Methomyl, (E,Z)-methyl N-{[(methylamino)carbonyl]oxy}ethanimidothioate, is a widely used pesticide that has been detected in many fatal cases of accidental exposure or suicide. Forensic toxicologists have been baffled that the blood methomyl concentration in persons who have died of methomyl poisoning is much lower than the expected concentration in blood. In this study, we speculated two mechanisms underlying the insufficient recovery of methomyl in blood. First, methomyl is decomposed by serum albumin as esterase. Second, methomyl is bound to a specific blood protein, resulting in insufficient recovery in the free form. However, human serum albumin does not show esterase activity for the decomposition of methomyl. On the contrary, specific methomyl hemoglobin adducts have been detected by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS). The mass spectra indicated that methomyl was specifically bound to tryptophan (W), tyrosine (Y), and valine (V) residues in hemoglobin. The amounts of W-and V-adducts dose-dependently increased in vitro when the methomyl concentration was lower than the lethal concentration. In addition, the W-adduct was detected in blood sampled from an autopsied subject who died of intentional methomyl ingestion, suggesting that the W-adduct could be used as a biomarker of methomyl poisoning. We were able to estimate the amount of methomyl ingested on the basis of the amount of the W-adduct.
-In order to elucidate the effect of chorioallantoic and yolk sac placenta on the embryonic/fetal toxicity in dibutyltin dichloride (DBTCl)-exposed rats, we examined the histopathological changes and the tissue distribution of dibutyltin in the placentas and embryos. DBTCl was orally administered to the groups at doses of 0 mg/kg during gestation days (GD)s 7-9 (control group) and 20 mg/kg during GDs 7-9 (GD7-9 treated group), and GDs 10-12 (GD10-12 treated group). The total fetal mortality was increased, and malformations characterized by craniofacial dysmorphism were detected in the GD7-9 treated group. The embryonic/fetal weight and placental weight showed a decrease in both DBTCl-treated groups. Histologically, some embryos on GD 9.5 in the GD7-9 treated group underwent apoptosis without any changes of yolk sac. In the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS), tin was detected in the embryo, allantois, yolk sac, ectoplacental cone and decidual mass surrounding the conceptus on GD 9.5 in the GD7-9 treated group. Thus, it is considered that the embryo in this period is specifically sensitive to DBTCl-induced apoptosis, compared with other parts. The chorioallantoic placentas in both DBTCl-treated groups showed the developmental delay and hypoplasia in the fetal parts of placenta, resulting from apoptosis and mitotic inhibition. Thus, it was speculated that the DBTCl-induced malformations and fetal resorption resulted from the apoptosis in the embryo caused by the direct effect of DBTCl. The DBTCl-induced lesions in the chorioallantoic placenta were a non-specific transient developmental retardation in the fetal parts of placenta, leading to intrauterine growth retardation.
