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N K Mottet

Publications and source records attributed to N K Mottet.

At least 37 records · Page 2Linked to original sources
PubMed1986

Effects of methylmercury on the morphogenesis of the rat cerebellum.

Developing rat cerebellums were examined following continuous methylmercury exposure via maternal drinking water at 12.5 ppm during gestation and the suckling period. The continuous exposure resulted in reductions of the total cerebellar cell population and higher mercury tissue burdens than previous acute-dose studies. Cell necrosis was not evident, but rather alterations in the pattern of mitotic figures were observed. A decreased number of cells in the methylmercury exposed cerebellums was associated with an increased number of mitotic figures in the early stages of mitosis and a decrease in the number in the middle and late stages. These in vivo exposure observations are consistent with in vitro cell cycle studies in which the cells were found to have accumulated in G2 and early M phases. Impaired cell proliferation is suggested to be a major mechanism of developmental neurotoxicity following continuous low-dose exposure to methylmercury.

Animals↗
PubMed1986

Glucocorticoid regulation of metallothionein during murine development.

During the second half of gestation in the mouse there is a rise in both fetal (4-fold) and maternal (10-fold) metallothionein-I (MT-I) mRNA in the liver (but not in the kidney). There is a large increase in plasma corticosterone (the predominant murine glucocorticoid hormone), as well as an increase in hepatic zinc, which is coincident with the induction of MT-I mRNA. Considering that both of these compounds are known to be effective inducers of MT-I mRNA, we set out to determine whether either one or both were involved in the developmental regulation of MT-I genes. Several lines of evidence suggest that corticosterone is the principal inducer of fetal MT-I mRNA: The induction of MT-I mRNA in the liver, but not in the kidney, mimics glucocorticoid regulation but not metal regulation. Reduction of maternal corticosterone levels by treating mice with metyrapone lowered MT-I mRNA levels but had no effect on zinc levels. A line of transgenic mice carrying a metallothionein-growth hormone fusion gene that is responsive to metals but unresponsive to glucocorticoids was not developmentally regulated. Based on these observations, we propose that corticosterone is responsible for the induction of MT-I mRNA and that the resulting MT sequesters zinc and copper which may be used later in development.

Animals↗
PubMed1986

Methylmercury effects on cell cycle kinetics.

Methylmercury (MeHg) effects on cell cycle kinetics were investigated to help identify its mechanisms of action. Flow cytometric analysis of normal human fibroblasts grown in vitro in the presence of BrdU allowed quantitation of the proportion of cells in G1, S, G2 and the next G1 phase. This technique provides a rapid and easily performed method of characterizing phase lengths and transition rates for the complete cell cycle. After first exposure to MeHg the cell cycle time was lengthened due to a prolonged G1. At 3 microM MeHg the G1 phase length was 25% longer than the control. The G1/S transition rate was also decreased in a dose-related manner. Confluent cells exposed to MeHg and replated with MeHg respond in the same way as cells which have not been exposed to MeHg before replating. Cells exposed for long times to MeHg lost a detectable G1 effect, and instead showed an increase in the G2 percentage, which was directly related to MeHg concentration and length of exposure. After 8 days at 5 microM MeHg, 45% of the population was in G2. The G2 accumulation was reversible up to 3 days, but at 6 days the cells remained in G2 when the MeHg was removed. Cell counts and viability indicated that there was not a selective loss of cells from the MeHg. MeHg has multiple effects on the cell cycle which include a lengthened G1 and decreased transition probability after short term exposure of cycling cells, and a G2 accumulation after a longer term exposure. There were no detectable S phase effects. It appears that mitosis (the G2 accumulation) and probably synthesis of some macromolecules in G1 (the lengthened G1 and lowered transition probability) are particularly susceptible to MeHg.

Cell Cycle↗
PubMed1986

Effects of methyl mercury on sperm oxygen consumption.

Oxygen consumption and percent motile spermatozoa were determined for semen samples from healthy male monkeys Macaca fascicularis. Methyl mercury was added to the samples, in the oxygen measurement chamber, at a concentration of 9 p.p.m. for 15 min. and then increased to 15 p.p.m. for 15-30 min. Oxygen consumption and percent motility were determined during each period. Methyl mercury addition resulted in decreased sperm motility, but we did not detect any inhibition in the rate of oxygen consumption accompanying the decreased motility. On the contrary, the rate of oxygen consumption increased at 15 p.p.m. within 15 min., while the sperm motility was close to zero. Antimycin inhibited the increased rate of oxygen consumption demonstrating the mitochondrial source of this increased rate. Oligomycin also inhibited the increased rate of oxygen consumption due to methyl mercury, thus excluding the possibility of uncoupling of mitochondrial oxidative phosphorylation. Interference with mitochondrial energy production does not seem to be the primary mechanism of methyl mercury-induced decreased spermatozoal motility. Methyl mercury interference with the dynein/microtubule sliding assembly now seems to us to be a more tenable hypothesis.

