Rapid effects of pesticides on human granulosa-lutein cells.
(9/39)
Following our previous demonstration that p,p'-DDE (dichlorodiphenylchloroethylene), at environmentally relevant concentrations, can rapidly increase intracellular calcium [Ca2+]i concentrations in human granulosa-lutein cells, we examined whether other pesticides, such as Kepone, o,p-DDE and methoxychlor, have similar effects. Cultured human granulosa-lutein cells were loaded with Fura-2 AM, and changes in [Ca2+]i concentrations within small areas of single cells were studied with a dynamic digital Ca2+ imaging system. Kepone, at concentrations of 0.2-2 nmol/ml, consistently increased [Ca2+]i concentrations 2-6 times higher than baseline values within minutes of exposure. Methoxychlor at concentrations of 2.8-280 nmol/ml failed to alter [Ca2+]i levels consistently in cells from 10 patients. However, at 0.28 and 1.4 nmol/ml, increases in [Ca2+]i concentrations could be elicited by methoxychlor. The isomer o,p-DDE at 3 nmol/ml increased [Ca2+]i in granulosa cells of 11/20 patients. Pertussis toxin treatment inhibited the [Ca2+]i increases induced by estradiol, p,p'-DDE, o,p-DDE and methoxychlor, but not by Kepone or progesterone, indicating that Kepone and progesterone may act through an insensitive G protein-coupled receptor. The [Ca2+]i increases induced by Kepone also occurred in Ca2+-free medium, suggesting that [Ca2+]i mobilization occurred from the smooth endoplasmic reticulum. Thapsigargin and cyclopiazonic acid, two inhibitors of the endoplasmic reticulum Ca2+ pump, also stimulated [Ca2+]i increases but did not inhibit the Ca2+ response to all the pesticides. These results demonstrate that pesticides can have a rapid effect on human granulosa-lutein cells, and a nongenomic mechanism of action is suggested. (+info)
Prevention of toxic environmental illness in the twenty-first century.
(10/39)
Previous introductions of new technologies have frequently resulted in unanticipated occupational and environmental illness. Prevention of such illness in the twenty-first century requires stringent application of two fundamental principles of public health: evaluation of new technologies before their introduction, and surveillance of exposed persons after the introduction of new technologies. Failure to establish these basic preventive mechanisms in advance will inevitably result in the development of new toxic diseases in the twenty-first century. (+info)
Bromotrichloromethane hepatotoxicity. The role of stimulated hepatocellular regeneration in recovery: biochemical and histopathological studies in control and chlordecone pretreated male rats.
(11/39)
It has been shown that BrCCl3 is a more potent hepatotoxin than CCl4. Pretreatment with nontoxic dietary levels of chlordecone (CD) results in amplification of BrCCl3 hepatotoxicity. The objective of this research was to investigate and compare the histopathological alterations during a time course after a low dose of BrCCl3 alone and in combination with dietary CD. Male Sprague-Dawley rats were maintained on 10 ppm dietary CD or normal diet for 15 days. On day 16, they received a single ip dose (30 microliters/kg) of BrCCl3 in corn oil (CO) vehicle or corn oil alone. Blood and liver samples were collected at 0, 3, 6, 12, 24, 36, 48, 72, 96, and 120 hr for serum enzymes and histopathological examination, respectively. Serum enzymes (SDH, ALT, AST) were significantly (p less than 0.05) elevated in rats receiving the CD + BrCCl3 combination in comparison to BrCCl3 alone. For 48 hr, a continuous increase in serum enzyme activities was detected in rats treated with CD + BrCCl3 combination, but not in the rats receiving other treatments (ND + BrCCl3, ND + CO, or CD + CO). The most extensive hepatolobular necrosis was observed in rats treated with the CD + BrCCl3 combination. Thirty-six hr after the administration of BrCCl3 to rats maintained on normal diet, high mitotic activity was observed, which continued through 72 hr resulting in complete restoration of hepatolobular structure. In contrast, rats receiving the combination of CD + BrCCl3 exhibited minimal and belated hepatomitotic activity for a short period of time, resulting in progressive hepatic failure, culminating in animal death. In conclusion, hepatotoxicity of a low dose of BrCCl3 alone appeared to be overcome via stimulated hepatocellular regeneration and hepatolobular restoration. CD appears to amplify BrCCl3 hepatotoxicity via interference with this hormetic mechanism, permitting a progressive and continued hepatic injury leading to complete hepatic failure, culminating in animal death. (+info)
Acceleration of autoimmunity by organochlorine pesticides: a comparison of splenic B-cell effects of chlordecone and estradiol in (NZBxNZW)F1 mice.
