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At least 865 records · Page 48Linked to original sources
PubMed1997

Estrogenic activity of a dieldrin/toxaphene mixture in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based estrogen receptor assays: no apparent synergism.

The estrogenic activity of dieldrin, toxaphene, and an equimolar mixture of both compounds (dieldrin/toxaphene) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 human breast cancer cells, and in yeast-based reporter gene assays. Treatment of the animals with 17beta-estradiol (E2) (0.0053 kg/day x3) resulted in a 3.1-, 4.8-, and 7.8-fold increase in uterine wet weight, peroxidase activity, and progesterone receptor binding, respectively. In contrast, treatment with 2.5, 15 and 60 micromol/kg (x3) doses of toxaphene, dieldrin, or dieldrin/toxaphene (equimolar) did not significantly induce a dose-dependent increase in any of the E2-induced responses. The organochlorine pesticides alone and the binary mixture did not bind to the mouse uterine estrogen receptor (ER) in a competitive binding assay using [3H]E2 as the radioligand. In parallel studies, estrogenic activities were determined in MCF-7 cells by using a cell proliferation assay and by determining induction of chloramphenicol acetyl transferase (CAT) activity in MCF-7 cells transiently transfected with plasmids containing estrogen-responsive 5'-promoter regions from the rat creatine kinase B and human cathepsin D genes. E2 caused a 24-fold increase in CAT activity in MCF-7 cells transiently transfected with creatine kinase B and a 3.8-fold increase in cells transiently transfected with the human cathepsin D construct. Treatment of MCF-7 cells with dieldrin, toxaphene, or an equimolar mixture of dieldrin plus toxaphene (10(-8)-10(-5) M) did not significantly induce cell proliferation or CAT activity in the transient transfection experiment with both plasmids. The relative competitive binding of the organochlorine pesticides was determined by incubating MCF-7 cells with 10(-9) M [3H]E2 in the presence or absence of 2 x 10(-7) M unlabeled E2 (to determine nonspecific binding), toxaphene (10(-5) M), dieldrin (10(-5) M), and equimolar concentrations of the dieldrin plus toxaphene mixture (10(-5) M). The binding observed for [3H]E2 in the whole cell extracts was displaced by unlabeled E2, whereas the organochlorine pesticides and binary mixture exhibited minimal to nondetectable competitive binding activity. E2 caused a 5000-fold induction of beta-galactosidase (beta-gal) activity in yeast transformed with the human ER and a double estrogen responsive element upstream of the beta-gal reporter gene. Treatment with 10(-6)-10(-4) M chlordane, dieldrin, toxaphene, or an equimolar mixture of dieldrin/toxaphene did not induce activity, whereas 10(-4) M endosulfan caused a 2000-fold increase in beta-gal activity. Diethylstilbestrol caused a 20-fold increase in activity in yeast transformed with the mouse ER and a single estrogen responsive element upstream of the beta-gal reporter gene. Dieldrin, chlordane, toxaphene, and endosulfan induced a 1.5- to 4-fold increase in activity at a concentration of 2.5 x 10(-5) M. Synergistic transactivation was not observed for any equimolar binary mixture of the pesticides at concentrations of either 2.5 x 10(-5) M or 2.5 x 10(-4) M. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based reporter gene assays, the activities of both dieldrin and toxaphene were minimal, and no synergistic interactions were observed with a binary mixture of the two compounds.

Animals↗
PubMed1976

Deldrin and parathion interaction in the prostate and liver of the mouse.

The oral administration of dieldrin (1.25 mg/kg daily x 5 or 10) and/or parathion (5.2, 2.6, or 1.3 mg/kg daily x 5 or u0) caused significant alterations in the metabolism of [1,2-3H]testosterone by the anterior prostate gland and by the hepatic microsomal enzyme system in the mouse. A 5-day parathion treatment followed by another 5-day treatment with dieldrin led to significant increases in the levels of [3H]androstanediol a [3H]androstenedione formed by the prostate gland in vitro. Dieldrin alone, dieldrin plus parathion, or dieldrin administration followed by parathion treatment caused significant reductions in the levels of [3H]androstenedione formed by hepatic microsomal enzymes. Concomitantly, significant increases were observed in hepatic 7alpha-and 6beta-testosterone hydroxylase activities in animals treated with parathion followed by dieldrin administration. The present findings revealed that the administration of parathion or dieldrin leads to changes in the metabolism of male sex hormones in mouse liver and sex accessory organs. In addition, the simultaneous administration of parathion and dieldrin leads to an interaction that can alter the biologic effects of either compound.

Androgens↗
PubMed1993

Organochlorine pesticides in Western Australian nursing mothers.

