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PubMed1999

Inhibition of transforming growth factor beta1-induced hepatoma cell apoptosis by liver tumor promoters: characterization of primary signaling events and effects on CPP32-like caspase activity.

The effects of the liver tumor promoters phenobarbital, clofibrate, dieldrin, and DDT on transforming growth factor-beta1 (TGFbeta)-induced apoptosis were studied in FTO-2B hepatoma cells. Inhibition of apoptosis by these compounds was strongly correlated with a decrease in CPP32-like caspase activity. Similar effects were obtained with insulin and dexamethasone. CPP32-like activity may thus provide a useful tool for quantiation of apoptosis under various treatment conditions. Diverse effects on apoptosis-associated cellular signaling proteins were observed: insulin led to an activation of the MAP kinases ERK1/2, of PKB/Akt and of NF-kappaB, phenobarbital and clofibrate enhanced NF-kappaB activity solely, while dexamethasone slightly enhanced NF-kappaB activity and increased the expression of Bcl-xL. Since inhibition of apoptosis was still detectable if the anti-apoptotic compounds were administered more than 10 h after TGFbeta, the diverse primary signals appear to converge at a presumably late stage of apoptosis, but upstream of activation of CPP32 or related caspases.

Animals↗
PubMed1998

The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication.

The bystander effect (BSE) is an interesting and important property of the herpes thymidine kinase/ganciclovir (hTK/GCV) system of gene therapy for cancer. With the BSE, not only are the hTK expressing cells killed upon ganciclovir (GCV) exposure but also neighboring wild-type tumor cells. On testing a large number of tumor cell lines in vitro, a wide range of sensitivity to bystander killing was found. Since transfer of toxic GCV metabolites from hTK-modified to wild-type tumor cells via gap junctions (GJ) seemed to be a likely mechanism of the BSE, we tested GJ function in these various tumors with a dye transfer technique and pharmacological agents known to affect GJ communication. We confirmed that mixtures of tumor cell resistant to the BSE did not show dye transfer from cell to cell while bystander-sensitive tumor cells did. Dieldrin, a drug known to decrease GJ communication, diminished dye transfer and also inhibited the BSE. Forskolin, an upregulator of cAMP did increase GJ, but directly inhibited hTK and therefore its effect on BSE could not be determined. We conclude that these observations further support port the concept that functional GJ play an important role in the BSE and further suggest that pharmacological manipulation of GJ may influence the outcome of cancer therapy with hTK/GCV.

Animals↗
PubMed1981

[The contamination of human milk with chlororganic pesticides (author's transl)].

A survey on the situation concerning the residues on pesticides in human milk in West Germany is given, based on own investigations. Nearly the whole pattern of chlororganic pesticides - DDT with its metabolites DDE and DDD, hexachlorobenzene (HCB), the different isomeres (alpha-, beta-, gamma-) of benzenehexachloride (BHC) as well as dieldrin and heptachloroepoxid - together with polychlorinated biphenyls (PCB) coming from the environment - were found in all samples of human milk, though in different concentrations. PCB, HCB and beta-BHC had been discovered in human milk only about ten years ago. The residues have decreased in the past years. The concentrations are still so high that the amounts consumed by the suckling exceed the ADI values for the contaminants in question. But in the opinion of the experts the advantages connected with the alimentation with human milk weigh more than the eventual risk by the contamination.

DDT↗
PubMed2004

The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity.

