PubMed Health⌕ Search

Biomedical subjects

N K Mottet

Publications and source records attributed to N K Mottet.

At least 19 recordsLinked to original sources
PubMed1998

Fetal, infant, and maternal toxicity of zidovudine (azidothymidine) administered throughout pregnancy in Macaca nemestrina.

The toxicity of azidothymidine (AZT) was studied in monkey dams and fetuses that were exposed to the drug over the entire gestational period. Fourteen virus-free female macaques (Macaca nemestrina) were randomly assigned to AZT or control groups. AZT animals received the drug through a gastric catheter at a dose of 1.5 mg/kg every 4 hours, which produced plasma concentrations similar to those in humans taking 500 to 600 mg/day of AZT. Control animals received water placebo, also through gastric catheter. Some animals participated in both groups. All females were mated with the same male; 41 matings produced 20 pregnancies, of which 16 were carried to term (9 in AZT females; 7 in control females). The AZT animals developed an asymptomatic macrocytic anemia, but hematologic parameters returned to normal when AZT was discontinued. Total leukocyte count decreased during pregnancy and was further affected by AZT administration. AZT-exposed infants were mildly anemic at birth. AZT caused deficits in growth, rooting and snouting reflexes, and the ability to fixate and follow near stimuli visually, but the deficits disappeared over time. These data indicate that early exposure to AZT in utero should have no irreversible adverse effects on the fetus.

Anemia↗
PubMed1996

Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure.

The effects of long-term subclinical exposure to methylmercury on the number of neurons, oligodendrocytes, astrocytes, microglia, endothelial cells and pericytes within the thalamus from the left side of the brain of the monkey Macaca fascicularis has been determined by use of the Optical Volume Fractionator stereological method. The accumulated burden of inorganic mercury (IHg) within these same cell types has been determined by autometallographic methods. Four groups of monkeys were exposed to methylmercury (MeHg; 50 micrograms Hg/kg body weight/day) by mouth for 6 months, 12 months, 18 months, or 12 months followed by 6 months without exposure (clearance group). Neurons, oligodendrocytes, endothelia, and pericytes did not show a significant change in cell number for any exposure group. Astrocyte cell number exhibited a significant decline for both the 6 month and clearance exposure groups. The microglia, in contrast, showed a significant increase in the 18 month and clearance exposure groups. Results from mercury speciation and quantification analysis of contralateral matched samples from the thalamus of the right side of the brain from these same monkeys indicated that MeHg concentrations plateaued at around 12 months exposure, whereas the inorganic levels, presumably derived from demethylation of MeHg, continued to increase throughout all exposure durations. Autometallographic determination of the distribution of IHg by cell type indicates that both the astrocytes and microglia contain substantially elevated IHg deposits relative to all other cell types. The data suggest that the inorganic mercury present in the brains, accumulating after long-term subclinical methyl mercury exposure, may be a proximate toxic form of mercury responsible for the changes within the astrocyte and microglial populations.

Animals↗
PubMed1995

Autometallographic determination of inorganic mercury distribution in the cortex of the calcarine sulcus of the monkey Macaca fascicularis following long-term subclinical exposure to methylmercury and mercuric chloride.

The distribution of accumulated inorganic mercury deposits in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl-mercury (MeHg) and mercuric chloride (inorganic mercury-IHg) has been determined by autometallography. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, and 18 months or 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered inorganic mercury (as HgCl2; 200 micrograms Hg/kg body wt/day) for 3 months by constant rate intravenous infusion via an indwelling catheter. Staining of IHg deposits in the MeHg-exposed groups increased for all cell types with increased length of exposure. The astrocytes and microglia in the MeHg exposure groups contained the largest deposits of IHg. Neurons in the 6-month MeHg exposure group were either not labeled or contained very fine deposits of IHg. The frequency of labeled neurons increased somewhat in the 12-month and clearance exposure groups. Virtually all neurons in the 18-month exposure group contained labeled deposits of IHg; however, these total deposits were considerably smaller than those present within the astrocytes and microglia. The majority of endothelial cells and pericytes did not contain notable mercury deposits, although scattered individual cells were heavily labeled. Labeled oligodendrocytes were relatively rare in all MeHg-exposed groups. Gitter cells, primarily located in a perivascular position, were common in the 12-month, 18-month, and clearance groups and many of these were found to be heavily labeled. The staining of mercury deposits in the IHg-exposed animals was low compared to the MeHg-exposed groups. The astrocytes and microglia were the primary cell types labeled. It is concluded that the astrocytes, and possibly microglia, are the primary location of the demethylation of MeHg into IHg within the cortex of the calcarine sulcus.