Adenosine Triphosphate↗
PubMed1986

The effect of low-level prenatal methylmercury exposure on visual recognition memory in infant crab-eating macaques.

Infant crab-eating macaques exposed in utero to maternal subclinical levels of methylmercury (MeHg) and their nonexposed controls were administered an adaptation of a standardized test of visual recognition memory. Exposed animals showed recognition deficits in that they directed significantly less visual attention to novel stimuli than did controls. These results parallel those obtained by other investigators with high-risk and teratogen-exposed human infants.

Animals↗
PubMed1985

The effects of methyl mercury binding to microtubules.

The effects of methyl mercury hydroxide (MeHg) on the in vitro polymerization and depolymerization of microtubules were studied. Polymerization was totally inhibited at 3.0 X 10(-5) M MeHg and depolymerization occurred at concentrations above 1.0 X 10(-5) M MeHg, reaching a maximal rate of -0.33%/min at 5.0 X 10(-5) M MeHg. At or above 1.0 X 10(-4) M MeHg, a mercury-protein aggregate formed in both the polymerization and depolymerization systems. Fifteen free sulfhydryl groups per tubulin dimer were determined, and MeHg bound to all 15. When MeHg bound to only 2 free sulfhydryl groups per dimer, it inhibited polymerization. MeHg bound to free sulfhydryl groups exposed uniquely on the surface of microtubules, as well as those free sulfhydryl groups exposed on the ends. These results show MeHg in vitro to be a potent microtubule assembly inhibitor at ratios stoichiometric with the tubulin dimer. The effects of MeHg on microtubules are presumably mediated through MeHg binding to free sulfhydryl groups both on the ends and on the surface of microtubules. The presence of binding sites (free sulfhydryl groups) on the microtubule surface suggests multiple classes of binding sites for MeHg.

Animals↗
PubMed1985

Health risks from increases in methylmercury exposure.

Our present knowledge of the human health effects of methylmercury exposure is derived from study of major outbreaks of human poisonings in Japan and Iraq and experimental studies on primates. Methylmercury readily passes through such physiological barriers as the blood-brain barrier, blood-testes barrier, and the placenta. Its major pathological effects are on the nervous and reproductive systems and the developing embryo/fetus. The neurotoxicity of methylmercury is well established in both humans and non-human primates. Lesions in the cerebral and cerebellar gray matter consist of necrosis and lysis of neurons, phagocytosis and gliosis. The changes are most prominent in the deep sulci and may have a vascular component. A late effect is cerebral atrophy. At high dose levels the liver, kidneys, and other organs may also have degenerative changes. Although not yet described in humans, a major effect of exposure of female primates is an adverse effect on pregnancy. Maternal female M. fascicularis blood mercury levels above 1 ppm are associated with a decreased pregnancy rate and increased abortion rate. To date our experimental data lack sufficient numbers to detect infrequent pregnancy effects below 1 ppm. Preliminary studies also reveal that methylmercury may also decrease the number and function (swim speed) of sperm. Both human and primate studies demonstrate deleterious effects of methylmercury on the developing embryo/fetus. Autopsies on human and primate infants reveal retarded brain development and the occurrence of a cerebral palsy-like behavior in the newborns, whereas the mother may be free of signs and symptoms of methylmercury toxicity. The fetal blood level of mercury is higher than the maternal level.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Cadmium hypersusceptibility in the C3H mouse liver: cell specificity and possible role of metallothionein.

The possible involvement of metallothionein (MT) gene expression dysfunction was examined in a strain of mouse which is unusually sensitive to cadmium toxicity, the C3H. C3H mice, and the relatively cadmium-insensitive Swiss mice, were injected sc with 20 microM CdCl2/kg body wt. This dose caused liver damage, visible at the light microscopic level, in the C3H but not the Swiss mice. These studies showed that MT-I mRNA and MT protein accumulation, as well as binding of cadmium by MT, were very similar in the two strains. These data suggested that altered expression of MT in the hepatic parenchyma was not a factor in the C3H hypersusceptibility. An electron microscopic examination of the early effects of cadmium injection indicated that the primary targets for toxicity in the C3H liver may be the endothelial cells. It is hypothesized that the widespread damage seen at later times resulted, secondarily, from ischemia produced in response to endothelial cell damage.

Animals↗
PubMed1984

Methylmercury exposure and reproductive dysfunction in the nonhuman primate.