A double null mouse line (2XENKO) lacking the xenobiotic receptors CAR (constitutive androstane receptor) (NR1I3) and PXR (pregnane X receptor) (NR1I2) was generated to study their functions in response to potentially toxic xenobiotic and endobiotic stimuli. Like the single knockouts, the 2XENKO mice are viable and fertile and show no overt phenotypes under normal conditions. As expected, they are completely insensitive to broad range xenobiotic inducers able to activate both receptors, such as clotrimazole and dieldrin. Comparisons of the single and double knockouts reveal specific roles for the two receptors. Thus, PXR does not contribute to the process of acetaminophen hepatotoxicity mediated by CAR, but both receptors contribute to the protective response to the hydrophobic bile acid lithocholic acid (LCA). As previously observed with PXR (Xie, W., Radominska-Pandya, A., Shi, Y., Simon, C. M., Nelson, M. C., Ong, E. S., Waxman, D. J., and Evans, R. M. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 3375-3380), pharmacologic activation of CAR induces multiple LCA detoxifying enzymes and provides strong protection against LCA toxicity. Comparison of their responses to LCA treatment demonstrates that CAR predominantly mediates induction of the cytochrome p450 CYP3A11 and the multidrug resistance-associated protein 3 transporter, whereas PXR is the major regulator of the Na+-dependent organic anion transporter 2. These differential responses may account for the significant sensitivity of the CAR knockouts, but not the PXR knockouts, to an acute LCA dose. Because this sensitivity is not further increased in the 2XENKO mice, CAR may play a primary role in acute responses to this toxic endobiotic. These results define a central role for CAR in LCA detoxification and show that CAR and PXR function coordinately to regulate both xenobiotic and bile acid metabolism.

Acetaminophen↗
PubMedDate not supplied

Termite control and other determinants of high body burdens of cyclodiene insecticides.

Breast milk fat concentrations of three cyclodiene insecticides--dieldrin, heptachlor epoxide, and oxychlordane--were measured in 797 primiparous women, and sources of exposure that contributed significantly to high body burdens were investigated. All three distributions were highly skewed to the right, with median concentrations falling between 0.007 and 0.039 mg/kg. Termite control of residence was associated consistently with being in the high-body-burden group for all three compounds, but the association was greatest for heptachlor. Age, socioeconomic status, residential area, smoking, and home use of insecticides were also associated with high body burden of one or more of the compounds, but the odds ratios were lower than those for termite control; the findings were inconsistent for the three compounds. The results for termite control remained statistically significant when we adjusted for the other factors; therefore, termite control of residence is an important risk factor for cyclodiene insecticide absorption.

Adipose Tissue↗
PubMed2000

Organochlorine insecticides in substantia nigra in Parkinson's disease.

The concentrations of organochlorine (OC) compounds in the substantia nigra (SN) were compared in Parkinson's disease (PD) with concentrations in brain from cortical Lewy body dementia (CLBD), Alzheimer's disease (AD), and nondemented nonparkinsonian controls (CON). The levels of the gamma isomer of hexachlorocyclohexane (gammaHCH, lindane) were significantly higher in PD tissues (mean +/- SD: 0.56 +/- 0.434 microg/g lipid) than in the other three groups (CLBD 0.052 +/- 0.101 microg/g lipid; AD none detected; CON 0.125 +/- 0.195; all differences from PD significant at p < .05, Mann-Whitney U-test). Dieldrin (HEOD) was higher in PD brain than in AD or control brain, while 1,1'-(2,2-dichloroethenyl diene)-bis(4-chlorobenzene) (p,p-DDE) and total Aroclor-matched polychlorinated biphenyls (matched PCBs) were only higher in PD substantia nigra when these concentrations were compared with those of CLBD. These findings are not inconsistent with the hypothesis derived from epidemiological work and animal studies that organochlorine insecticides produce a direct toxic action on the dopaminergic tracts of the substantia nigra and may contribute to the development of PD in those rendered susceptible by virtue of cytochrome P-450 polymorphism, excessive exposure, or other factors.

Alzheimer Disease↗
PubMedDate not supplied

Average Swedish dietary intakes of organochlorine contaminants via foods of animal origin and their relation to levels in human milk, 1975-90.

The organochlorine contaminant (OCC) data generated by the Swedish National Food Administration (NFA) since 1973 has been utilized to calculate average Swedish dietary intakes. Direct food consumption statistics based on the yearly per capita Swedish consumption of five principal food groups has been used with OCC levels over 5-year periods, up to 1992. The present study shows the decline in OCC dietary intakes between 1975 and 1990. It is suggested that this is principally because of a decline in OCC concentrations in foods of animal origin rather than because of changes in food consumption patterns. The estimated intakes for the DDT complex, HCH isomers, dieldrin and HCB are generally well below the ADIs established by FAO/WHO. For total PCBs, no such ADI/TDI has been set up, either by FAO/WHO or in a Nordic PCB risk assessment. However, when compared with a US FDA guideline, the average Swedish total PCB dietary intake in 1990 is approximately 10-fold lower. Finally, this study shows the good relationship between OCC dietary intakes via foods of animal origin and the concentrations measured on a fat weight basis in Swedish human milk.

