Nickilou Y. Krigbaum

Prenatal exposure to the pesticide DDT and hypertension diagnosed in women before age 50: a longitudinal birth cohort study.

Background: Elevated levels of the pesticide DDT (dichlorodiphenyltrichloroethane) have been positively associated with blood pressure and hypertension in studies among adults. Accumulating epidemiologic and toxicologic evidence suggests that hypertension during adulthood may also be affected by earlier life and possibly the prenatal environment. Objectives: We assessed whether prenatal exposure to the pesticide DDT increases risk of adult hypertension. Methods: We examined concentrations of DDT (p,p´- and o,p´-) and its metabolite p,p´-DDE (dichlorodiphenyldichloroethylene) in prenatal serum samples from a subset of women (n = 527) who had participated in the prospective Child Health and Development Studies birth cohort in the San Francisco Bay area while they were pregnant between 1959 and 1967. We surveyed daughters 39–47 years of age by telephone interview from 2005 to 2008 to obtain information on self-reported physician-diagnosed hypertension and use of hypertensive medication. We used multivariable regression analysis of time to hypertension based on the Cox proportional hazards model to estimate relative rates for the association between prenatal DDT exposures and hypertension treated with medication in adulthood, with adjustment for potential confounding by maternal, early-life, and adult exposures. Results: Prenatal p,p´-DDT exposure was associated with hypertension [adjusted hazard ratio (aHR) = 3.6; 95% CI: 1.8, 7.2 and aHR = 2.5; 95% CI: 1.2, 5.3 for middle and high tertiles of p,p´-DDT relative to the lowest tertile, respectively]. These associations between p,p´-DDT and hypertension were robust to adjustment for independent hypertension risk factors as well as sensitivity analyses. Conclusions: These findings suggest that the association between DDT exposure and hypertension may have its origins early in development.

A Cohort study evaluation of maternal PCB exposure related to time to pregnancy in daughters

BackgroundPolychlorinated biphenyls (PCBs) remain ubiquitous environmental contaminants. Developmental exposures are suspected to impact reproduction. Analysis of mixtures of PCBs may be problematic as components have a complex correlation structure, and along with limited sample sizes, standard regression strategies are problematic. We compared the results of a novel, empirical method to those based on categorization of PCB compounds by (1) hypothesized biological activity previously proposed and widely applied, and (2) degree of ortho- substitution (mono, di, tri), in a study of the relation of maternal serum PCBs and daughter’s time to pregnancy.MethodsWe measured PCBs in maternal serum samples collected in the early postpartum in 289 daughters in the Child Health and Development Studies birth cohort. We queried time to pregnancy in these daughters 28–31 years later. We applied a novel weighted quantile sum approach to find the bad-actor compounds in the PCB mixture found in maternal serum. The approach includes empirical estimation of the weights through a bootstrap step which accounts for the variation in the estimated weights.ResultsBootstrap analyses indicated the dominant functionality groups associated with longer TTP were the dioxin-like, anti-estrogenic group (average weight, 22%) and PCBs not previously classified by biological activity (54%). In contrast, the unclassified PCBs were not important in the association with shorter TTP, where the anti-estrogenic groups and the PB-inducers group played a more important role (60% and 23%, respectively). The highly chlorinated PCBs (average weight, 89%) were mostly associated with longer TTP; in contrast, the degree of chlorination was less discriminating for shorter TTP. Finally, PCB 56 was associated with the strongest relationship with TTP with a weight of 47%.ConclusionsOur empirical approach found some associations previously identified by two classification schemes, but also identified other bad actors. This empirical method can generate hypotheses about mixture effects and mechanisms and overcomes some of the limitations of standard regression techniques.

Maternal infection and stress during pregnancy and depressive symptoms in adolescent offspring

Maternal infection during pregnancy has been linked to increased risk of offspring depression. Additionally, maternal stress during pregnancy has been consistently linked with adverse offspring outcomes associated with depression. Relatedly, stress has been associated with increased risk of infection; however no study has investigated stress-infection interactions during pregnancy and risk for offspring depression. Participants were drawn from the Child Health and Development Studies (CHDS), a prospective, longitudinal study that enrolled pregnant women from 1959 to 1966. Maternal health and birth outcome information were collected, as well as open-ended interviews about worrisome events during pregnancy. The present study included participants from a subsample of women whose offspring (n = 1711) completed self-reports of depressive symptoms during adolescence. Results indicated that maternal infection during only the second trimester was associated with higher scores on adolescent offspring depressive symptoms, while controlling for maternal education at birth, adolescent age, and maternal depressive symptoms at adolescence. Maternal experiences of daily stress during pregnancy moderated this association, such that mothers diagnosed with second trimester infection and who experienced daily stress had offspring with significantly higher depression scores than mothers of adolescents diagnosed with an infection alone. Findings have potential implications for prevention and intervention strategies.

Response to the Letter by Stoop, P.

Author(s): Cohn, Barbara A; La Merrill, Michele; Krigbaum, Nickilou Y; Yeh, Gregory; Park, June-Soo; Zimmermann, Lauren; Cirillo, Piera M

Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

Response to the Letter by Paumgartten F.

Author(s): Cohn, Barbara A; La Merrill, Michele; Krigbaum, Nickilou Y; Yeh, Gregory; Park, June-Soo; Zimmermann, Lauren; Cirillo, Piera M

Abstract P3-07-35: Findings from the first prospective womb to breast cancer study: New gestational biomarkers support proof of concept that gestation is a window of susceptibility for the breast

Rationale. Here we provide the first prospective evidence for proof of concept that gestation is an important window of susceptibility for breast cancer. These findings could open the field to interdisciplinary investigation of mechanisms, and interventions via clinical and experimental science. Objective. We tested the hypothesis that biomarkers in gestation predict early-onset breast cancer. Data were prospectively collected including maternal and paternal peri-conceptual body mass, tobacco and alcohol use, maternal pregnancy weight gain, pregnancy complications and outcomes, placental morphology assessed by a standardized examination at birth, and environmental chemicals recently assayed in archived maternal perinatal serum samples. This investigation was based on the observation of 20,000 pregnancies beginning in 1959, with surveillance for both maternal (F0) and offspring (F1) cancer in the Child Health and Development Studies pregnancy cohort. This report is based on the first 133 breast cancer cases in F1 that occurred from 1992-2012, diagnosed at ages 32 to 52. Results. We observed gestational biomarkers of breast cancer risk which were independent of maternal history of breast cancer and race. Highlights of significant findings include independent, higher risk for women who: were born to mothers who lost weight during pregnancy (3-fold increase in risk, p Conclusions. Here we provide a high level of evidence for the existence of gestational biomarkers for breast cancer. Prospective design and direct clinical observation of pregnancies eliminates reporting and misclassification bias. Findings extend the discussion of gestational biomarkers beyond birthweight and pre-eclampsia which have been previously reported. The importance of the gestation window for breast cancer in humans is in line with toxicological evidence in animal models and strongly suggests the existence of opportunities for primary prevention beginning before birth. Citation Format: Barbara Cohn, Nickilou Krigbaum, Lauren Zimmermann, Piera Cirillo. Findings from the first prospective womb to breast cancer study: New gestational biomarkers support proof of concept that gestation is a window of susceptibility for the breast [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-35.