Animals↗
PubMed1995

Demethylation of methyl mercury in different brain sites of Macaca fascicularis monkeys during long-term subclinical methyl mercury exposure.

Total (T-Hg) and inorganic (I-Hg) mercury concentrations were determined in specific brain sites (cerebellum, occipital pole, pons, motor strip, frontal pole, temporal pole, thalamus, and pituitary) of female Macaca fascicularis monkeys exposed to daily peroral doses (50 micrograms Hg/kg body weight) of methyl mercury (MeHg) for 6, 12, or 18 months, or to continuous iv infusion of HgCl2 (200 micrograms Hg/kg body wt). In normal weight monkeys (2.4-4.1 kg body wt), the average concentration of MeHg (calculated as T-Hg minus I-Hg) was about the same in all brain sites, except the pituitary--3.0 micrograms Hg/g at 6 months, 4.2 micrograms/g at 12 months, and 4.3 micrograms Hg/g at 18 months. MeHg concentrations in the pituitary were about 50% of those in the other brain sites. In a group of monkeys that were kept unexposed for 6 months following 12 months of MeHg exposure, T 1/2 for MeHg was about 37 days in all brain sites, with the exception of the pituitary, where it was shorter. The concentration of I-Hg increased in all brain sites, but especially in the thalamus and pituitary, with the time of MeHg exposure. In most brain sites, I-Hg constituted about 9% of T-Hg at 6 and 12 months, and 12% of T-Hg at 18 months. In the pituitary, I-Hg increased from 20% of T-Hg at 6 months to 46% at 18 months. Elimination T 1/2 for I-Hg was extremely long, 230-540 days in most brain sites and considerably longer in the thalamus and pituitary. The concentration of I-Hg in the thalamus did not decrease during the clearance period (6 months), while I-Hg in the pituitary continued to increase in spite of no additional exposure. The MeHg exposed monkeys had several times higher I-Hg concentrations in the brain than monkeys exposed to HgCl2, indicating that I-Hg was formed by demethylation of MeHg in the brain, and not by brain uptake of I-Hg formed by demethylation elsewhere in the body. There were large variations in the relative concentration of I-Hg between individual monkeys, but not between brain sites (except thalamus and pituitary). Obese monkeys (5.0-6.1 kg body wt) exposed to MeHg had higher concentrations of both MeHg and I-Hg than normal weight monkeys in all brain sites, except in the pituitary.

Animals↗
PubMed1994

Speciation of mercury in the primate blood and brain following long-term exposure to methyl mercury.

Total (T-Hg) and inorganic (I-Hg) mercury in blood and brain of female Macaca fascicularis monkeys, exposed to daily peroral doses of methyl mercury (MeHg; 50 micrograms Hg/kg body wt) for 6, 12, or 18 months, or to continuous iv infusion of HgCl2 (200 micrograms Hg/kg body wt) for 3 months, were determined. In normal weight monkeys (2.4-4.1 kg body wt) exposed to MeHg, steady state of T-Hg in blood (1.1 micrograms Hg/g) was reached in about 4 months. The elimination T1/2 in blood was 26 days. I-Hg constituted 7% of T-Hg in blood. The average concentration of MeHg in occipital pole and thalamus was about 3 micrograms Hg/g at 6 months and 4.5 micrograms Hg/g at 12-18 months. Accumulation in brain seemed to be biphasic. Following termination of 12 months exposure, elimination T1/2 for MeHg in brain was 35 days. I-Hg constituted about 9% of T-Hg in brain at 6-12 months, 18% at 18 months, and 74% at 6 months after termination of exposure. The I-Hg concentrations were somewhat higher in thalamus than in occipital pole. The elimination T1/2 for I-Hg was extremely long, on the order of years. Most likely, the I-Hg was formed by demethylation of MeHg in the brain. In monkeys exposed to HgCl2, blood levels of 0.6 micrograms I-Hg/g gave rise to brain I-Hg levels of about 0.1 micrograms/g only. In three heavy weight monkeys (5.0-6.1 kg body wt) exposed to MeHg, blood Hg increased to about 2 micrograms Hg/g, indicating a limited distribution of MeHg to fat. The Hg concentrations in brain (7-22 micrograms Hg/g) were considerably higher than those in normal weight monkeys, due to the high blood Hg levels in combination with a high brain-to-blood distribution ratio.