The mating reaction is triggered by specific pheromones in a wide variety of organisms. Small peptides are used as mating pheromones in yeasts and fungi. In the fission yeast Schizosaccharomyces pombe, M-factor is a C terminally farnesylated nonapeptide secreted from M-cells, and its counterpart, P-factor, is a simple peptide composed of 23 amino acids. The primary structure requirements for the biological activity of pheromone peptides remain to be elucidated. Here, we conducted comprehensive substitution of each of the amino acids in M-factor peptide and inspected the mating ability of these missense mutants. Thirty-five sterile mutants were found among an array of 152 mutants with single amino acid substitutions. Mapping of the mutation sites clearly indicated that the sterile mutants were associated exclusively with four amino acid residues (VPYM) in the carboxyl-terminal half. In contrast, the substitution of four amino-terminal residues (YTPK) with any amino acid had no or only a slightly deleterious effect on mating. Furthermore, deletion of the three N-terminal residues caused no sterility, although truncation of a fourth residue had a marked effect. We conclude that a farnesylated hexapeptide (KVPYMC Far -OCH 3 ) is the minimal M-factor that retains pheromone activity. At least 15 nonfunctional peptides were found to be secreted, suggesting that these mutant M-factor peptides are no longer recognized by the cognate receptor. SEXUAL reproduction in eukaryotes promotes genome diversity by genetic recombination and thus may accelerate evolution. As a result, mating behavior is important for reproduction. Like many fungi, the fission yeast Schizosaccharomyces pombe has two mating types, termed h + (P) and h 2 (M) (Gutz et al. 1974;Egel 1989Egel , 2004. Two haploid cells of opposite mating types mate and form a diploid zygote on starvation of nitrogen (Egel 1971). The diploid zygote undergoes meiosis and forms four haploid spores (Bresch et al. 1968;Gutz et al. 1974;Egel 1989;Nielsen 2004). Spores germinate in rich nutrient medium and proliferate as haploid vegetative cells.The specificity of mating types in fission yeast is primarily determined by molecular recognition between a peptide mating pheromone and its cognate receptor. The mating reaction proceeds through several distinguishable steps (Egel 1989;Nielsen 2004). First, cells adhere to each other to form large cell aggregates in a reaction that is termed cell agglutination. Second, cells in aggregates protrude a conjugation tube toward a cell of opposite mating type. M-and P-cells make most contact at the cell tips, where the cell walls separating them are dissolved. Third, the juxtaposed plasma membranes are fused together. Last, after cell fusion, two nuclei derived from each mating type fuse together to form a diploid cell.A wide variety of organisms use chemical signals to attract the opposite sex and facilitate mating with partners. In S. pombe, M-cells secrete the mating pheromone M-factor, which is specifically recognized by its cogna...
Malathion, diethyl 2-[(dimethoxyphosphinothioyl)thio]butanedioate, is one of most widely used organophosphoryl pesticide, and it has been detected in several clinical cases of accidental exposure and suicide. It is reported that the observed malathion concentration in blood of persons who suffer from malathion poisoning is smaller than the expected concentration. Because malathion is bound to human serum albumin (HSA), recovery of malathion in the free form is insufficient. We detected malathion adducts in HSA by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q/TOF–MS). The mass spectra showed that malathion was preferably bound to the lysine (K) and cysteinylproline (CP) residues of HSA. The K- and CP-adducts of malathion were increased in vitro with a dose-dependent fashion when its concentration was smaller than the lethal dose. Further, the K-adduct was also detected in post-mortem blood of an autopsied subject suffering from intentional malathion ingestion. These results suggest that the K-adduct seems to be available to use a biomarker of malathion poisoning, and the determination of the K-adduct could make possible to estimate the amount of malathion ingestion.
In order to clarify the histological localization of cadmium (Cd) in the placenta, we analyzed paraffin sections of placentas from rats with a single Cd exposure on gestation day 18 by the LA-ICP-MS imaging method compared with the histopathological changes. The placentas were sampled at 1 hour, 2 hours, 3 hours, 6 hours, and 24 hours after treatment. Histopathologically, the trophoblasts in the labyrinth zone of the Cd group showed swelling at 1 hour. At 2 and 3 hours, the trophoblasts showed swelling and vacuolar degeneration. At 6 and 24 hours, the syncytiotrophoblasts selectively underwent necrosis/apoptosis, resulting in a decrease in number. Remarkable metallothionein expression was observed in the trophoblastic septa, particularly cytotrophoblasts at 24 hours. The LA-ICP-MS analysis detected the localization of Cd in the fetal part of the placenta from 1 hour onwards. In particular, the intensity of Cd was prominent in the labyrinth zone and tended to increase with the progression of trophoblastic septa damages. The LA-ICP-MS analysis using the paraffin sections detected the localization of Cd in the fetal part of the placenta, and this methodology will be one of the valuable tools to detect heavy metals in toxicological pathology.
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