacrylamides, which have a wide variety of industrial applications. The principal toxic effect of acrylamide, both in animals and in humans, is neurotoxicity. Peripheral nervous system effects are most prominent, but central nervous system effects have also been reported. Acrylamide is metabolized to the epoxide glycidamide, whose adducts to hemoglobin and to DNA have been identified in animals and humans. This metabolite may be involved in the reproductive and carcinogenic effects of acrylamide. In the present study we investigated whether glycidamide would exert neurotoxic effects similar to those caused by its parent compound. Male rats were injected i.p. with acrylamide (25 or 50 mg/kg) or glycidamide (50 or 100 mg/kg) daily for 8 days. Reduced weight gain was evident in animals exposed to glycidamide or to the higher dose of acrylamide. Both compounds induced lethargy and ataxia, but the posture of glycidamide-treated rats differed from that of animals treated with acrylamide. At the high doses, both compounds significantly affected rats' behavior in the rotarod test; on the other hand, only acrylamide was effective in the hindlimb splay test. Acrylamide inhibited activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in sciatic and tibial nerves, as well as in brain. Glycidamide inhibited GAPDH activity only in brain and activity of creatine kinase in both peripheral and central tissues. Acrylamide also caused profound urinary retention and distended bladders, while the effects of glycidamide were minimal. Morphological abnormalities were seen in sciatic nerves and dorsal root ganglion cells of rats treated with acrylamide (50 mg/kg x 12), but not in rats exposed to glycidamide (100 mg/kg x 11). These results indicate that the toxicities of acrylamide and glycidamide differ and suggest that acrylamide itself may be primarily responsible for its peripheral neurotoxicity.

Acrylamide↗

PubMed1995

Long-lasting microencephaly following exposure to cocaine during the brain growth spurt in the rat.

In utero exposure to cocaine has been shown to produce somatic and behavioral effects. As microencephaly is often present in children born from cocaine-addicted mothers, aim of the present study was to develop an animal model for cocaine-induced microencephaly. Rats were treated with cocaine (20, 30 or 50 mg/kg/day, s.c., each dose divided in two equal doses given 3 h apart) from postnatal day 4 through 10. None of the doses had any effect on growth, however, at 50 mg/kg, cocaine caused a significant decrease in brain weight, measured on day 12. The effect of cocaine was similar in male and female rats, and microencephaly was still present in 45-day-old animals. When the same dose of cocaine was given as a single daily injection, long-lasting microencephaly was also present, but it was accompanied by a decrease in body weight and significant toxicity. Ethanol (4 g/kg), used as a positive control, also caused microencephaly without affecting body weight, but, differently from cocaine, its effect was more pronounced in female animals. Blood and brain levels of cocaine and its metabolites norcocaine and benzoylecgonine were measured by HPLC during treatment (postnatal day 8). After administration of the 50 mg/kg dose, concentrations of cocaine were 1.92 micrograms/g in brain and 0.94 microgram/ml in blood. These levels are encountered in cases of cocaine overdoses and have been found in meconium of newborns from crack-addicted mothers.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