(12/39)
The weakly estrogenic organochlorine pesticide chlordecone can accelerate the development of systemic lupus erythematosus (SLE) in ovariectomized (NZBxNZW)F1 mice, with a shortened time to appearance of autoantibodies and disease similar to that produced by treatment with the sex hormone 17beta-estradiol (E2). It is unclear whether chlordecone and E2 share the same pathways in mediating this effect. The effects of chlordecone and E2 treatment on splenic germinal center (GC) and marginal zone B cells were examined. Both chlordecone and E2 activated splenic B cells and enhanced GC reactions, as shown by upregulated protein expression of GL7, CXCR5, and CXCR4. Both treatments increased B-cell bcl-2 and shp-1 gene expression and enhanced ICAM-1 and VCAM-1 protein levels in GC B cells. Chlordecone reduced total B cell and GC B-cell apoptosis without affecting proliferation, another feature shared by E2 treatment. However, chlordecone treatment did not alter the composition of splenic B-cell subsets in marked contrast to the decrease in transitional B cells and increase in marginal zone B cells seen in E2-treated mice. The differences in effects between chlordecone and E2 indicate that chlordecone is not functioning simply as an estrogen mimic with respect to effects on the immune system. Similarities in the effects of chlordecone and E2 on specific immune functions, such as diminished apoptosis in GC B cells, may provide valuable clues regarding key events in the acceleration of autoimmunity by E2, chlordecone, and other agents. (+info)
Diminished prolactin from chlordecone treatment in ovariectomized (NZBxNZW)F(1) mice.
(13/39)
In murine models of systemic lupus erythematosus (SLE), administration of either prolactin or estradiol (E2) increases autoimmunity, and there is evidence that elevated prolactin in response to E2 administration may contribute substantially to E2 effects. Hormonal influence on SLE can extend to environmental agents, as demonstrated by the ability of estrogenic organochlorine pesticides such as chlordecone to accelerate the development of lupus in female (NZBxNZW)F(1) mice. In order to evaluate a potential role for prolactin in chlordecone effects on SLE, it was necessary to first determine whether treatment with chlordecone, like E2, results in elevated prolactin levels. Ovariectomized (NZBxNZW)F(1) mice were treated for 5-6 weeks with chlordecone or E2 in doses shown previously to significantly shorten the time to onset of SLE. At the end of the treatment period, serum prolactin levels were increased 10- to 20-fold in E2-treated mice compared to untreated controls, but decreased in an apparent dose-dependent manner in mice treated with chlordecone. Prolactin receptor in purified splenic B and CD4 T cells from treated animals, assessed through measurement of mRNA using quantitative real-time PCR, was increased by E2 treatment but unchanged in response to chlordecone. These observations suggest that the role of prolactin in eliciting autoimmunity in E2-treated animals is absent in the case of chlordecone, and by implication, that chlordecone possesses other actions that can replace the contribution of prolactin to development of SLE. (+info)
Chlordecone altered hepatic disposition of [14C]cholesterol and plasma cholesterol distribution but not SR-BI or ABCG8 proteins in livers of C57BL/6 mice.
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Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ERalpha) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice.
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