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Biomedical subjects

T J Sobotka

Publications and source records attributed to T J Sobotka.

At least 19 recordsLinked to original sources
PubMed1996

Neurobehavioral dysfunctions associated with dietary iron overload.

Excessive dietary Fe is known to be toxic, but the extent of neurobiological involvement is not clear. In the present study male weanling rats were fed diets containing Fe at 35 (control), 350, 3500, or 20000 ppm for 12 wk. An Fe-deficient group (4 ppm) was included for comparison. Rats were tested for behavioral and body weight changes at various times after initiation of diets, and liver and brain nonheme Fe were measured at term. Excess dietary Fe, primarily at 20000 ppm, significantly decreased activity, habituation, reflex startle, and conditioned avoidance response performance, and enhanced prepulse modulation of startle. Body weights were also markedly decreased. Fe-deficient animals showed similar behavioral effects but more moderate body weight changes. Liver nonheme Fe varied directly with dietary levels. Whole-brain nonheme Fe was significantly reduced in Fe-deficient animals but increased only at the 20000-ppm level. Homeostatic mechanisms appear to regulate whole-brain Fe more effectively under conditions of dietary Fe overload than under conditions of Fe deficiency. The behavioral changes associated with dietary Fe overload may represent secondary consequences of systemic toxicity.

Anemia, Iron-Deficiency↗
PubMed1992

Revisions to the FDA's Redbook guidelines for toxicity testing: neurotoxicity.

In 1982, the Food and Drug Administration issued a publication, known as the Redbook, that described the current toxicological principles used for the safety assessment of regulated food and color additives. However, this document contained only minimum reference to neurotoxicity as a specific toxicological concern and only general mention of the types of data that should be collected to detect and assess adverse changes to the nervous system. The general nature of the toxicological information typically derived from studies based on the original Redbook has had only limited use as a guide for comprehensive assessment of neurotoxic hazard. This limitation is one of the issues being addressed in the current efforts to update the information provided in the Redbook. In the revised Redbook, neurotoxicity, encompassing adverse structural and functional changes to the nervous system, is explicitly identified as an important criterion in the assessment of food chemical safety. The proposed strategy for evaluating neurotoxic hazard has a tiered testing approach. Accordingly, testing would initially involve the identification of chemicals presumptively associated with neurotoxic effects. As appropriate, subsequent testing would be carried out to confirm and delineate the scope of the neurotoxicity, to determine the dose response kinetics, and to define the no-adverse-effect levels.

Animals↗
PubMed1991

Extracellular concentrations of amino acid transmitters in ventral hippocampus during and after the development of kindling.

This study examined the possible involvement of amino acid release from ventral hippocampus in the establishment and maintenance of kindling in rats. Release of amino acids from ventral hippocampus was measured by microdialysis coupled with high-performance liquid chromatography. Samples were obtained by microdialysis perfusion of freely moving animals receiving deep prepiriform cortex (DPC) electrical stimulation. Samples of perfusate were collected before, during and after kindling was established. DPC kindling stimulation significantly increased concentrations of glutamate (Glu) and glycine (Gly) in perfusate from ventral hippocampus during kindling. Increased basal release of Glu was evident up to 30 days after the last electrical stimulation. We conclude that release of Glu and Gly in the ventral hippocampus may play an important role during establishment, but not in maintenance of kindling.

Amino Acids↗
PubMed1991

Prolonged alterations in canine striatal dopamine metabolism following subtoxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 4'-amino-MPTP are linked to the persistence of pyridinium metabolites.

