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Biomedical subjects

K R Reuhl

Publications and source records attributed to K R Reuhl.

At least 73 records · Page 4Linked to original sources
PubMed1985

Acute trimethyltin intoxication in the monkey (Macaca fascicularis).

Adult cynomolgus monkeys were administered trimethyltin (TMT) iv in dosages ranging from 0.75 to 4.0 mg TMT/kg and observed for behavioral changes. Animals were subsequently killed for light and electron microscopic examination. TMT showed a dose-related toxicity, with high dose animals (4.0 and 3.0 mg/kg) dying within 24 hr, and low dose animals (0.75 mg/kg) surviving without morphological effects. Animals given 1.10 mg TMT/kg displayed a reproducible clinical course, characterized by tremor, hyperactivity, and ataxia which progressed to stupor and finally unconsciousness. By light microscopy, neuropathology was most pronounced in the CA-3 and CA-4 regions of Ammon's horn. Degenerating pyramidal neurons, micro- and astrogliosis, and neuronophagia were commonly observed. Mild degenerative changes were identified in amygdala, medulla, spinal cord, and Purkinje cells. The fascia dentata remained intact. Ultrastructurally, injured neurons contained accumulations of lysosomes and lysosome-like structures within perikarya and neurites. Demyelination or vascular damage was not observed. Data indicate the monkey to be highly sensitive to TMT, with morphological injury most severe in limbic structures.

Animals↗
PubMed1984

Developmental neuropathology of organotin compounds.

The literature concerning the developmental neuropathology of organotins is reviewed. To date, neuropathological effects have been convincingly demonstrated for trimethyltin (TMT) and triethyltin (TET). Both compounds may damage the developing CNS; however they have different cellular targets. TMT is a neuronotoxin which damages areas of the limbic system, cerebral cortex, and brainstem. TET is a myelinotoxin which causes massive myelinic edema by yet undetermined mechanisms. Neuronal death is also seen following TET intoxication during the neonatal period, possibly as a result of elevated intracranial pressure. The neuropathological features of TMT and TET intoxication during early life are presented. Neurochemical and behavioral alterations resulting from congenital and/or neonatal exposure to organotins are also discussed.

Animals↗
PubMed1983

The effect of methylmercury on the distribution and excretion of selenium by the guinea pig.

The influence of methylmercury (MeHg) on the tissue and subcellular binding of selenium was determined. Adult female guinea pigs received either 75Se (as sodium selenite) or MeHg (as chloride) followed 5 h later by an equimolar dose of 75Se. Animals were sacrificed 1, 3, 7, and 13 days after administration. Pretreatment with MeHg significantly altered the organ distribution of 75Se, particularly during the first week of the study. 75Se concentrations were markedly reduced in most organs of animals receiving both 75Se and MeHg except the liver, which contained markedly elevated 75Se levels. The subcellular distribution of 75Se was also altered by MeHg. Within liver, kidney and brain, 75Se was primarily bound to nuclear and mitochondrial fractions in both treatment groups, but nuclear binding was higher in animals receiving both compounds. Within nuclear fractions, most 75Se was bound to insoluble-nonhistone proteins. In the presence of MeHg, total nuclear binding of 75Se increased, but total binding to insoluble-nonhistone proteins decreased. MeHg also reduced the total 75Se binding to high molecular weight proteins of the soluble fraction. Alterations in tissue and subcellular binding of MeHg and Se may contribute to the lower degree of toxicity observed in animals receiving both compounds.

Animals↗
PubMed1983

Demethylation and excretion of methyl mercury by the guinea pig.

Female guinea pigs were dosed po with 1.0 mg CH3 203Hg/kg as methylmercuric chloride, 10 times over a 3-week period. Tissue distribution, excretion, and accumulation of inorganic and organic mercury were studied. The highest concentration of mercury was found in the kidney. The greatest decreases of mercury levels were observed in the small bowel, red blood cells, liver, and cerebrum. The half-life of whole body clearance, based on a single compartment model, was 31.6 days. Mercury in the kidney, liver, and cerebrum was bound mainly by nuclear and soluble fractions. The highest ratio of inorganic to total mercury was seen in the kidney, 60% of this being as inorganic mercury. Excretion of mercury in the feces was measured throughout the experiment. The relationship of organic to inorganic mercury was relatively constant at about 1:3. Data on the effects of methyl mercury on tissue concentrations of zinc and copper show that the only change in the copper content was a marked increase in the kidney.

Animals↗
PubMed1983

Developmental effects of trimethyltin intoxication in the neonatal mouse. I. Light microscopic studies.

