Authors: Stacey A Rimkus, David A Wassarman

Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biological and molecular functions of ATM observed in mammals are conserved in Drosophila melanogaster. As an example, conditional loss-of-function ATM alleles in flies cause progressive neurodegeneration through activation of the innate immune response. However, unlike in mammals, null alleles of ATM in flies cause lethality during development. With the goals of understanding biological and molecular roles of ATM in a whole animal and identifying candidate therapeutics for A-T, we performed a screen of 2400 compounds, including FDA-approved drugs, natural products, and bioactive compounds, for modifiers of the developmental lethality caused by a temperature-sensitive ATM allele (ATM8) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM8 flies, including Ronnel, which is an organophosphate. Ronnel and other suppressor compounds are known to cause mitochondrial dysfunction or to inhibit the enzyme acetylcholinesterase, which controls the levels of the neurotransmitter acetylcholine, suggesting that detrimental consequences of reduced ATM kinase activity can be rescued by inhibiting the function of mitochondria or increasing acetylcholine levels. We carried out further studies of Ronnel because, unlike the other compounds that suppressed the developmental lethality of homozygous ATM8 flies, Ronnel was toxic to the development of heterozygous ATM8 flies. Ronnel did not affect the innate immune response of ATM8 flies, and it further increased the already high levels of DNA damage in brains of ATM8 flies, but its effects were not harmful to the lifespan of rescued ATM8 flies. These results provide new leads for understanding the biological and molecular roles of ATM and for the treatment of A-T.

Topics: Alleles; Animals; Ataxia Telangiectasia Mutated Proteins; DNA Damage; Drosophila Proteins; Drosophila melanogaster; Drug Evaluation, Preclinical; Female; Genes, Insect; Genes, Lethal; Immunity, Innate; Male; Mutation; Nerve Degeneration; Organothiophosphorus Compounds; Phenotype; Protein Serine-Threonine Kinases

PubMed: 29338042
DOI: 10.1371/journal.pone.0190821

Systemic activity of coumaphos, famphur, crufomate, ronnel, and phosmet given orally to hens for control of the northern fowl mite, Ornitbonyssus sulviarum (Canestrini and Fanzago).

Authors: J A DeVaney, G W Ivie

Coumaphos (O-(3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl)O,O-diethyl phosphorothioate), famphur (O-[p-(dimethylsulfamoyl)phenyl] O,O-dimethyl phosphorothioate). crufomate (4-tert-butyl-2-chlorophenyl methyl methylphosphoramidate), ronnel (O,O-dimethyl O-(2,4,5-trichlorophenyl) phosphorothioate) and phosmet (O,O-dimethyl phosphorodithioate S-ester with N-(mercaptomethyl) phthalimide) were administered as systemic acaricides (either single or multiple oral doses or as feed additives) for control of the nortnern fowl mite, Ornithonyssus sylviarum (Canestrini and Fanzago), on caged White Leghorn hens. None of the treatments controlled the mites, but some hens were poisoned.

Topics: Animals; Chickens; Coumaphos; Insecticides; Mite Infestations; Organophosphorus Compounds; Organothiophosphates; Organothiophosphorus Compounds; Phosmet; Poultry Diseases; Sulfonamides

PubMed: 6157151
DOI: 10.3382/ps.0591208

Authors: A B HADAWAY, F BARLOW

The authors have evaluated a number of organophosphorus compounds for residual contact toxicity to adult Anopheles stephensi. Fenthion and malathion were the most promising of the compounds, and wettable powder deposits at a dosage of 1 g/m(2) on plywood remained effective for five months. There was, however, a rapid loss of effectiveness on dried mud bricks stored at 25 degrees C and 50%-55% relative humidity.Diazinon and ronnel were less persistent on plywood. Guthion and coumaphos, although highly toxic by topical application, were both ineffective as contact insecticides when applied as solids in suspension. Trithion and methyl trithion were relatively low in toxicity both by topical application and as contact insecticides.