Administration, Oral↗
PubMed1994

Effects of methyl mercury on the cell cycle of primary rat CNS cells in vitro.

Methyl mercury (MeHg) may interfere with cell cycle progression in a number of ways, most notably through an inhibition of protein synthesis or through effects on mitotic spindle performance; both mechanisms have experimental support. Results from investigations into the effects of MeHg exposure on cell cycle progression in a primary fetal rat CNS culture are presented here. Colchicine was also investigated because it is a well-characterized mitotic inhibitor. Flow cytometric DNA content analysis was utilized to determine the cell cycle distribution histograms of control and treated cultures. In addition, a flow cytometric technique which involves the incorporation of 5-bromo-2'-deoxyuridine into newly synthesized DNA was used to discriminate between successive cell cycles. Exposure of the CNS cell cultures to MeHg (2 and 4 microM) over a period of 0-48 hr led to a G2/M-phase inhibition as determined by flow cytometric DNA content analysis. Whereas exposure to 2 microM MeHg resulted in G2/M-phase inhibition, an analysis of cell cycle progression demonstrated an inhibition of cell cycling through any phase following exposure to 4 microM MeHg; these effects occurred in the first round of cell division following plating. Exposure to colchicine (25 nM) resulted in a G2/M-phase arrest similar to that observed with MeHg (2 microM). However, a comparison of the cytotoxicity patterns between MeHg-treated and colchicine-treated cultures suggests that MeHg-induced cytotoxicity cannot be solely ascribed to G2/M-phase arrest, since at equivalent levels of G2/M-phase arrest, MeHg was more cytotoxic than colchicine. These results are consistent with the hypothesis that microtubules, and the mitotic spindle, are especially sensitive to MeHg exposure.

Animals↗
PubMed1994

Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure.

The number of neurons, astrocytes, reactive glia, oligodendrocytes, endothelia, and pericytes in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl mercury (MeHg) and mercuric chloride (inorganic mercury; IHg) has been estimated by use of the optical volume fractionator stereology technique. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, 18, and 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered IHg (as HgCl2; 200 micrograms Hg/kg body wt/day) by constant rate intravenous infusion via an indwelling catheter for 3 months. Reactive glia showed a significant increase in number for every treatment group, increasing 72% in the 6-month, 152% in the 12-month, and 120% in the 18-month MeHg exposed groups, and the number of reactive glia in the clearance group remained elevated (89%). The IHg exposed group showed a 165% increase in the number of reactive glia. The IHg exposed group and the clearance group had low levels of MeHg present within the tissue; however, the level of IHg was elevated in both groups. These results suggest that the IHg may be responsible for the increase in reactive glia. All other cell types, including the neurons, showed no significant change in number at the prescribed exposure level and durations. The identities of the reactive glial cells and the implications for the long-term function and survivability of the neurons due to changes in the glial population following subclinical long-term exposure to mercury are discussed.

Analysis of Variance↗
PubMed1992

Birth weight of children and cadmium accumulation in placentas of female nickel-cadmium (long-life) battery workers.