Macaca fascicularis females were monitored daily through four menstrual cycles then orally administered 0, 50, or 90 micrograms/kg/day methylmercury hydroxide (MeHg). Females were monitored through four additional menstrual cycles and after approximately 124 days of MeHg treatment were time-mated to nontreated males. MeHg treatment did not affect menstrual cycle or menses length. The relationship between dosage of MeHg and reproductive outcome approached but did not reach statistical significance. Reproductive failure (i.e., nonconception, abortion) was, however, related to a significantly higher blood Hg concentration than reproductive success for MeHg-treated females. The offspring of MeHg-treated females tended to be smaller than control infants, but no statistically significant decrease in gestation, birthweight, or crown-rump length was observed. None of the females receiving MeHg exhibited signs of MeHg toxicity during breeding or pregnancy. Daily treatment with 90 micrograms/kg/day MeHg for nearly 1 year, however, produced signs of toxicity in four of seven females. Toxicity was related to increased maternal size, duration of MeHg treatment, and a blood Hg concentration of 2.3 to 2.8 ppm.

Animals↗
PubMed1983

Arsenic-induced exencephaly in the mouse and associated lesions occurring during neurulation.

Early tissue damage following a teratogenic dose of arsenic to the dam was studied in mice with the objective of detecting the primary lesion associated with the development of exencephaly. Animals were killed 6 to 21 h after a single 45 mg/kg intraperitoneal injection of sodium arsenate on day 8 of pregnancy and neurulation-stage embryos were fixed for histological and ultrastructural examination. In the prospective hindbrain, the most consistent feature associated with arsenate treatment was the widely separated neural folds which were not positioned for closure. Intracytoplasmic inclusions, interpreted as necrotic debris, were most numerous in the apical portion of the neural folds, sometimes extending into the mesenchyme, but they were not extensive in most embryos. In the prospective forebrain, necrotic debris was found throughout the neuroepithelium, in contrast to the posterior portions of the developing brain. It is not clear that necrosis of the neuroepithelium or mesenchyme would in itself be the primary lesion associated with exencephaly, although death of specific cells such as those participating in the fusion process could be involved. The potential effect of arsenate on physiological and biochemical processes which could affect neural tube closure is discussed.

Abnormalities, Drug-Induced↗
PubMed1983

First trimester serum zinc concentrations in human pregnancy.

Serum zinc concentrations in the 1st trimester of human pregnancy were evaluated in 106 women whose dates of conception were precisely determined by basal body temperature monitoring and human chorionic gonadotropin levels. Data are reported by intervals of postovulatory days. Sera were analyzed for zinc by atomic absorption spectrophotometry after acid digestion. Mean 1st trimester serum zinc concentrations, determined by 20-day increments from ovulation, were 0.97 +/- 0.22, 0.68 +/- 0.14, 0.77 +/- 0.18, and 0.70 +/- 0.15 micrograms/ml; differences between means were significant at p less than 0.005, less than 0.005, and less than 0.01, respectively. These differences could not be related to diet, supplement use, or hematocritic changes. No differences were apparent between diabetic and nondiabetic subjects. Of the 25 samples from women who aborted spontaneously, zinc concentration of seven were lower than interval means.

Abortion, Spontaneous↗
PubMed1983

Evidence for a new model of tumor progression from carcinogenesis and tumor promotion studies with 7-bromomethylbenz[a]anthracene.

7-Bromoethylbenz[a]anthracene (BrMeBA) has been shown previously to be a modest initiator of tumors in mouse skin and a powerful promoter. Evidence has also been presented that carcinomas and papillomas arising in mouse skin from a two-stage induction regimen (initiation and promotion) originate in two separate populations, rather than representing progressive stages on a single pathway. In this report, we show that 10 nmol of BrMeBA applied biweekly to female SENCAR mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA) is an effective promoting dose. The question of whether BrMeBA or its solvolysis product, 7-hydroxymethylbenz[a]anthracene, is the effective promoter was tested in Charles River CD-1 mice, in which 90 nmol of BrMeBA applied weekly following a single dose of 200 nmol of DMBA induced papillomas in 17 weeks (median induction time) and carcinomas in 43 weeks after beginning of promotion. Without DMBA initiation, papillomas appeared 11 weeks later in much lower yield, while carcinomas appeared 14 weeks later. Animals treated with 7-hydroxymethylbenz[a]anthracene for 82 weeks had developed only 16 tumors in eight animals (initiated) or six tumors in five animals (uninitiated), with survivals of 18 of 30 and 19 of 30, respectively. In SENCAR mice treated with 90, 30, or 10 nmol of BrMeBA biweekly, the ratio of total carcinomas to total papillomas in initiated mice was about half that in uninitiated mice, due primarily to a large reduction in papilloma incidence in uninitiated mice. When adjusted for the number of papillomas, the risk of developing the first carcinomas at any time was dependent only on the dose of BrMeBA and not on whether DMBA was given first. An attempt to inhibit BrMeBA promotion with the antiinflammatory steroid fluocinolone acetonide resulted in inhibition of DMBA-initiated papillomas but had no effect on the carcinoma latent period of incidence. The results are explained in terms of new models of tumor progression which suggest either that promotors with the capabilities of 12-O-tetradecanoylphorbol-13-acetate can divert cells at a minimum level of initiation from progression to cancer or that initiation can create at least two populations of altered cells, one (or more) of which is less likely to progress to cancer than normal cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Pathogenic mechanisms of heterotopic neural tissue associated with anencephaly.