Animals↗
PubMedDate not supplied

Critical parameters in the MCF-7 cell proliferation bioassay (E-Screen).

The MCF-7 cell proliferation bioassay has grown in popularity as a rapid test for detecting potentially oestrogenic compounds. Several MCF-7 cell sublines with different sensitivities to oestrogens are currently used, with maximal proliferation responses ranging from two- to 10-fold above those of hormone-free controls. In the highly responsive MCF-7 BUS cell line, we evaluated critical assay parameters for test performance, including growth conditions, initial seeding densities and differences in growth stimulation in medium containing human serum or fetal calf serum as well as appropriate solvents for oestrogen-mimicking compounds. Modifications significantly reduced the labour-intensive steps and overall assay costs without affecting the sensitivity of the assay. Using this optimized test regimen, the responsiveness of treated MCF-7 BUS cells was consistently increased up to 11-fold over hormone-free controls. The specificity was characterized by examining the effects of oestradiol-17beta, the anti-oestrogen ICI 182,780, and dieldrin, a recognized xeno-oestrogen. The improved proliferation bioassay will be a useful tool in identifying potential xeno-oestrogens.

Biological Assay↗
PubMed2004

Age at natural menopause and exposure to organochlorine pesticides in Hispanic women.

A cross-sectional study was conducted to evaluate the relationship between exposure to selected organochlorine pesticides (OCP) (p,p'-DDT, p',p'-DDE, dieldrin, hexachlorobenzene, beta-hexachlorocyclohexane [beta-HCH], oxychlordane, trans' nonachlor) and age at natural menopause in a sample of 219 menopausal women participating in the Hispanic Health and Nutrition Examination Survey in 1982-1984. Information on age at menopause, reproductive history, demographic variables, and potential confounding variables was collected via interview. Analysis of variance was employed to compare adjusted mean age at natural menopause among women by category of serum OCP level. Serum levels of p,p'-DDT, p,p'-DDE, beta-HCH, and trans-nonachlor were associated with a younger age at menopause. In particular, women with exposure levels in the highest exposure categories (serum p,p'-DDT > or = 6ppb, beta-HCH > or = 4ppb, or trans-nonachlor > or = 2ppb) had an adjusted mean age at menopause on average 5.7, 3.4, and 5.2 yr earlier, respectively, than women with serum levels of these pesticides below the detection limit. Women with serum p,p'-DDE levels greater than 23.6 ppb (highest quintile) had an adjusted mean age at menopause 1.7 yr earlier than women with serump,p'-DDE levels less than 5.5 ppb (lowest quintile). However, no consistent dose-response effect was apparent across low, medium, and high exposure categories. Interactions were detected for p,p'-DDT in combination with beta-HCH, trans-nonachlor, or oxychlordane, as well as beta-HCH in combination with oxychlordane.

Adolescent↗
PubMed1976

Deldrin toxicity and successive discrimation reversal in squirrel monkeys (Saimiri sciureus).

Seven squirrel monkeys were systematically exposed to dieldrin (C12H10DC16) at two oral doses: 0.10 and 0.01 mg/kg-day. Two zero-dose controls were included. After 55 days of exposure dose assignments were shifted and continued for an additional 54 days. The higher dose group was shifted to zero exposure and lower dose group was shifted to high-dose exposure. Controls continued at zero exposure. The monkeys were presented with a visual nonspatial successive discrimination reversal task. During the first 55 days (preshift), control and low-dose monkeys learned the task; high-dose monkeys did not (p less than 0.001). During the subsequent 54 days (postshift), all groups performances remained at the approximate level achieved at the end of the preshift period. It was concluded that the high dose disrupted learning acquisition. This effect is speculated to be attributed to disruption of hippocampal activity. The low dose had no effect on task acquisition or maintenance.

Animals↗
PubMed1990

Organochlorine compounds in human adipose tissue from north Texas.