OBJECTIVES: To measure the concentrations of organochlorine (OC) pesticides in nursing mothers in Western Australia and to evaluate the safety of these concentrations for breast-fed infants; to evaluate the need for future monitoring of OC pesticide concentrations and to determine whether breast milk is an accurate substitute for adipose tissue in future monitoring programs. DESIGN: Two cohorts of nursing mothers were recruited during the period October 1990 to March 1991. Levels of OC pesticides were measured in 128 samples of breast milk and 31 samples each of adipose tissue, maternal blood and cord blood. Laboratory analysis was by gas chromatography with electron capture. Health Department studies since 1974 were collated and levels of OC pesticides compared over time. RESULTS: DDT (dichlorodiphenyltrichloroethane), HCB (hexachlorobenzene) and dieldrin were found in all samples of breast milk and adipose tissue. A significant fall in the levels of OCs was noted since the 1974 survey, with the current concentrations of the cyclodienes (heptachlor, chlordane and dieldrin) being close to the limit of detection of the assay. The acceptable daily intake for dieldrin was exceeded in 90% of infants and for heptachlor in 2% of infants. The daily intakes of the other OCs were below the respective acceptable levels. HCB was detected at a median level of 0.1 mg/kg in both breast milk and adipose tissue despite being deregistered in 1972. As there is no current acceptable daily intake for HCB, the safety of this level could not be assessed by this method. A low correlation was found between levels of the cyclodiene pesticides in breast milk and adipose tissue, but levels of DDT and HCB were closely correlated. CONCLUSIONS: Restrictions on the use of the OC insecticides (DDT, aldrin, dieldrin, heptachlor and chlordane) have resulted in reduced concentrations of these chemicals in breast milk and adipose tissue as compared with previous studies. The dieldrin intake of breast-fed infants consistently exceeded the acceptable daily intake; the heptachlor intake exceeded the acceptable daily intake in some infants, but the low concentrations of heptachlor in breast milk made accurate measurement difficult. The concentrations of DDT and chlordane in breast milk did not pose a hazard to breast-fed infants. The significance of the levels of the fungicide HCB in breast milk cannot be determined. The widespread distribution of HCB, its marked persistence in the environment and its potential for human toxicity indicate a need for continued monitoring, for which breast milk is a suitable medium. The poor correlation between concentrations of dieldrin, heptachlor and chlordane in breast milk and adipose tissue may reflect the technical difficulty of measuring chemical concentrations close to the limit of detection. As aldrin is a registered pesticide and the dieldrin intake of breast-fed infants is consistently above the acceptable daily intake, monitoring of dieldrin should continue. Further population monitoring of DDT, heptachlor and chlordane is unlikely to be of value.

Adipose Tissue↗
PubMed1995

Oxidative stress in nongenotoxic carcinogenesis.

The induction of oxidative stress in the target tissue has been proposed as a possible mechanism of action for nongenotoxic carcinogens. A variety of nongenotoxic hepatocarcinogens including peroxisome proliferators, organochlorines, barbiturates, and metals have been shown to produce an increase in reactive oxygen species (ROS) in the liver. Our group has examined the induction of oxidative stress by the organochlorine mouse hepatic carcinogen, dieldrin. Using a salicylate spin trap assay, dieldrin was found to produce mouse liver-specific increases in ROS in cultured hepatocytes. Increased amounts of hepatic 8-hydroxy-2'-deoxyguanosine and malondialdehyde (MDA) and decreased levels of cellular antioxidants were also seen in cultured mouse hepatocytes following dieldrin treatment. In subchronically dieldrin-treated mice and rats, hepatic vitamin E (Vit E) was decreased correlated with dieldrin dose. While Vit E levels were decreased in both rats and mice, the normal lower levels of Vit E in the mouse resulted in a subsequent oxidative stress, evidenced by an increase in MDA formation in the mouse liver. Dieldrin also produced a dose-dependent increase in DNA synthesis in the mouse (not the rat) following subchronic treatment. These effects seen in both cells in culture and in vivo were species specific, organ specific, and dose dependent which directly correlated with the observed pattern of cancer induction for dieldrin in rodents (mouse liver-specific). These findings support a possible role for the induction of oxidative stress in nongenotoxic hepatic carcinogenesis possibly through modulation of gene expression.

Animals↗
PubMed1996

Reversibility of promoter induced hepatic focal lesion growth in mice.