Single toxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).HCl (2.5 mg/kg i.v.) and 4'-amino-MPTP.2HCl (22.5 mg/kg) induce loss of striatal dopamine (DA) and tyrosine hydroxylase (TH) activity and of nigral DA neurons in the dog. To examine the subacute neurochemical changes induced by low doses of MPTP and 4'-amino-MPTP, dose-response studies of these compounds were carried out in the dog, using 6- and 3-week survival times for these two compounds, respectively. Low single doses of MPTP (1.0, 0.5, and 0.1 mg/kg i.v.) and 4'-amino-MPTP (15, 7.5, and 3.75 mg/kg i.v.) did not cause depletion of canine striatal DA or TH or a loss of nigral neurons. However, levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased in a dose-related fashion, with significant loss of DOPAC being evident 6 weeks after the lowest administered dose of MPTP and 3 weeks after 4'-amino-MPTP. This selective loss of DA metabolites following nontoxic doses of MPTP and 4'-amino-MPTP led to a shift in the ratio of DA to DOPAC or HVA, which was characteristic for each compound. The measurement of striatal 1-methyl-4-phenylpyridinium (MPP+) and 4'-amino-MPP+ levels revealed that high concentrations (up to 150 microM) persist in the striatum for weeks following administration of a single nontoxic dose of MPTP or 4'-amino-MPTP. A causal relationship between the striatal concentration of MPP+ or 4'-amino-MPP+ and the change in DA metabolism as reflected in the DA/DOPAC ratio is suggested by a significant correlation between these measures. It is suggested that presynaptic sequestration and retention of MPP+ and 4'-amino-MPP+ by striatal DA terminals result in the inhibition of the monoamine oxidase contained within these terminals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1990

Alterations in acetylcholine-induced stimulation of inositol phospholipid hydrolysis in the dorsal hippocampus of kindled rats.

Agonist-induced turnover or release of inositolphosphates (IP) was studied in the dorsal and the ventral hippocampus 24 h, 1 month, and 3 months after the last electrical stimulus of kindled rats. A significant increase in acetylcholine (ACh)-stimulated IP turnover was observed in dorsal, but not ventral, hippocampus 24 h and 1 month after the last electrical stimulus. However, this effect was not evident 3 months after kindling. The excitatory amino acids (quisqualic acid and ibotenic acid) at the concentrations used, however, failed to produce any change in receptor-stimulated release or turnover of IP. Thus the changes in ACh-induced IP release, although long-term, are not permanent and do not appear to be released to the neurobiological alterations associated with the long-term maintenance of the kindling phenomenon.

Acetylcholine↗
PubMed1990

Systemic administration of kainic acid increases GABA levels in perfusate from the hippocampus of rats in vivo.

The ventral hippocampi of male, Fischer-344 rats were implanted with microdialysis probes and the effects of systemically administered kainic acid (KA) (8 mg/kg, s.c.) on the in vivo release of amino acids were measured for four hours after administration. In order to measure GABA release in vivo, gamma-vinyl-GABA (GVG), an irreversible inhibitor of GABA transaminase, was injected intrahippocampally prior to perfusion. GVG pretreatment resulted in measurable levels of GABA in the perfusate without significant effects on the release of aspartate, glutamate, glutamine, glycine or taurine. Following GVG pretreatment systemic administration of KA produced a time-dependent increase in GABA, as well as all other amino acids except glutamine, which was initially decreased. These results show for the first time that systemically administered KA increases extracellular GABA levels, an effect previously reported only in vitro. These data suggest that prior to destruction of GABA-containing interneurons in the hippocampus, there is an increased activity of those GABA interneurons reflected as an increase in extracellular GABA levels.

Amino Acids↗
PubMed1989

Immunomodulatory effects of footshock in the rat.

Intermittent inescapable footshock (IIFS) treatment, administered to 3-month-old male rats, resulted in analgesia as well as discrete immunological and endocrine changes. The splenic lymphocyte proliferative response to concanavalin A (ConA) and phytohemagglutinin (PHA) was decreased by 20% and 41%, respectively. The primary IgM plaque forming cell (PFC) response to sheep red blood cells (SRBC), however, was not altered by IIFS administered either immediately or 24 h after injection of SRBC. IIFS also produced a significant (20-fold) increase in plasma corticosterone (CORT) as compared to non-shocked controls. The shock-induced suppression of splenic lymphocyte mitogenic response to PHA was blocked by 10 mg/kg naltrexone (NTX) administered immediately before IIFS. NTX alone had no effect on this mitogen response. However, NTX significantly attenuated the shock-induced rise in CORT even though NTX alone significantly elevated CORT in the non-shocked controls. These data suggest that IIFS alters cellular immune response but not the primary IgM PFC response (a measure of humoral immune function) and that the immunomodulatory effects may involve both an opioid and a corticosteroid component with respect to alterations in the splenic lymphocyte mitogenic response to PHA.

