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. (1/504)

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.  (+info)

Comparison of short-term estrogenicity tests for identification of hormone-disrupting chemicals. (2/504)

The aim of this study was to compare results obtained by eight different short-term assays of estrogenlike actions of chemicals conducted in 10 different laboratories in five countries. Twenty chemicals were selected to represent direct-acting estrogens, compounds with estrogenic metabolites, estrogenic antagonists, and a known cytotoxic agent. Also included in the test panel were 17beta++-estradiol as a positive control and ethanol as solvent control. The test compounds were coded before distribution. Test methods included direct binding to the estrogen receptor (ER), proliferation of MCF-7 cells, transient reporter gene expression in MCF-7 cells, reporter gene expression in yeast strains stably transfected with the human ER and an estrogen-responsive reporter gene, and vitellogenin production in juvenile rainbow trout. 17beta-Estradiol, 17alpha-ethynyl estradiol, and diethylstilbestrol induced a strong estrogenic response in all test systems. Colchicine caused cytotoxicity only. Bisphenol A induced an estrogenic response in all assays. The results obtained for the remaining test compounds--tamoxifen, ICI 182.780, testosterone, bisphenol A dimethacrylate, 4-n-octylphenol, 4-n-nonylphenol, nonylphenol dodecylethoxylate, butylbenzylphthalate, dibutylphthalate, methoxychlor, o,p'-DDT, p,p'-DDE, endosulfan, chlomequat chloride, and ethanol--varied among the assays. The results demonstrate that careful standardization is necessary to obtain a reasonable degree of reproducibility. Also, similar methods vary in their sensitivity to estrogenic compounds. Thus, short-term tests are useful for screening purposes, but the methods must be further validated by additional interlaboratory and interassay comparisons to document the reliability of the methods.  (+info)

Worldwide trends in DDT levels in human breast milk. (3/504)

BACKGROUND: Concern over human breast milk contamination with the pesticide DDT (1,1,1-trichloro-2,2-bis(chlorodiphenyl)ethane) has prompted numerous studies around the world during the last five decades. This article examines trends in reported DDT levels, and the apparent effect of restrictions on DDT use. METHODS: More than 130 published values for DDT in human milk since 1951 were compiled, and trend lines were fit for regions of the world. RESULTS: Population means have declined in much of the world, from 5000-10000 microg DDT/kg milk fat to around 1000 today in many areas. Although different regions have different means, the decline seen in various countries corresponds to their restricting DDT use. DISCUSSION: DDT concentrations in human milk have declined in most areas of the world, consistent with restrictions on its use. Nevertheless, levels can be high in areas still using DDT, even higher than the World Health Organization's recommended limit for infants. These results indicate that population averages can be reduced by a predictable amount as DDT use is restricted.  (+info)

Serum concentrations of organochlorine compounds and the subsequent development of breast cancer. (4/504)

A nested case-control study was conducted to examine the association between serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the primary metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), and polychlorinated biphenyls (PCBs) and the development of breast cancer up to 20 years later. Cases (n = 346) and controls (n = 346) were selected from cohorts of women who donated blood in 1974, 1989, or both, and were matched on age, race, menopausal status, and month and year of blood donation. Analyses were stratified by cohort participation because median DDE and PCB concentrations among the controls were 59 and 147% higher in 1974 than 1989, respectively. Median concentrations of DDE were lower among cases than controls in both time periods [11.7% lower in 1974 (P = 0.06) and 8.6% lower in 1989 (P = 0.41)]. Median concentrations of PCBs were similar among cases and controls [P = 0.21 for 1974 and P = 0.37 for 1989 (Wilcoxon signed rank test)]. The risk of developing breast cancer among women with the highest concentrations of DDE was roughly half that among women with the lowest concentrations, whether based on concentrations in 1974 [odds ratio (OR), 0.50; 95% confidence interval (CI), 0.27-0.89; P(trend) = 0.02] or in 1989 (OR, 0.53; 95% CI, 0.24-1.17; P(trend) = 0.08). The associations between circulating concentrations of PCBs and breast cancer were less pronounced but still in the same direction (1974: OR, 0.68; 95% CI, 0.36-12.9; P(trend) = 0.2; and 1989: OR, 0.73; 95% CI, 0.37-1.46; P(trend) = 0.6). Adjustment for family history of breast cancer, body mass index, age at menarche or first birth, and months of lactation did not materially alter these associations. These associations remained consistent regardless of lactation history and length of the follow-up interval, with the strongest inverse association observed among women diagnosed 16-20 years after blood drawing. Results from this prospective, community-based nested case-control study are reassuring. Even after 20 years of follow-up, exposure to relatively high concentrations of DDE or PCBs showed no evidence of contributing to an increased risk of breast cancer.  (+info)

DDE and DDT in breast adipose tissue and risk of female breast cancer. (5/504)