The effect of cessation of phenobarbital and dieldren treatment on hepatic focal lesion growth in male B6C3F1 mice was investigated. Following induction of lesions by diethylnitrosamine, mice were placed on control NIH-07 diet (control diet) or NIH-07 diet containing either dieldrin (10.0 mg/kg diet) or phenobarbital (500 mg/kg diet). Mice were sacrificed after 30 and 60 days of dietary treatment. Two additional groups of mice were fed either the dieldren- or phenobarbital-containing diet for 30 days followed by feeding of NIH-07-only diet for an additional 30 days. The effect of treatment and removal of dieldrin or phenobarbital on lesion growth was examined by measuring both the number of focal lesions per liver and the relative volume of focal lesions. In addition, the rate of cell proliferation and programmed cell death in focal lesion growth was investigated by examining DNA synthesis and apoptosis in the focal lesions. Dietary dieldrin or phenobarbital increased the number of focal lesions and the focal lesion volume. In both dieldrin- and phenobarbital-treated mice, an increased number of eosinophilic lesions were seen. The focal lesion volume was increased in both eosinophilic and basophilic lesions. Dieldrin and phenobarbital treatment also increased the DNA synthetic labeling index in both eosinophilic and basophilic lesions. Removal of dieldrin or phenobarbital from the diet after 30 days of promoter treatment decreased the total number and volume of hepatic focal lesions. The labeling index of the focal lesions was also decreased in these mice. At the terminal sacrifice, the percentage of apoptotic cells in focal lesions was higher in mice fed dieldrin- or phenobarbital-containing diets for the entire 60 days than in mice returned to control diet for the last 30 days. Eosinophilic lesions were more dependent on the presence of a promoting stimulus than the basophilic lesions. These data indicate that induction and maintenance of the growth of some preneoplastic lesions in the mouse may be dependent upon continuous tumor promoter treatment.

Animals↗
PubMed1999

Monograph: reassessment of human cancer risk of aldrin/dieldrin.

In 1987, the US Environmental Protection Agency (EPA) classified aldrin and dieldrin as category B2 carcinogens, i.e. probable human carcinogens, based largely on the increase in liver tumors in mice fed either organochlorine insecticide. At that date, the relevant epidemiology was deemed inadequate to influence the cancer risk assessment. More time has now elapsed since early exposures of manufacturing workers to aldrin/dieldrin; therefore, updated epidemiological data possess more power to detect exposure-related differences in cancer risk and mortality. Also, recent experimental studies provide a plausible mode of action to explain the mouse specificity of dieldrin-induced hepatocarcinogenesis and call into question the relevance of this activity to human cancer risk. This monograph places this new information within the historic and current perspectives of human cancer risk assessment, including EPA's 1996 Proposed Guidelines for Carcinogen Risk Assessment. Updated epidemiological studies of manufacturing workers in which lifetime exposures to aldrin/dieldrin have been quantified do not indicate increased mortality or cancer risk. In fact, at the middle range of exposures, there is evidence of a decrease in both mortality from all causes and cancer. Recent experimental studies indicate that dieldrin-induced hepatocarcinogenesis in mice occurs through a nongenotoxic mode of action, in which the slow oxidative metabolism of dieldrin is accompanied by an increased production of reactive oxygen species, depletion of hepatic antioxidant defenses (particularly alpha-tocopherol), and peroxidation of liver lipids. Dieldrin-induced oxidative stress or its sequelae apparently result in modulation of gene expression that favors expansion of initiated mouse, but not rat, liver cells; thus, dieldrin acts as a nongenotoxic promoter/accelerator of background liver tumorigenesis in the mouse. Within the framework of EPA's Proposed Guidelines for Carcinogen Risk Assessment, it is proposed that the most appropriate cancer risk descriptor for aldrin/dieldrin, relating to the mouse liver tumor response, is 'not likely a human carcinogen', a descriptor consistent with the example of phenobarbital cited by EPA.

Aldrin↗
PubMed2000

Activation of neutrophil calcium-dependent and -independent phospholipases A2 by organochlorine compounds.

The production of reactive oxygen species by organochlorine pesticides has been implicated in the toxicity and carcinogenicity of these compounds; however, the mechanism by which these agents stimulate the production of oxygen radicals is unknown. Phospholipase A2 (PLA2)-mediated release of arachidonic acid has been shown to play an essential role in superoxide anion (O2-) production in neutrophils exposed to various physiologic and pharmacologic agents. Therefore, studies were performed to determine if the organochlorine pesticides, lindane and dieldrin, activate neutrophils to produce O2- by a mechanism that requires PLA2. Production of O2- and 3H-AA release increased with similar kinetics and concentration-response relations in neutrophils activated with either dieldrin or lindane. Significant release of 3H-AA was seen in neutrophils stimulated with dieldrin or lindane in calcium-free medium and in the presence of the intracellular calcium chelator BAPTA-AM, suggesting that these agents stimulate a PLA2 that does not require calcium for activation. In addition, both O2- production and 3H-AA release were inhibited in a concentration-dependent manner by BEL, a mechanism-based inhibitor of calcium-independent PLA2. These data suggest that dieldrin and lindane stimulate O2- production by a mechanism that involves PLA2. However, release of 3H-AA was not abrogated completely by BEL nor, in the case of dieldrin, preserved entirely in the absence of calcium. This suggests that more than one isoform of PLA2 is activated by dieldrin and by lindane, and that one isoform is calcium-dependent.

Animals↗