DDE and PCB serum concentration in maternal blood and their adult female offspring.

BACKGROUND: Dichlorodiphenyl dichloroethylene (DDE) and polychlorinated biphenyls (PCBs) can be passed from mother to offspring through placental transfer or breastfeeding. Unknown is whether maternal levels can predict concentrations in adult offspring. OBJECTIVES: To test the association between maternal blood levels of DDE and PCBs and adult female offspring levels of these compounds using data from the Michigan Fisheaters'Cohort. METHODS: DDE and PCB concentrations were determined in 132 adult daughters from 84 mothers. Prenatal exposures were estimated based on maternal DDE and PCB serum levels measured between 1973 and 1991. Levels in adult daughters were regressed on maternal and estimated prenatal exposure levels, adjusting for potential confounders using linear mixed models. Confounders included daughter's age, birth order, birth weight, number of pregnancies, the length of time the daughter was breast-fed, the length of time the daughter breast-fed her own children, last year fish-eating status, body mass index, and lipid weight. RESULTS: The median age of the participants was 40.4 years (range 18.4-65.4, 5-95 percentiles 22.5-54.6%, respectively). Controlling for confounders and intra-familial associations, DDE and PCB concentrations in adult daughters were significantly positively associated with estimated prenatal levels and with maternal concentrations. The proportion of variance in the adult daughters' organochlorine concentrations explained by the maternal exposure levels is approximately 23% for DDE and 43% for PCBs. The equivalent of a median of 3.67 µg/L prenatal DDE and a median of 2.56 µg/L PCBs were 15.64 and 10.49 years of fish consumption, respectively. When controlling for effects of the shared environment (e.g., fish diet) by using a subsample of paternal levels measured during the same time frames (n=53 and n=37), we determined that the direct maternal transfer remains important. CONCLUSIONS: Estimated intra-uterine DDE and PCB levels predicted concentrations in adult female offspring 40 years later. Interpretation of adverse health effects from intra-uterine exposures of persistent pollutants may need to consider the sustained impact of maternal DDE and PCB levels found in their offspring.

Prenatal and concurrent exposure to halogenated organic compounds and gene expression of CYP17A1, CYP19A1, and oestrogen receptor alpha and beta genes.

OBJECTIVE: To determine whether prenatal exposure to dichlorodiphenyl ethylene (DDE) and polychlorinated biphenyls (PCBs) and concurrent exposure to DDE, PCBs and polybrominated diphenylethers (PBDEs) affect gene expression of aromatase (CYP19A1), 17-α-hydroxylase (CYP17A1), and oestrogen receptors α and ß (ESR 1 and ESR2). METHODS: Based on maternal PCB and DDE levels in the parent generation of the Michigan Fisheater Cohort determined between 1973 and 1991, individual prenatal exposures were estimated and have been published. In 2007, female adult offspring of this cohort were examined. Gene expression and concurrent lipid-adjusted exposures to DDE, PCBs and PBDEs were measured in blood and serum, respectively. Using mixed models and path analyses, gene-expression data were regressed on prenatal and concurrent exposures controlling for confounders. RESULTS: 139 daughters of Michigan fisheaters (65.3%) participated in the investigation. While prenatal PCB levels were statistically significantly associated with decreased expression of the aromatase and 17-α-hydroxylase genes, prenatal DDE levels were significantly related to increased gene expression of aromatase but not of 17-α-hydroxylase. The DDE association seems to be mediated by concurrent lipid-adjusted p,p'-DDE serum levels. Prenatal and concurrent exposure of both PCBs and DDE had comparable effects. No association was found for PBDEs or for the gene expression of ESR 1 and ESR2. CONCLUSIONS: A 40-year antecedent prenatal exposure and concurrent levels of PCBs and DDE are associated with the expression of aromatase and 17-α-hydroxylase genes. Prenatal exposures to organochlorines may instigate long-term alterations of gene expression. Mechanisms of prenatal induction of persistent gene-expression alterations are speculated to be epigenetic in nature.

Association of age at menarche with adult leg length and trunk height: Speculations in relation to breast cancer risk.

BACKGROUND: It seems paradoxical that both increased height and earlier age at menarche (which predicts for shorter stature) are both associated with increased breast cancer risk. METHODS: Retrospective data from a parental cohort coupled with prospective interviews with and anthropometric measurements from their daughters were used. Multivariable linear regression analyses were conducted using mixed regression models to account for same-family participants. RESULTS: Controlling for birth weight, maternal height, and birth cohort, and analyzed as a group, a 1-year increase in the age at menarche predicted an increase in standing height, leg length, and trunk height of 0.76, 0.41, and 0.35 cm, respectively. However, when stratifying by birth year (prior to 1966 vs 1966 or after), these relationships were true only for those born prior to 1966. CONCLUSION: Given the height-breast cancer risk association, the emerging evidence linking breast cell proliferation to hormones associated with growth, and the finding in this study that the relationship between age at menarche and adult height no longer exists for women born in 1966 or later, it is possible that the long-established relationship between age at menarche and breast cancer risk may also no longer exist.

Development of a clinical decision rule for triage of women with palpable breast masses.