A case-control study was conducted in Connecticut from 1994 to 1997 to investigate the relation between dichlorodiphenyldichloroethane (DDE) and dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk. Cases and controls were women aged 40-79 years, who had breast-related surgery at the Yale-New Haven Hospital and from whose surgical specimen the authors could obtain at least 0.4 g of breast adipose tissue for chemical analyses. A total of 304 incident breast cancer cases (including 62 in situ carcinomas) and 186 benign breast disease controls were recruited into the study. Tissue levels of DDE and DDT were measured using gas chromatography. Statistical significance for comparisons of mean levels of DDE and DDT was calculated using analysis of variance and rank sum tests. A logistic regression model was used to estimate the association and to control confounding. The age-adjusted geometric mean tissue level of DDE for cases (736.5 ppb) was similar to that for the controls (784.1 ppb). DDT levels were also similar for cases (51.8 ppb) and controls (55.6 ppb). The adjusted odds ratio is 0.9 (95% confidence interval: 0.5, 1.5) for DDE and 0.8 (95% confidence interval: 0.5, 1.5) for DDT when the highest quartile was compared with the lowest. These results do not support an association between adipose tissue levels of DDE and DDT and breast cancer risk.  (+info)

Identification of two nuclear androgen receptors in kelp bass (Paralabrax clathratus) and their binding affinities for xenobiotics: comparison with Atlantic croaker (Micropogonias undulatus) androgen receptors. (6/504)

Two distinct nuclear androgen receptors (ARs) were identified in brain and ovarian tissues of kelp bass, Paralabrax clathratus, termed kbAR1 and kbAR2, which correspond to the two nuclear ARs we have previously characterized in Atlantic croaker, Micropogonias undulatus, termed acAR1 and acAR2. Scatchard analysis of nuclear fractions of whole brain tissue demonstrated that kbAR1 had a single class of high-affinity binding sites for testosterone (T; K(d) of 1. 8 nM and B(max) of 1.0 pmol/g tissue), whereas cytosolic fractions of kbAR2 ovarian tissue had a single class of high-affinity binding sites for dihydrotestosterone (DHT; K(d) of 0.1 nM and B(max) of 0.5 pmol/g tissue). Competition studies showed that both kbAR1 and kbAR2 were specific for androgens. However, kbAR1 bound only T with high affinity, whereas kbAR2 bound DHT, mibolerone, 17alpha-methyl-testosterone, T, and 11-ketotestosterone with high affinity. In addition, we examined the binding affinities of dichlorodiphenyltrichloroethane and its derivatives, several hydroxylated polychlorinated biphenyl (PCB) congeners, PCB mixtures, and the fungicide vinclozolin and its two metabolites M1 and M2 for the two ARs in Atlantic croaker ovarian, testicular, and brain tissues and in kelp bass ovarian and brain tissues. Only 4, 4'-PCB-3-OH and 2',5'-PCB-3-OH demonstrated greater than 50% displacement of [(3)H]testosterone from either acAR1 or kbAR1. In contrast, with the exception of vinclozolin, all of the xenobiotics examined demonstrated binding to acAR2 in testicular and ovarian tissues. The binding affinities were highest in the testicular tissue with M2, 2,2'5'-PCB-4-OH, and o,p'-DDD all binding with EC(50)s less than 10 microM. The binding affinities of xenobiotics to kbAR2 in ovarian tissue were similar to their binding affinities for ovarian acAR2. The finding that AR1 and AR2 possess different binding affinities for natural androgens and synthetic steroids, as well as for xenobiotics, suggests that the activities of androgens and of certain xenobiotics will depend upon the type of AR present within the target tissue.  (+info)

Effects of parathyroid hormone-related protein on human mesangial cells in culture. (7/504)

Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar biological effects through the PTH/PTHrP receptor. Because PTHrP exhibits vasodilatory properties, we evaluated the hypothesis that this hormone interacts with human mesangial cells (HMC). The PTHrP prevented both the expected reduction in the planar cell surface area and the increase in myosin light-chain phosphorylation induced by platelet-activating factor (PAF) on HMC, in a dose-dependent manner. This effect was completely blocked by pertussis toxin and dideoxyadenosine, suggesting that a G protein-coupled receptor and cAMP are important in the PTHrP transduction mechanism. Moreover, PTHrP increased cAMP synthesis and thymidine incorporation in HMC. However, whereas RT-PCR and Southern and Northern blot analyses demonstrated the expression of human PTH/PTHrP receptor in human kidney cortex, no expression could be demonstrated in HMC. These results show that PTH and PTHrP directly interact with mesangial cells. These effects might be mediated by a receptor different from the PTH/PTHrP receptor.  (+info)

ESAT-6 subunit vaccination against Mycobacterium tuberculosis. (8/504)

The ESAT-6 antigen from Mycobacterium tuberculosis is a dominant target for cell-mediated immunity in the early phase of tuberculosis (TB) in TB patients as well as in various animal models. The purpose of our study was to evaluate the potential of ESAT-6 in an experimental TB vaccine. We started out using dimethyl dioctadecylammonium bromide (DDA), an adjuvant which has been demonstrated to be efficient for the induction of cellular immune responses and has been used successfully before as a delivery system for TB vaccines. Here we demonstrate that, whereas immune responses to both short-term-culture filtrate and Ag85B are efficiently induced with DDA, this adjuvant was inefficient for the induction of immune responses to ESAT-6. Therefore, we investigated the modulatory effect of monophosphoryl lipid A (MPL), an immunomodulator which in different combinations has demonstrated strong adjuvant activity for both cellular and humoral immune responses. We show in the present study that vaccination with ESAT-6 delivered in a combination of MPL and DDA elicited a strong ESAT-6-specific T-cell response and protective immunity comparable to that achieved with Mycobacterium bovis BCG.  (+info)