Topics: Animals; Anopheles; Insecticides; Mosquito Control; Organophosphate Poisoning; Organothiophosphorus Compounds; Phosphorus; Poisons

PubMed: 13951701
DOI: No ID Found

Authors: G P GEORGHIOU, M J GARBER

In view of the increasing importance of carbamic acid esters in insect control, the authors have conducted studies on the inheritance of carbamate-resistance in the housefly Resistance to Isolan (1-isopropyl-3-methyl-5-pyrazolyl dimethylcarbamate) in carbamate-selected strains is inherited as a partially dominant major single factor, without sex linkage or appreciable cytoplasmic influence. Inclusion of piperonyl butoxide as a synergist with Sevin (1-naphthyl methylcarbamate), Zectran (4-dimethylamino-3,5-xylyl methylcarbamate), or m-isopropylphenyl methylcarbamate also produced evidence of monofactorial inheritance.In contrast, resistance to Isolan and to a combination of Sevin and piperonyl butoxide in a ronnel-selected strain is inherited in a pattern suggestive of a polygenic system.The results obtained are discussed in the light of previously established data on the rate of development, stability and regression of carbamate-resistance.

Topics: Animals; Carbamates; Genetics; Houseflies; Insect Control; Insecticide Resistance; Insecticides; Organothiophosphorus Compounds; Research

PubMed: 14310905
DOI: No ID Found

Authors: Ayako Kanno, Tsuyoshi Kawakami, Yasuo Takahashi...

A reproducible method for monitoring traces of cholinesterase (ChE) inhibitors in aqueous samples is described: the method is based on chemical oxidation and a ChE inhibition assay. Chlorine was tested as an oxidizing reagent for conversion of various thiophosphorus pesticides (P=S compounds) into their P=O analogs, which have higher ChE-inhibiting activity. After treating buffered pesticide solutions (pH 6.0) with chlorine (final concentration less than 10 mg/l) of at 25°C for 15 min, the ChE-inhibiting activities and detection limits for each pesticide were determined. Greater ChE-inhibiting activities, leading to lower detection limits (ppb levels), were observed for the chlorine-treated solutions fortified azinphos methyl, diazinon, isoxathion and ronnel etc. No changes in the ChE-inhibiting activities were observed for carbamate pesticide solutions tested before and after chlorination, but an additive effect showed against ChE when these compounds were mixed with paraoxon in water. This combination of oxidative derivatization and ChE inhibition assay was applied successfully to the detection and determination of ChE inhibitors in natural and drinking water samples.

Topics: Acetylcholinesterase; Carbamates; Cholinesterase Inhibitors; Drinking Water; Environmental Monitoring; Hypochlorous Acid; Insecticides; Organophosphorus Compounds; Oxidants; Water Pollutants, Chemical

PubMed: 22467030
DOI: 10.2131/jts.37.389

Authors: G N Berge, M Mondain-Monval, A Smith...

The possible effect of fenchlorphos, 0-0-dimethy1-0-(2.4.5-trichlorophenyl) phosphorothioate, upon the reproductive endocrinology in blue foxes (Alopex lagopus) was investigated. Five females were administered fenchlorphos orally at a dose of 100 mg/kg daily from 10 days before oestrus and up to the 21st day of gestation. This dose represents the therapeutic dose for the treatment of sarcoptic mange. Blood samples were collected for the analyses of progesterone, oestradiol-17β and luteinizing hormone (LH) in plasma. The vixens were ovario-hysterectomized on day 23, except 1 animal in the control group which was operated on day 17. Additionally, sperm quality and mating performance in 3 male blue foxes, which were administered 100 mg/kg fenchlorphos daily during the first 3 weeks of the mating season, were examined. Pregnancy was recorded in 2 medicated and 4 control animals. No pathological changes were observed in the uterus and the ovaries. The plasma concentrations of the hormones were similar to those obtained from the control group. No evidence of any disturbances concerning spermatogenesis in the males was observed. However, their libido appeared to be reduced. None of the males achieved a mating during and after the period of medication.