In a retrospective epidemiological study on the birth weight of 266 children of 137 female workers in a nickel-cadmium battery factory, 157 children of workers occupationally exposed to cadmium were compared with 109 born to non-occupationally exposed workers. No effect of cadmium exposure on birth weight was detected, but a statistically significant effect on birth weight of smoking during pregnancy was observed. In a prospective study on the same population of female battery workers, 27 placentas were collected and the cadmium distribution and concentration in tissue subsamples determined. Placental cadmium concentrations were positively correlated with maternal blood cadmium. The cadmium concentration in placentas ranged from < 0.002 to 0.095 microgram/g (wet weight), the mean concentration +/- SD was 0.021 +/- 0.022 microgram/g (wet weight). Morphological and ultrastructural studies of placental tissues did not reveal any effect of cadmium. This study did not provide any evidence in support of the hypothesis that the placenta may be the critical organ in exposure to cadmium.

Adolescent↗
PubMed1990

Pathways of human exposure to arsenic in a community surrounding a copper smelter.

Several studies have found elevated levels of urinary arsenic among residents living near a copper smelter in Tacoma, Washington. To assess pathways of exposure to arsenic from the smelter, biological and environmental samples were collected longitudinally from 121 households up to 8 miles from the smelter. The concentration of inorganic and methylated arsenic compounds in spot urine samples was used as the primary measure of exposure to environmental arsenic. Urinary concentration of arsenic dropped off to a constant background level within one-half mile of the smelter in contrast to environmental concentrations, which decreased more steadily with increasing distance. Among all age-sex-specific groups in all areas, only children ages 0-6 living within one-half mile of the smelter had elevated levels of arsenic in urine. A separate analysis of data for these children suggests that hand-to-mouth activity was the primary source of exposure. Inhalation of ambient air and resuspension of contaminated soil were not important sources of exposure for children or adults.

Adolescent↗
PubMed1990

The effect of variable environmental arsenic contamination on urinary concentrations of arsenic species.

Urinary arsenic species have been determined for approximately 3000 urine samples obtained from residents of a community surrounding an arsenic-emitting copper smelter. Levels of inorganic, monomethylated and dimethylated arsenic species ranged from less than 1 microgram/L (the instrumental detection limit) to 180 micrograms/L seen for dimethyl arsenic. Comparison of a subsample of this population that had the least environmental contamination with the subsample having highest environmental arsenic concentrations showed small but statistically significant differences in urinary arsenic levels for all species except dimethylated arsenic. However, for children under 7 years of age living in areas with increased environmental arsenic contamination, there was a larger and equally significant (p less than 0.001) increase in all urinary species. This effect was more pronounced in males (5-fold increase in median sum of species concentration over control group) than in females (2-fold increase in median sum of species concentration over control group) and was observed as a weaker effect in the next higher age group (7-13 years of age). Reported consumption of seafood also was significantly related to increased urinary dimethyl arsenic, but changes in distribution among the urinary arsenic species detected was not a sensitive indicator of recent seafood consumption.

Arsenic↗
PubMed1989

Analysis of methyl mercury binding sites on tubulin subunits and microtubules.

We have studied the localization and affinity of methyl mercury hydroxide (MeHg) binding sites on microtubules. There is one class of binding sites for MeHg on tubulin, a high affinity class with fifteen sites. MeHg binds to tubulin stoichiometrically within microtubules, and does not induce microtubule disassembly at this low binding ratio. MeHg binds in microtubules either in the presence or absence of free tubulin subunits but free subunits act as uncompetitive inhibitors for MeHg binding to the polymer. These stoichiometric polymer surface binding sites for MeHg apparently do not interfere with subsequent polymerization, in contrast to the multiple sites in the free dimer whose occupation blocks subsequent assembly. In assembly cycles that follow MeHg binding to polymers, we continue to find MeHg bound to microtubules at substoichiometric ratios. Dimers with higher levels of MeHg binding are rendered assembly incompetent. These results show MeHg to have one class of binding site on tubulin, and the MeHg binding site, both to the polymer surface and to the free dimer, to be the same.

Binding Sites↗
PubMed1989

Kinetics of methyl mercury in blood and brain during chronic exposure in the monkey Macaca fascicularis.

