Exposure to polychlorinated biphenyl (PCB) congeners measured shortly after giving birth and subsequent risk of maternal breast cancer before age 50

Discrete windows of susceptibility to toxicants have been identified for the breast, including in utero, puberty, pregnancy, and postpartum. We tested the hypothesis that polychlorinated biphenyls (PCBs) measured during the early postpartum predict increased risk of maternal breast cancer diagnosed before age 50. We analyzed archived early postpartum serum samples collected from 1959 to 1967, an average of 17 years before diagnosis (mean diagnosis age 43 years) for 16 PCB congeners in a nested case–control study in the Child Health and Development Studies cohort (N = 112 cases matched to controls on birth year). We used conditional logistic regression to adjust for lipids, race, year, lactation, and body mass. We observed strong breast cancer associations with three congeners. PCB 167 was associated with a lower risk (odds ratio (OR), 75th vs. 25th percentile = 0.2, 95 % confidence interval (95 % CI) 0.1, 0.8) as was PCB 187 (OR, 75th vs. 25th percentile = 0.4, 95 % CI 0.1, 1.1). In contrast, PCB 203 was associated with a sixfold increased risk (OR, 75th vs. 25th percentile = 6.3, 95 % CI 1.9, 21.7). The net association of PCB exposure, estimated by a post-hoc score, was nearly a threefold increase in risk (OR, 75th vs. 25th percentile = 2.8, 95 % CI 1.1, 7.1) among women with a higher proportion of PCB 203 in relation to the sum of PCBs 167 and 187. Postpartum PCB exposure likely also represents pregnancy exposure, and may predict increased risk for early breast cancer depending on the mixture that represents internal dose. It remains unclear whether individual differences in exposure, response to exposure, or both explain risk patterns observed

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

Background: Polychlorinated 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. Methods: We 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. Results: Bootstrap 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%. Conclusions: Our 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

in Utero Exposure to antiemetic and Risk of adult-Onset Colorectal Cancer

BACKGROUND: Incidence rates of colorectal cancer (CRC) are increasing among adults born in and after the 1960s, implicating pregnancy-related exposures introduced at that time as risk factors. Dicyclomine, an antispasmodic used to treat irritable bowel syndrome, was initially included in Bendectin (comprising doxylamine, pyridoxine, and dicyclomine), an antiemetic prescribed during pregnancy in the 1960s. METHODS: We estimated the association between in utero exposure to Bendectin and risk of CRC in offspring of the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in Oakland, CA, between 1959 and 1966 (n = 14 507 mothers and 18 751 liveborn offspring). We reviewed prescribed medications from mothers\u27 medical records to identify those who received Bendectin during pregnancy. Diagnoses of CRC in adult (aged ≥18 years) offspring were ascertained by linkage with the California Cancer Registry. Cox proportional hazards models were used to estimate adjusted hazard ratios, with follow-up accrued from birth through cancer diagnosis, death, or last contact. RESULTS: Approximately 5% of offspring (n = 1014) were exposed in utero to Bendectin. Risk of CRC was higher in offspring exposed in utero (adjusted hazard ratio = 3.38, 95% confidence interval [CI] = 1.69 to 6.77) compared with unexposed offspring. Incidence rates of CRC were 30.8 (95% CI = 15.9 to 53.7) and 10.1 (95% CI = 7.9 to 12.8) per 100 000 in offspring exposed to Bendectin and unexposed, respectively. CONCLUSIONS: Higher risk of CRC in offspring exposed in utero may be driven by dicyclomine contained in the 3-part formulation of Bendectin used during the 1960s. Experimental studies are needed to clarify these findings and identify mechanisms of risk

in-Utero Exposure to antibiotics and Risk of Colorectal Cancer in a Prospective Cohort of 18 000 adult offspring