Animals↗
PubMed1989

Food and Drug Administration: approach to evaluating neurotoxicity.

One of the primary features of the mission of the Food and Drug Administration is to assure with reasonable certainty that no harm will result from the intended use of chemicals added to food. In carrying out this mission the FDA uses a structured process to assess the safety of each food chemical. The detailed mechanics of this process are described in an FDA document entitled "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Use in Food" (Food and Drug Administration, 1982). Central to its evaluation the FDA requires a collective set of information, including estimates of the anticipated human exposure to the food chemical and a broad-based toxicological profile. Certainly, any adverse effect observed in the nervous system is recognized as an important element in the determination of chemical safety and follow-up information which would enable an assessment of such an effect to be included in the toxicological profile. The agency's current approach to evaluating neurotoxicity should be viewed within the context of its overall strategy for the safety assessment of food chemicals. Four basic premises underlie the FDA's approach to safety assessment.

Animals↗
PubMed1989

Oral administration of aspartame is not proconvulsant in rats.

These experiments examined the potential for single or repeated doses of aspartame to exacerbate or facilitate the production of seizures in Fischer-344 rats. In adult animals, 1,000 mg/kg of aspartame given by gavage acutely or over a 14 day period had no significant effect on the rate of kindling induced by stimulation of the prepyriform cortex. A single dose of 1,000 mg/kg of aspartame had no effect on the number of animals developing tonic seizures after electroconvulsive shock, nor did aspartame affect the frequency or duration of seizure activity after pentylenetetrazol. In a second series of studies, young male and female rats were dosed with 1,000 mg/kg of aspartame on day 3-13 or 21-35 of age. Prior exposure to aspartame had no significant effect on the rate of kindling at 90 days of age. These experiments indicate that aspartame does not act a pro-convulsant in rats.

Administration, Oral↗
PubMed1983

A developmental toxicity and psychotoxicity evaluation of FD and C red dye #3 (erythrosine) in rats.

Two experiments were conducted to evaluate FD and C Red Dye #3 for its developmental toxicity and psychotoxicity. Adult Sprague-Dawley rats were fed diets containing the dye for 2 weeks and were then bred. The diets were continued for the females throughout gestation and lactation and were provided continuously to their offspring thereafter. The treatment groups for Experiment 1 were Red Dye #3 as 0.0, 0.25, 0.5, or 1.0% of the diet (w/w), and a positive control group treated with the toxin hydroxyurea on days 2-10 of life (50 mg/kg/day, s.c.); Experiment 2 was a replication of Experiment 1 with the same dose groups, but without the positive control group. Parental animals were evaluated for weight and food consumption, and females for reproductive success. The offspring were assessed on a series of tests using the Cincinnati Psychoteratogenicity Screening Test Battery, plus weight, food consumption, physical landmarks of development, and brain weight. Red-3 produced no reductions in parental or offspring weight or food consumption. Red-3 significantly increased preweaning offspring mortality in the first experiment, but not in the second. Behaviorally, Red-3 produced no dose-dependent effects that replicated across the two experiments. It was concluded that no evidence was obtained that dietary exposure to FD and C Red Dye #3 (erythrosine) is psychotoxic to developing rats.

Animals↗
PubMed1983

Developmental toxicity and psychotoxicity of FD and C red dye No. 40 (allura red AC) in rats.

Adult Sprague-Dawley rats were fed diets containing FD and C red dye No. 40 for 2 weeks and were then bred. The diets were continued for the females throughout gestation and lactation and were provided continuously to their offspring thereafter. The treatment groups were: FD and C red dye No. 40 as 0.0, 2.5, 5.0 or 10.0% of the diet, and a positive control group treated with the toxin hydroxyurea on days 2-10 of life with 50 mg/kg/day given s.c. as a positive control group. Parental animals were evaluated for weight and food consumption, and females for reproductive success. The offspring were assessed on a series of tests using the Cincinnati Psychoteratogenicity Screening Test Battery. Additional measures were weight, food consumption, physical landmarks of development, and brain weight. Red-40 significantly reduced reproductive success, parental and offspring weight, brain weight, survival, and female vaginal patency development. Behaviorally, R40 produced substantially decreased running wheel activity, and slightly increased postweaning open-field rearing activity. Overall, R40 produced evidence of both physical and behavioral toxicity in developing rats at doses of up to 10% of the diet.