The effects of trimethyltin (TMT) intoxication on the developing mouse brain were studied. BALB/c mice were injected intraperitoneally with 3.0 mg TMT/kg body weight on postnatal day 3. Animals were sacrificed at selected intervals to 30 days of age and their brains examined by light microscopy. Increased eosinophilia and granularity of hippocampal pyramidal neurons and neurons of the pyriform cortex were detected as early as 16 hours post-administration. Extensive degenerative and necrotic charges were observed 1 to 10 days post-administration, particularly in hippocampal region CA-3 of Ammon's horn. Cerebellar Purkinje and granule neurons, basal ganglia and cerebral cortex were involved to a lesser extent. Pathological changes of granule cells in the fascia dentata were much less extensive than reported in adult mice. Astrogliosis was occasionally pronounced. Distribution of lesions within the hippocampus indicate that acute neonatal TMT exposure results in a different regional pattern of injury than in acutely treated adult mice.

Animals↗
PubMed1982

The effects of plant-incorporated methylmercury on its distribution, excretion and demethylation patterns in the rat.

Rats were dosed once per os with either plant-incorporated or solution-radioactive methylmercury (MeHg). While whole-body retention did not change, the incorporation into some organs was approx. 2.5 X higher when administered Hg was in the plant-incorporated rather than in solution form. The only noticeable change in demethylation occurred in the cerebrum where MeHg:Hg ratios were 79:10 (plant-incorporated MeHg) and 65:24 (solution-MeHg). Between 5 to 7% of the total mercury was excreted in faeces and urine either in the inorganic (faeces) or organic (urine) forms. Mercury levels in mitochondrial and soluble fractions of cerebrum were noticeably lower with plant-MeHg than with solution-MeHg.

Animals↗
PubMedDate not supplied

Effect of selenium on distribution, demethylation, and excretion of methylmercury by the guinea pig.

The influence of selenium on methylmercury excretion, organ and subcellular distribution, and demethylation was studied in the guinea pig at different times following a single equimolar dose (50 miroM/kg) of CH203 3) HgCl and Na2SeO3 administered separately or concomitantly per os. Excretion of mercury through feces was the dominant clearance pathway in both groups. Selenium significantly decreased excretion of total and organic mercury in feces during the course of the study, but in the urine only on d 13. Selenium also significantly decreased the concentration of total mercury in major organs. The exception was brain on d 1, in which mercury levels were higher in the presence of selenium; however, on d 7 and 13 both cerebrum and cerebellum showed lower mercury levels as compared to the group treated with methylmercury alone. Selenium had no significant effect on the subcellular mercury distribution in the liver, kidney, and cerebrum, other than that which could be accounted for the whole organ uptake. The level of organic mercury in most of the analyzed organs was significantly decreased by the presence of selenium; however, relative proportions of inorganic to organic mercury remain unchanged. The single exception was kidney, where selenium markedly decreased the relative amount of inorganic mercury.

Animals↗
PubMedDate not supplied

Mechanisms of injury in the central nervous system.

Neurotoxicants with similar structural features or common mechanisms of chemical action frequently produce widely divergent neuropathologic outcomes. Methylmercury (MeHg) produces marked cerebellar dysmorphogenesis during critical periods of development. The pathologic picture is characterized by complete architectural disruption of neuronal elements within the cerebellum. MeHg binds strongly to protein and soluble sulphydryl groups. Binding to microtubular -SH groups results in catastrophic depolymerization of immature tyrosinated microtubules. However, more mature acetylated microtubules are resistant to MeHg-induced depolymerization. In contrast to MeHg, the structurally similar organotin trimethyltin (TMT) elicits specific apoptotic destruction of pyramidal neurons in the CA3 region of the hippocampus and in other limbic structures. Expression of the phylogenetically conserved protein stannin is required for development of TMT-induced lesions. Inhibition of expression using antisense oligonucleotides against stannin protects neurons from the effects of TMT, suggesting that this protein is required for expression of neurotoxicity. However, expression of stannin alone is insufficient for induction of apoptotic pathways in neuronal populations. The aromatic nitrocompound 1,3-dinitrobenzene (DNB) has 2 independent nitro groups that can redox cycle in the presence of molecular oxygen. Despite its ability to deplete neural glutathione stores, DNB produces edematous gliovascular lesions in the brain stem of rats. Glial cells are susceptible despite high concentrations of reduced glutathione compared with neuronal somata in the central nervous system (CNS). The severity of lesions produced by DNB is modulated by the activity of neurons in the affected pathways. The inherent discrepancy between susceptibility of neuronal and glial cell populations is likely mediated by differential control of the mitochondrial permeability transition in astrocytes and neurons. Lessons learned in the mechanistic investigation of neurotoxicants suggest caution in the evaluation and interpretation of structure-activity relationships, eg, TMT, MeHg, and DNB all induce oxidative stress, whereas TMT and triethyltin produce neuronal damage and myelin edema, respectively. The precise CNS molecular targets of cell-specific lipophilic neurotoxicants remain to be determined.

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