BACKGROUND: Incidence rates of colorectal cancer (CRC) are increasing among younger adults and in mid-life, implicating exposures in early life as risk factors. We examined the association between in-utero exposure to antibiotics and risk of CRC in adult offspring. METHODS: The Child Health and Development Studies is a prospective cohort of women receiving prenatal care between 1959 and 1966 in Oakland, California, with deliveries through June 1967. Diagnosed conditions and all prescribed medications were abstracted from mothers\u27 medical records beginning 6 months prior to pregnancy through delivery. We identified mothers who received antibiotics in pregnancy, including penicillins, tetracyclines, short-acting sulfonamides and long-acting sulfonamides. Diagnoses of CRC in adult (age ≥18 years) offspring were ascertained through 2021 by linkage with the California Cancer Registry. Cox proportional models were used to estimate adjusted hazard ratios (aHR), with follow-up accrued from birth through cancer diagnosis, death or last contact. RESULTS: Of 18 751 liveborn offspring, about 15% (n = 2635) were exposed in utero to antibiotics: 5.4% (n = 1016) to tetracyclines, 4.9% (n = 918) to penicillins, 4.2% (n = 785) to short-acting sulfonamides and 1.5% (n = 273) to long-acting sulfonamides. Compared with offspring not exposed, associations between in-utero exposure and CRC in adult offspring were: aHR 1.03 (95% CI 0.32, 3.31) for tetracyclines; aHR 1.12 (95% CI 0.35, 3.58) for penicillins; aHR 0.83 (95% CI 0.20, 3.42) for short-acting sulfonamides; and aHR 4.40 (95% CI 1.63, 11.88) for long-acting sulfonamides. CONCLUSION: Our findings support an association between in-utero exposure to long-acting sulfonamides and CRC in adulthood

The Association of PNPLA3 Variants with Liver Enzymes in Childhood Obesity Is Driven by the Interaction with Abdominal Fat

BACKGROUND AND AIMS: A polymorphism in adiponutrin/patatin-like phospholipase-3 gene (PNPLA3), rs738409 C->G, encoding for the I148M variant, is the strongest genetic determinant of liver fat and ALT levels in adulthood and childhood obesity. Aims of this study were i) to analyse in a large group of obese children the role of the interaction of not-genetic factors such as BMI, waist circumference (W/Hr) and insulin resistance (HOMA-IR) in exposing the association between the I148M polymorphism and ALT levels and ii) to stratify the individual risk of these children to have liver injury on the basis of this gene-environment interaction. METHODS: 1048 Italian obese children were investigated. Anthropometric, clinical and metabolic data were collected and the PNPLA3 I148M variant genotyped. RESULTS: Children carrying the 148M allele showed higher ALT and AST levels (p = 0.000006 and p = 0.0002, respectively). Relationships between BMI-SDS, HOMA-IR and W/Hr with ALT were analysed in function of the different PNPLA3 genotypes. Children 148M homozygous showed a stronger correlation between ALT and W/Hr than those carrying the other genotypes (p: 0.0045) and, therefore, 148M homozygotes with high extent of abdominal fat (W/Hr above 0.62) had the highest OR (4.9, 95% C. I. 3.2-7.8, p = 0.00001) to develop pathologic ALT. CONCLUSIONS: We have i) showed for the first time that the magnitude of the association of PNPLA3 with liver enzymes is driven by the size of abdominal fat and ii) stratified the individual risk to develop liver damage on the basis of the interaction between the PNPLA3 genotype and abdominal fat

Correlation of body mass index with serum DDTs predicts lower risk of breast cancer before the age of 50: prospective evidence in the Child Health and Development Studies.

Many suspected breast cancer risk factors, including the pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE), are stored in fat where they could influence carcinogenesis. We tested the hypothesis that the relationship of DDT and DDE (DDTs) with adiposity is modified by disposition to develop breast cancer. We predicted that concentrations of serum DDTs would be inversely correlated with body mass index (BMI) during active exposure when DDTs move into the larger fat pool. We described this correlation at an average of 17 years before breast cancer was diagnosed, in a prospective nested case-control study in the Child Health and Development Studies. Women entered the study during pregnancy from 1959 to 1966 when DDT was in active use. In total, 133 breast cancer cases were diagnosed under the age of 50 as of 1998. Mean time to diagnosis was 17 years. In total, 133 controls were matched to cases on birth year. We observed the expected inverse correlation of serum DDTs with BMI only in women who remained cancer-free and not in women who ultimately developed breast cancer (p for interaction < 0.05). Findings suggest that vulnerability to breast cancer before the age of 50 may be associated with an uncoupling of the inverse correlation between BMI and serum DDTs. Investigation into mechanisms may eventually reveal early biomarkers of breast cancer risk