Central nervous tissue was found in both the lung and the abdominal surface of the diaphragm in an anencephalic baby with gastroschisis. These findings support the hypothesis that the heterotopic neural tissue in anencephalic babies is due to transamniotic implantation. It thus appears that the pathogenic mechanism of the heterotopic neural tissue in the lung is aspiration.

Anencephaly↗
PubMed1981

DDT acceleration of mammary gland tumors induced in the male Sprague-Dawley rat by 2-acetamidophenanthrene.

2-Acetamidophenanthrene (AAP) yields adducts to rat liver DNA and RNA in amounts comparable to those found for the potent hepatocarcinogen 2-acetamidofluorene, but is not hepatocarcinogenic. This suggested that AAP might initiate liver tumors, but was incapable of causing their progression to a detectable state. To test this hypothesis, the protocol devised by Peraino was used, in which 21-day-old male Sprague-Dawley rats were fed 0.02% AAP in a grain diet for three weeks. this was followed by long-term feeding of 0.05% 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT). The mean latent period of all tumors (primarily mammary tumors) was reduced about six months by the DDT feeding. No tumors were found in rats treated with DDT only. Livers in all animals appeared normal at autopsy or on laparotomy, and showed barely detectable signs of toxicity upon histological examination. Thus, we have found that a once wide-spread environmental chemical acts as a tumor accelerator on a major target for human tumors. Because this finding is in the male rat, the significance of this result for breast cancer in women is uncertain.

Animals↗
PubMed1980

The effect of a body burden of methylmercury on hepatic regeneration.

The model of hepatic regeneration is chosen to study the effect of methylmercury burden on cell proliferation. The results show that chronic methylmercury burden impedes the rate of thymidine incorporation during the process of DNA synthesis. At 24 hours after partial hepatectomy, thymidine incorporation in the mercury exposed rats is 53% of the controls. Counts of labeled hepatocytes in radioautographic preparations also support this observation. This remarkable difference in DNA synthetic activity at 24 hours also reflects in the DNA content and liver, weights at 72 hours after partial hepatectomy (Liver weights 2.36 +/- 0.21 gm/100 gm B. W. vs. 2.67 +/- 0.31 gm/100 B. W., P < 0,05; DNA contents 160.78 +/- 36.76 microgram/gm vs. 214.80 +/- 37.908 microgram/gm, P < 0.05). After two weeks, no significant difference is noted in liver weight, DNA content and synthetic activity. On the other hand, protein content and biosynthesis in the liver of methylmercury burdened rats shows no significant difference from the controls in all the periods studied. From these data it is concluded that the dividing fraction of hepatocytes is reduced in methylmercury-treated group at an early stage of regeneration when cell proliferation is most active.

Animals↗
PubMed1979

Some effects of continuous low-dose congenital exposure to methylmercury on organ growth in the rat fetus.

Congenital low-dose exposure of rat fetuses to methylmercury produced smaller offspring without anatomical abnormalities. The present study explored the mechanisms of the smallness of fetuses. The pregnant rats were given methylmercury water (25 ppm) from day 1 of pregnancy continuously until day 20 of gestation. There was a negative correlation of fetal weight and maternal and fetal mercury burden. The whole organ DNA and protein content of the livers and kidneys in the experiments were significantly lower than the control (P less than 0.05) indicating that there were fewer cells per organ in the mercury exposed fetuses. When the data were compared on a per gram of tissue basis, there was no significanct difference, indicating that the number and size of the cells of each were not diminished. The incorporation of 3H-thymidine into fetal tissue DNA was also substantially lower in the experimental group indicating decreased proliferative activity. We conclude from this study that, at least for some major organs, the decreased size in the mercury exposed fetuses is due to fewer cells in the organs due to decreased proliferative activity.

Abnormalities, Drug-Induced↗
PubMed1978

Aluminum induced pulmonary granulomatosis.

The association of aluminum dusts and pulmonary fibrosis with emphysema in workers in the aluminum processing and manufacturing industries is well established. The early and minimal reactions of the lungs to the aluminum dusts are not known. This report presents the first case of pulmonary granulomatosis associated with aluminum inhalation. The occupational history of this patient was thoroughly examined, and the aluminum was identified by electron probe microanalysis of the lung biopsy specimen. The granulomatous response in this patient was similar to that observed in rabbits following aluminum dust inhalation. Hypersensitivity or individual idiosyncrasy may play a role in the development of the pulmonary granulomas following exposure to aluminum.

Adult↗