Animals↗
PubMed1981

Developmental neurobehavioral toxicity of butylated hydroxyanisole (BHA) in rats.

Butylated hydroxyanisole (BHA) was fed to rats throughout development (from prior to conception through 90 days of postnatal age) in doses of 0, 0.125, 0.25 or 0.5 percent (w/w) of the diet. A fifth group was also prepared as a positive control by administering 50 mg/kg/day of the antimitotic agent hydroxyurea on days 2-10 of postnatal age. Offspring from all groups were reared by their natural dams and were evaluated blind with respect to treatment assignment in a battery of standardized behavioral tests between 3 and 90 days of age. BHA at 0.5% of the diet impaired offspring growth during the last week of preweaning development and increased preweaning mortality (13.5%). No changes in maternal weight, reproductive performance or mortality were observed. No reductions in offspring growth after weaning or changes in day 90 brain weights were found. BHA at 0.25 and 0.125% of the diet had no effect on growth, reproduction or mortality; although a marginal increase was seen in the 0.25% BHA offspring mortality up to 30 days of age (8.3%, p = 0.06). BHA at 0.5 and 0.25% of the diet delayed startle development and showed a marginal trend towards increased diurnal running wheel activity; no other behavioral effects were found. Comparison of the present results to a similar study using BHT clearly indicates that BHA at equivalent dietary doses is considerably less toxic than BHT. The present results also suggest that BHA is not a potent behavioral toxin, although it is developmentally toxic using non-behavioral measures.

Aging↗
PubMed1978

Neurobehavioral studies of tremorgenic mycotoxins verruculogen and penitrem A.

Verruculogen (V) and penitrem A (PA) represent a group of toxic secondary metabolites of mold contaminants of foodstuffs known as 'tremorgenic mycotoxins', which produce a unique neurotoxic syndrome characterized by sustained tremors, limb weakness, ataxia and convulsions. In the present study the intraperitoneal median tremogenic dose in mice for V was found to be 0.92 mg/kg and that for PA, 0.19 mg/kg. Behavioral and neurochemical parameters were assessed following acute exposure to varying neurotoxic and subneurotoxic doses of these mycotoxins. Measures of spontaneous motor activity (photoactometer) and exploratory reflex behaviors (open field) were markedly depressed by both V and PA. Notably, at dose levels of V or PA that were not accompanied by any overt signs of neurotoxicity, significant neuromotor depression was still observed. Acquisition of a conditioned avoidance shuttle response was disrupted, but only at a high neurotoxic dose level of V. Neurochemical analyses revealed no clear catecholaminergic or cholinergic involvement in the neurotoxic syndrome of eigher V or PA.

Acetylcholinesterase↗
PubMed1977

Tartrazine and the developing nervous system of rats.

Rat dams were exposed to the artificial food color tartrazine (FD&C Yellow no. 5) at dietary levels of 0, 1, and 2% during gestation and lactation. The experimental offspring were continued on the same diets for approximately 3 months after weaning. No adverse physical or behavioral effects were noted in the dams. Fetal development and postnatal viability of the offspring were also normal. The only effect on postnatal development of the central nervous system (CNS) was a small transient change in neuromotor clinging ability of female offspring. The limited effect of tartrazine on the CNS was further evidenced by the facts that (1) the neurobehavioral profiles of the experimental weanlings revealed no significant abnormalities, and (2) morphochemical analysis of brain tissue, as well as brain weights, revealed no abnormalities. Tartrazine did appear to exert more general signs of toxicity in the offspring--namely, depressed body weight, an apparent reduction in thymus weight, and a slight elevation of red blood cells and hemoglobin.

Animals↗