The disposition parameters derived from a compartmental model kinetic analysis of blood Hg levels in nonpregnant, adult female Macaca fascicularis given daily doses of MeHg did not vary with either dosage level (50, 70 or 90 micrograms MeHg/kg b.wt.day) or duration of exposure (up to 507 day). In contrast, blood clearance of Hg in pregnant females was dose-dependent; it being higher at the 90 micrograms MeHg/kg b.wt.day than at the lower dosage levels. Hg levels in the brain of adult fascicularis relative to blood Hg also increased at the highest level of exposure. Blood Hg half-life in neonate fascicularis was similar to half-life in their mothers (adults). Finally, the regional distribution of mercury in the brains of adult and neonate fascicularis exposed to low and intermediate levels of MeHg resembles the reported distribution of mercury in the brains of adult and neonate humans environmentally exposed to MeHg. Consequently, M. fascicularis may be an especially appropriate animal model for studying the neurotoxic mechanisms of chronic methyl mercury exposure.

Animals↗
PubMed1988

Effect of methylmercury body burden on kidney following unilateral nephrectomy.

The model of renal enlargement after unilateral nephrectomy is chosen to study the effect of methylmercury (MeHg) burden on organ growth. The results show that MeHg burden only impedes DNA synthesis, but not other macromolecular synthesis (RNA and protein). Despite the gradual increase of kidney weight and increase of total RNA and protein content in the remaining kidney, DNA remained unchanged. There is no difference between the control and the MeHg-treated group. 3H-thymidine incorporation study shows that unilateral nephrectomy elicited minimal DNA synthesis in the remaining kidney. Again there is no statistically significant difference of 3H-thymidine incorporation between the control and the MeHg-treated group. On a separate experiment, the folic-acid-induced renal DNA synthesis is also suppressed by MeHg burden. From these data it is concluded that chronic exposure to MeHg does not affect one of the cellular repair mechanisms: hypertrophy.

Animals↗
PubMed1987

Biologic variables in the hair uptake of methylmercury from blood in the macaque monkey.

The total mercury (Hg) in hair and blood of 45 young healthy adult female Macaque fascicularis given 0, 50, 70, or 90 micrograms MeHg/kg body wt orally in apple juice daily revealed a close and constant ratio between blood Hg and hair. The amount of hair Hg does not increase with time (maximum period of observation 490 days) at a given dose level. Also the ratio was unchanged between background and subtoxic dose levels. Individuals at a given dose level with a higher-than-average blood level had a proportionately higher hair level. The Macaque blood/hair ratio is markedly lower than that reported for humans. Pregnancy did not have an appreciable effect on the hair mercury level. Review of the known variables in human and Macaque hair growth and structure does not provide an explanation for the difference. We suggest that an as yet unidentified biological variable(s), possibly circumfollicular blood flow, could account for the difference. This ratio difference notwithstanding, controlled studies on Macaque hair such as this add support for the validity of terminal hair as a trace metal exposure indicator.

Animals↗
PubMed1987

Effects of methyl mercury on testicular functions in Macaca fascicularis monkeys.

These studies were performed to investigate the effects of MeHg on testicular function in Macaca fascicularis monkeys. In an in vivo study involving oral treatment of adult males Macaca fascicularis monkeys with MeHg for 20 weeks, changes in spermatozoal production, motility and morphology and in serum testosterone were followed before, during and after treatment. MeHg treatment significantly decreased % motile spermatozoa and scores for sperm speed and forward progression and increased % abnormal sperm tail forms, at sub-neurotoxic levels. The MeHg-induced increase in semen abnormalities was not accompanied by any significant changes in serum levels of testosterone. No consistent histological abnormalities were detected in testicular biopsies from the treated animals at the end of the treatment period. A good recovery pattern was observed for the MeHg effects on sperm motility while this was unclear for the effects on sperm morphology.

Animals↗
PubMed1987

Advantages of using aquatic animals for biomedical research on reproductive toxicology.

Major advantages of the use of aquatic animals, such as trout, English sole, or sea urchins, for studying the mechanisms of reproductive toxicology are discussed. The remarkable synchrony of differentiation of gametes in large quantities for detailed morphologic and biochemical measurements enables research not readily done on mammalian nonseasonal breeders. Structural differences such as the absence of a fibrous sheath in the more simple structure of fish and sea urchin sperm flagella facilitates comparative study of the mechanism of action of microtubules in flagella movement and the coupling of mitochondrial energy production to microtubules movement.

Animals↗