BACKGROUND AND OBJECTIVE: Given the large numbers of open breast biopsies performed in women who have benign breast masses, we developed a clinical decision rule (CDR), called BREASTAID, to triage women into open biopsy or follow-up. METHODS: A prospective cohort design was used to obtain data on 452 palpable breast masses evaluated at a referral clinic. Breast cancer was defined as ductal carcinoma in situ or invasive cancer at open biopsy. Separate logistic regression models were developed at three logical stages of the clinical workup. Bayes' theorem was applied in a stepwise fashion to revise model probabilities to generate a final probability of cancer. Receiver operator characteristics curves were generated to determine the optimum cut-point. Results derived from the CDR were compared with actual clinical practice. RESULTS: A total of 452 masses in 380 women were included. Clinical practice resulted in 180 masses (39.8%) undergoing open biopsy, 41 (22.8%) of which were cancers. Age, history of breast cancer in the mother, mass size, mammography findings, and fine needle aspiration biopsy results were included in the final models. When applied to the derivation dataset, BREASTAID successfully identified 40 of 41 cancer masses (sensitivity 97.6%, 95% confidence interval [CI] 94.1-99.9), and 350 of 411 noncancer masses (specificity 85.2%, 95% CI 81.8-88.5). BREASTAID would have reduced the number of biopsies performed on the 411 benign masses from 139 to 61. CONCLUSIONS: This study demonstrated that a CDR based on routinely collected clinical variables has the potential to accurately triage women with palpable breast masses. Further validation of the rule is required before its clinical use can be considered.

Common classification schemes for PCB congeners and the gene expression of CYP17, CYP19, ESR1 and ESR2.

BACKGROUND: Reliable techniques to measure polychlorinated biphenyl (PCB) congeners make the clearer definition of their effects on human health possible. Given that PCBs are classified as endocrine disrupters, we sought to explore the expression of some key genes involved in sex steroid metabolism. OBJECTIVES: To examine common classification schemes of PCB congeners and determine whether exposure to groups classified by mechanism of action alter the gene expression (GE) of CYP17, CYP19, and ESR1 and ESR2. METHODS: GE and exposure to various classifications of lipid-adjusted PCB congeners were examined in 139 daughters of the Michigan Fisheaters' Cohort. Using mixed models analyses and adjusting for age, menopausal status, and current use of oral contraceptives and hormone replacement therapy, GE data were regressed on exposure to PCB congener groupings based on mechanism of action. RESULTS: Three novel findings are elucidated: first, that up-regulation of CYP19 expression is associated with exposure to PCB groupings containing dioxin-like, potentially anti-estrogenic, immunotoxic congeners, including PCB IUPAC #74, #105, #118, #138, #156, #157, #158, #167, and #170 from this cohort. Second, that exposure to similar congeners (PCB IUPAC #105, #156, #157, #158, and #167 in this cohort) but using a classification based solely on hormonal mechanisms of action is associated with increased expression of ESR2. Third, that increased expression of CYP17 is of borderline significance when associated with exposure to PCB IUPAC #118, #138, and #156. CONCLUSIONS: These findings are both counter-intuitive and intriguing. Rather than exhibiting anti-estrogenic effects alone, they suggest that these congeners up-regulate the major enzyme involved in estrogen synthesis and tend to confirm previous findings of links between AhR and ER signaling pathways. Replication of these findings, expansion of the number of genes examined, exploration of mixtures of environmental chemicals, and subsequent study of health outcomes in a larger cohort are future priorities.

BREASTAID: Clinical results from early development of a clinical decision rule for palpable solid breast masses.

OBJECTIVE: To develop a clinical decision rule (entitled BREASTAID) that will predict the probability of malignancy in women with palpable solid breast masses. SUMMARY BACKGROUND DATA: Currently, 80% of open breast biopsies are benign, resulting in excessive economic, psychologic, and physical morbidity. METHODS: A total of 452 solid breast masses were evaluated in a surgical breast clinic between November 1994 and February 1998. Breast cancer status was defined histologically as ductal carcinoma in situ or invasive cancer. Noncancer status included benign histology, mass resolution, or stability at 12-month follow-up. Data were collected on risk factors, clinical breast examination, mammography, and cytology results. Three multiple logistic regression models were used to generate the probability of cancer at 3 logical steps in the workup; Bayes' theorem was applied in a stepwise fashion to generate a final probability of cancer. RESULTS: A model incorporating only clinical breast examination and mammography resulted in an excessive number of either missed cases or biopsies compared with one that included cytology. Using a cut-point of 4%, this latter BREASTAID model had 97.6% sensitivity and 85.1% specificity. Compared with triple diagnosis, BREASTAID would have reduced the open biopsy rate from 39.8% (180 of 452) to 22.3% (101 of 452), improving the diagnostic yield from 22.7% to 40.6%. CONCLUSIONS: This study convincingly demonstrates that at minimum, clinical, radiologic, and cytologic evaluations are required to accurately evaluate a solid breast mass. BREASTAID has the potential to minimize the number of open biopsies performed while allowing safe triage to follow-up. Before widespread application, further validation studies are required.