This paper reports a preliminary study that was conducted to determine the concentrations of organochlorine compounds in the adipose tissue of residents of North Texas. Thirty-five human adipose tissue samples were obtained during autopsy between 1987 and 1988 from persons who had no known occupational exposure to organochlorine pesticides. These samples were analyzed by electron-capture gas chromatographic methods for the presence of beta-benzene hexachloride, o,p'-DDE, p,p'-DDE, o,p'-DDT, p,p'-DDT, dieldrin, oxychlordane, and heptachlor epoxide. The findings indicate greater than 97% occurrence for each compound with the exception of o,p'-DDE and o,p'-DDT, each of which occurred in 54% of the population sampled. Statistical analyses of the data showed strong positive correlations between adipose tissue concentrations and age for oxychlordane, heptachlor epoxide, p,p'-DDT, p,p'-DDE, and total DDT (the normalized sum of DDT and its analogues) (p less than or equal to .05). Statistically significant differences (p less than or equal to .05) in geometric mean concentrations between all age groups were found for total DDT and p,p'-DDE. However, the group means comparison test was only significantly different between the 41-60 yr and 61 and over age groups for p,p'-DDT, oxychlordane, and heptachlor epoxide. No statistically significant difference was found between sexes in this study. The geometric means of pesticide concentrations in adipose tissue were compared with those reported in previous U.S. Environmental Protection Agency surveys for the general population. This comparison clearly indicates a declining temporal trend in environmental exposure for banned DDT analogues; however, a consistent temporal trend exists for oxychlordane and heptachlor epoxide--pesticides whose uses are currently restricted but not proscribed.

Adipose Tissue↗
PubMed2004

Sample purification for analysis of organochlorine pesticides in sediment and fish muscle.

The methods of sample purification for determinations of organochlorine pesticides (OCPs) in sediment and fish muscle were investigated in this study. A two-step procedure with preliminary cleanup and florisil column fraction was adopted. The working conditions of florisil column were firstly optimized. As to preliminary cleanup, liquid-liquid extraction by mixture of dimethyl formamide (DMF) and hexane and sulphonation by concentrated sulfuric acid were applied respectively and compared for the studied samples. The results indicated that liquid-liquid distribution could effectively separate lipids from fish muscle extracts, while failed in elimination of chlorophyll extracted from the relicts of hydrophytes in the sediment sample. In view of the sample appearance and clarity of gas chromatogram, sulphonation was more suitable to purify the sediment sample, however, the recoveries of the spiked standards were poor. The use of eluting solvent with stronger polarity could improve the corresponding recoveries significantly. Due to complete loss of Dieldrin, Endrin, and Endrin aldehyde after sulphonation, this pretreatment was improper to the three components. Sulfur, as the particular disturbing element in sediment, could be removed sufficiently by addition of activated copper powder. The relevant detection limits of the selected methods for OCPs in the studied substrates were also provided.

Animals↗
PubMed1990

Mutations in the Ha-ras proto-oncogene in spontaneous and chemically induced liver tumours of the CF1 mouse.

Mutations in codon 61 of the Ha-ras proto-oncogene have been shown to occur with a high frequency in both spontaneous and carcinogen-induced liver tumours of the B6C3F1 mouse. In the present study we analysed the frequency and pattern of Ha-ras mutations in liver tumours in a different strain of mice, namely the CF1 mouse. These liver tumours occurred spontaneously or after administration of either aflatoxin B1, phenobarbital or dieldrin. Mutation analysis was performed by in vitro amplification of DNA using the polymerase chain reaction combined with selective oligonucleotide hybridization. Our results demonstrate the presence of mutations in the Ha-ras gene in liver tumours of the CF1 strain. In total, 6 out of 35 liver tumours of male CF1 mice, two of them occurring after treatment with the tumour promoter phenobarbital solely, contained mutations at either the first or second base of codon 61 of the Ha-ras gene. The types of mutations found in liver tumours of the CF1 mouse were very similar to those described in the B6C3F1 mouse, indicating that mutations in the Ha-ras proto-oncogene may represent a critical event in mouse hepatocarcinogenesis.

Aflatoxin B1↗
PubMed1984

Irreversibility of liver tumors in C3H mice.