Topics: Animals; Estradiol; Female; Foxes; Libido; Luteinizing Hormone; Male; Organothiophosphorus Compounds; Pregnancy; Pregnancy, Animal; Progesterone; Reproduction; Spermatogenesis; Spermatozoa

PubMed: 6193696
DOI: 10.1186/BF03546747

Authors: G N Berge, I Nafstad

Pregnant blue foxes (Alopex lagopus) were administered fenchlorphos (0-0-dimethyl-0-(2,4,5-trichlorophenyl) phos-phorothioate) orally at a dose of 100 mg/kg/day in different periods of gestation. The dose chosen represents the therapeutic dose for the treatment of parasitic lesions. At term the mean number of whelps were recorded, and they were killed and examined for external, visceral and skeletal malformations. Of 19 medicated vixens the mean number of live whelps at term was 1.2 per vixen versus 9.5 in the control group. There was an evident predominance of males in the medicated groups. Several malformations of the head were registered, among them incomplete ossification of the skull bones, cleft palate, hydrocephalus internus and externus. Minor malformations like extra ribs or missing ribs occurred in the medicated groups. Congenital alopecia, hypoplastic kidneys, and hydronephrosis were observed in all the whelps in 1 medicated group. No significant difference in total brain weight, cerebellum weight or the cerebellum-to-total-brain weight was observed. Histological examination of the cerebellum showed a narrowing or absence of the granular and the molecular layers of the cortical zone.

Topics: Abnormalities, Drug-Induced; Alopecia; Animals; Female; Foxes; Gestational Age; Hydronephrosis; Male; Organothiophosphorus Compounds; Pregnancy

PubMed: 6191556
DOI: 10.1186/BF03546761

Authors: D F Paris, J E Rogers

We investigated the effect of preincubation of environmental waters amended with inorganic nutrients (nitrogen, phosphorus, and traces of iron and magnesium) on the kinetics of the microbial transformation of phenol, propanil, propyl ester of (2,4-dichlorophenoxy)acetic acid, methyl parathion, Ronnel, and methoxychlor in pond and river waters. No effect on the second-order rate constants for these compounds was observed, although there was an increase in the bacterial populations and the pseudo-first-order rate constants. The use of nutrient-amended waters could be a useful tool for estimating second-order rate constants for an expanded number of compounds. This technique would provide a larger data base for predicting the behavior of xenobiotic compounds in the environment by using currently available mathematical models.

PubMed: 16346980
DOI: 10.1128/aem.51.2.221-225.1986

Authors: G N Berge, S H Sterri, N E Søli...

The uterine acetylcholinesterase and total cholinesterase (acetylcholinesterase plus butyrylcholinesterase) activities in normal and fenchlorphos treated blue fox vixens were determined during various reproductive states. AChE and Total-ChE of non-medicated vixens in oestrus were about one half of those in anoestrus. In pregnant uteri (luteal phase) the activities were 25 % and 30% compared to anoestrus. In vixens given 100 mg/kg fenchlorphos for 3 weeks during anoestrus, the remaining activity of AChE in uterus were in average 37%. Pregnant and non-pregnant vixens in the luteal phase medicated prior to mating and during time of implantation, displayed AChE activities which were only moderabely reduced (remaining activities 83% and 72% compared to medicated animals in anoestrus: remaining activity 37%). Plasma ChE-activity increased during pregnancy in the controls while enzyme activity was strongly reduced in animals given 100 mg/kg fenchlorphos daily through the whole pregnancy. It was concluded that the previous reported embryotoxic effect of fenchlorphos in the blue fox did not seem to be directed towards the moderate inhibition of the uterine cholinesterases.

Topics: Anestrus; Animals; Cholinesterases; Estrus; Female; Foxes; Organothiophosphorus Compounds; Uterus

PubMed: 2462338
DOI: 10.1186/BF03548400

Authors: I Nafstad, G Berge, E Sannes...

Fenchlorphos was administered orally in doses of 0, 12.5, 25 and 50 mg per kg to pregnant rabbits from day 6 to 18 of gestation. No effect on implantation efficacy, number of live fetuses, or fetal weight was observed. The incidence of major malformations such as cardiovascular and brain anomalies was, however, increased in the medicated groups. Major skeletal malformations were more frequent in the medicated groups; minor skeletal variation were about equal in all groups. Dose-relationship was observed for cardiovascular malformations and cerebellar hypoplasia.

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Brain; Dose-Response Relationship, Drug; Female; Heart Defects, Congenital; Organothiophosphorus Compounds; Pregnancy; Rabbits

PubMed: 6197870
DOI: 10.1186/BF03546733