Environmental contaminants and body fat distribution.
The effect of body mass index (BMI) and waist:hip ratio (WHR) on plasma levels of organochlorines [i.e., 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE)] was investigated in a sample of black and white women drawn from a population-based study in North Carolina. Organochlorine levels were determined in plasma samples from 99 women selected on the basis of race (black versus white) and quartile of the WHR (1st versus 4th). Of a panel of 20 organochlorine compounds tested, only DDE was detectable in most study subjects. Measurements of height, weight, and waist and hip circumferences were taken during an in-person interview. Information was elicited regarding dietary, residential, and breast-feeding histories. Results of multiple regression analyses indicate that black women had significantly higher plasma levels of DDE than white women. These levels were independent of BMI and WHR. BMI but not WHR was also found to be an independent predictor of DDE plasma level. These results suggest that black/white differences should be considered in studies that explore the relationship between environmental contaminants and various disease outcomes, such as breast cancer risk. In addition, BMI may affect circulating levels of contaminants and should also be considered a potentially important modifying factor for exposure to lipophilic substances. (+info)
Serum concentrations of organochlorine compounds and the subsequent development of breast cancer.
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.
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)
Dichlorodiphenyldichloroethylene potentiates the effect of protein kinase A pathway activators on progesterone synthesis in cultured porcine granulosa cells.
The insecticide dichlorodiphenyltrichloroethane (DDT) and its major metabolite p,p'-dichlorodiphenyldichloroethylene (DDE) have been implicated as endocrine-modulating chemicals. The DDT metabolite p, p'-DDE has been found contaminating human tissues and follicular fluid because of dietary exposure. We investigated the effects of DDE on progesterone synthesis in a stable porcine granulosa cell line, JC-410, and in primary cultures of porcine granulosa cells. Progesterone synthesis was not affected by 0.1-100 ng/ml DDE in the JC-410 cells. However, 10 ng/ml DDE increased 8-bromo-cAMP (8-Br-cAMP)-stimulated progesterone synthesis 0.4-fold (P < 0.05) over the levels observed with 1 mM 8-Br-cAMP alone. The effect of cholera toxin (CT) on progesterone synthesis was increased 0.7-fold (P < 0.05) by 10 ng/ml DDE over the value observed with 30 ng/ml CT alone. In primary cultures of porcine granulosa cells, 10 ng/ml DDE potentiated CT-stimulated progesterone synthesis 1.2-fold over the value observed with CT alone. In the JC-410 cells, 1 and 10 ng/ml DDE increased CT-stimulated cytochrome P450-cholesterol side-chain cleavage (P450(scc)) mRNA levels 0.3- and 0.4-fold, respectively, over the values obtained with CT alone. Neither basal nor CT-stimulated cAMP levels were changed by DDE. We conclude that DDE affects granulosa cell response to protein kinase A activators by altering the expression of the P450(scc) gene. (+info)
Detection of the environmental antiandrogen p,p-DDE in CD and long-evans rats using a tier I screening battery and a Hershberger assay.
In this report, p,p'-DDE, a weak androgen receptor (AR) antagonist, has been examined in a Tier I screening battery designed to detect endocrine-active compounds (EACs). The screening battery that was used to examine p,p'-DDE was an abbreviated version of a proposed Tier I screening battery (Cook et al., 1997, Regul. ToxicoL Pharmacol. 26, 60-68) that consisted of a 15-day intact male in vivo battery and an in vitro yeast transactivation system (YTS). In addition, strain sensitivity differences were evaluated using male Crl:CDIGS BR (CD) and Long-Evans (LE) rats. Finally, p,p'-DDE was examined in a Hershberger assay designed to detect AR agonists. In the in vivo male battery using CD rats, responses to p,p'-DDE included organ weight changes (increased relative liver weight and decreased absolute epididymis weight) and hormonal alterations (increased serum estradiol [E2] levels and decreased serum FSH and T4 levels). Responses to p,p'-DDE in LE rats included organ weight changes (increased relative liver weight, absolute epididymis weight, relative accessory sex gland [ASG] unit weight, as well as the individual component weights of the ASG [prostate and seminal vesicles]), and hormonal alterations (increased serum testosterone [T], E2, dihydrotestosterone [DHT], thyroid-stimulating hormone [TSH], and decreased T4 levels). These data demonstrate that there are considerable strain-sensitivity differences to p,p'-DDE exposure. The described in vivo male battery using CD rats did not identify p,p'-DDE as an EAC. In contrast, the in vivo male battery using LE rats identified p,p'-DDE as a EAC. Evaluation of the data for the LE rats demonstrate that p,p'-DDE appears to be acting as an AR antagonist whose primary effects are more potent centrally than peripherally. In the YTS for the AR, p,p'-DDE had an EC50 value of 3.5 x 10(-4) M; however, in the AR YTS competition assay, p,p'-DDE did not inhibit DHT binding to the AR. p,p'-DDE was inactive in the YTS containing the estrogen receptor or progesterone receptor at the concentrations evaluated. In the Hershberger assay, p,p'-DDE administration caused antiandrogen-like effects characterized by attenuation of the testosterone propionate-induced increases in reproductive-organ weights. In summary, these data suggest that strain selection will affect the ability to detect certain weak EACs. However, a Tier I screening battery consisting of both in vivo and in vitro endpoints would reduce the chance that weak-acting compounds such as p,p'-DDE would not be identified as potential EACs. (+info)
Isolation of Terrabacter sp. strain DDE-1, which metabolizes 1, 1-dichloro-2,2-bis(4-chlorophenyl)ethylene when induced with biphenyl.