The present study was designed to test the possibility that spontaneous regression of hepatocellular tumors might be observed in mice. This problem was studied by sequential liver biopsies in C3H male mice that had been treated with dieldrin (CAS: 60-57-1) as well as in animals treated with N-diethylnitrosamine (CAS: 55-18-5) and in untreated control mice. Adenomas were seen in some animals at the second laparotomy when there had been no tumor at the first laparotomy. In a few mice there was histologic progression from adenoma to carcinoma. A change in predominant cell type in adenomas from clear to basophilic or eosinophilic was also observed in some cases. Additional hepatocellular carcinomas were observed in some animals necropsied at 2 years of age. These observations suggest that spontaneous hepatic tumors and tumors in mice treated with either complete carcinogens or nongenotoxic compounds have a strong tendency to progress. Tumor regression in mice appears to be unusual. No consistent relationship of histologic grade of hepatocarcinoma to the type of chemical employed was observed.

Animals↗
PubMedDate not supplied

Genetic sexing for a mosquito sterile-male release.

Two strains of Anopheles culicifacies have been synthesized in which the dieldrin resistance locus on chromosome 3 has been translocated to the Y chromosome. Both strains appear sufficiently stable for the preferential recovery of males for mass production of mosquitoes for field releases.

Animals↗
PubMedDate not supplied

Esterases in the malaria vector mosquito, Anopheles culicifacies. Genetic and linkage analyses of an alpha and beta polymorphism.

The genetic and linkage analyses of an alpha and beta esterase polymorphism in Anopheles culicifacies are presented. A survey of laboratory strains uncovered four electrophoretic variants for the alpha esterase and two for the beta esterase. Genetic analyses indicated that the variants of the alpha esterase are under the control of codominant alleles of a single locus and that this locus is linked to the locus controlling the expression of the codominant alleles of the beta esterases. The esterases are not linked either to sex (chromosome 1) or to maroon eye (chromosome 2) but to the chromosome 3 markers, dieldrin resistance and phosphoglucomutase. The gene sequence is Est-alpha--Dl--Pgm--Est-beta dnd the recombination frequencies are as follows: Est-alpha--Dl = 2.9 percent; Dl--Pgm = 5.8 percent; Pgm--Est-beta = 6.4 percent; Est-alpha--Est-beta = 15.1 percent, Est-alpha--Pgm = 8.7 percent and Dl--Est-beta = 12.2 percent.

Animals↗
PubMed2003

Effect of organochlorine pesticides on maturation of starfish and mouse oocytes.

Methoxychlor, lindane, and dieldrin are organochlorine pesticides that have been described as altering different reproductive functions in mammals and in invertebrates. However, few data have been published concerning the effects these pesticides have on oocyte maturation and fertilization. The aim of this study was to determine whether these compounds could affect maturation of mouse and starfish oocytes. We observed that germinal vesicle breakdown (GVBD) in starfish oocytes was significantly inhibited by the pesticides. Furthermore, formation of the first meiotic spindle and extrusion of the first polar body were also altered in mouse as well as in starfish. Our results suggest that the three pesticides act on common intracellular targets in invertebrates as well as in vertebrates.

Animals↗
PubMed1998

Predicting insecticide resistance: mutagenesis, selection and response.

Strategies to manage resistance to a particular insecticide have usually been devised after resistance has evolved. If it were possible to predict likely resistance mechanisms to novel insecticides before they evolved in the field, it might be feasible to have programmes that manage susceptibility. With this approach in mind, single-gene variants of the Australian sheep blowfly, Lucilia cuprina, resistant to dieldrin, diazinon and malathion, were selected in the laboratory after mutagenesis of susceptible strains. The genetic and molecular bases of resistance in these variants were identical to those that had previously evolved in natural populations. Given this predictive capacity for known resistances, the approach was extended to anticipate possible mechanisms of resistance to cyromazine, an insecticide to which L. cuprina populations remain susceptible after almost 20 years of exposure. Analysis of the laboratory-generated resistant variants provides an explanation for this observation. The variants show low levels of resistance and a selective advantage over susceptibles for only a limited concentration range. These results are discussed in the context of the choice of insecticides for control purposes and of delivery strategies to minimize the evolution of resistance.

Animals↗