Terrabacter sp. strain DDE-1, able to metabolize 1,1-dichloro-2, 2-bis(4-chlorophenyl)ethylene (DDE) in pure culture when induced with biphenyl, was enriched from a 1-1-1-trichloro-2, 2-bis(4-chlorophenyl)ethane residue-contaminated agricultural soil. Gas chromatography-mass spectrometry analysis of culture extracts revealed a number of DDE catabolites, including 2-(4'-chlorophenyl)-3,3-dichloropropenoic acid, 2-(4'-chlorophenyl)-2-hydroxy acetic acid, 2-(4'-chlorophenyl) acetic acid, and 4-chlorobenzoic acid. (+info)
Cancer mortality and environmental exposure to DDE in the United States.
To explore the role of DDE, the major and most persistent DDT derivative, in cancer etiology, we examined the association of the 1968 adipose DDE levels of population samples from 22 U.S. states with age-adjusted mortality rates between 1975 and 1994 for multiple myeloma; non-Hodgkin lymphoma (NHL); and cancer of the breast, corpus uteri, liver, and pancreas. Separate analyses were conducted by gender and race. Covariates in the regression models included average per-capita income, percent metropolitan residents, and the population density. Liver cancer mortality increased significantly with adipose DDE levels in both sexes among whites, but not among African Americans. No association was observed for pancreatic cancer and multiple myeloma. Breast cancer mortality was inversely correlated with adipose DDE levels among both white and African American women. Significant inverse correlations were also observed for uterine cancer among white women, whereas no association was observed for African Americans and for NHL among whites (men and women) and African American women. The results for pancreatic cancer, multiple myeloma, NHL, breast cancer, and uterine cancer did not support the hypothesis of an association with past adipose levels of the DDT derivative DDE. The multivariate analysis confirmed most findings. The association between liver cancer and DDE observed among whites, particularly in view of the occurrence of hepatic neoplasms in laboratory animals exposed to DDT, warrants further investigation. (+info)
Environmental estrogens induce transcriptionally active estrogen receptor dimers in yeast: activity potentiated by the coactivator RIP140.
We used three yeast genetic systems to investigate the estrogen-like activity of octylphenol (OP), bisphenol-A (BPA), o,p'-DDT, and o, p'-DDE to induce human estrogen receptor (hER) dimerization and transcriptional activation. We have demonstrated that OP, BPA, and o, p'-DDT can induce hER ligand-dependent dimerization using a yeast two-hybrid assay. All three xenoestrogens, plus estradiol, enhanced estrogen response element (ERE)-dependent transcriptional activation of hER. In the presence of receptor interacting protein 140 (RIP140), ERE-dependent activity was dramatically amplified by 100-fold for estradiol, OP, BPA, and o,p'-DDT. A yeast whole-cell [(3)H]estradiol binding assay was developed to determine the site of interaction on the hER. We determined nonspecific binding by parallel incubations run in the presence of 5 microM unlabelled estradiol in PCY2 yeast. At the concentrations tested, unlabeled estradiol, OP, and BPA displaced [(3)H]estradiol in this binding assay, whereas the concentrations of o,p'-DDT and o,p'-DDE tested were insufficient to inhibit binding. Incubating yeast in the presence of increasing concentrations of estradiol and OP (1 microM) or BPA (1 microM) neither blocked nor altered the effect of estradiol on hER activity. We observed no agonistic activity of o,p'-DDE in any of the yeast models used. These results suggest that OP, BPA, and o,p'-DDT exert their estrogen-like activity through the ER in a manner similar to that of estradiol, and the coactivator RIP140 markedly potentiates this activity. (+info)