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High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, carnitine shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk., (Copyright © 2019. Published by Elsevier Inc.)

Objective: We examined the relation between maternal anthropometry and mammographic density in the adult daughter using prospectively collected data., Methods: Our study included a total of 700 mother-daughter dyads participating in an adult follow-up of women born in 2 US birth cohorts: the Child Health and Development Study and the Boston, Massachusetts, and Providence, Rhode Island sites of the National Collaborative Perinatal Project., Results: We observed an increased percent breast density at a mean age of 43.1 years in the daughters of mothers who gained 5 kg or less during pregnancy compared with mother-daughter pairs in which the mother gained 5 to 10 kg (β = 4.8, 95% confidence interval: 1.0 to 8.6). The daughters of mothers who were overweight at the time of conception (prepregnancy BMI ≥25) and who gained >5 kg during pregnancy had a lower percent density (β = -3.2, 95% confidence interval: -6.2 to -0.2) compared with mothers with a BMI <25 at conception who gained >5 kg., Conclusions: We did not find any strong and consistent patterns between maternal anthropometry and the daughter's breast density, a strong predictor of breast cancer risk. A modest association between low gestational weight gain and increased breast density 40 years later in the daughter was observed, even after accounting for adult body size, and if confirmed, possible mechanisms need to be further elucidated., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2016 by the American Academy of Pediatrics.)

Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in breast cancer risk. A cross-sectional analysis of alcohol consumption and hormone levels in 339 pregnant women sampled from the Child Health and Development Study cohort was undertaken. Alcohol intake was queried from 1959 to 1966, long before any hazards of drinking during pregnancy were publicized. Third trimester serum hormone levels including estradiol and testosterone were analyzed. Among 339 pregnant women, 196 reported some alcohol consumption during pregnancy. The drinkers were divided into three groups with intake levels of 0.2-0.5, 0.6-2.0, and 2.1-12.5 ounces of ethanol per week. The second group corresponds to a median intake of approximately 2 drinks per week, and the last group corresponds to a median intake of approximately 1 drink per day, which is considered "light" to "moderate" drinking. Maternal estradiol levels were not associated with alcohol intake during pregnancy. However, serum testosterone was significantly lower, by 12.2%, in the latter two groups of drinking pregnant women, [confidence interval (CI)=-3.0 to 25.2] and 25.6% (CI=9.2-39.5), respectively. The alcohol intakes reported are far below those shown to cause fetal alcohol syndrome, or any of the fetal alcohol effects so far studied. Light alcohol intake during pregnancy is associated with lower maternal testosterone. The health implications are uncertain, but may include an increased breast density in the daughters of drinking mothers.

BackgroundSerum DDTs during or just after pregnancy were associated with breast cancer in mothers (F0), and with breast cancer, mammographic density, and obesity in adult daughters (F1) in the Child Health and Development Studies multi-generational cohort in prior publications. Here, we investigate F0 perinatal serum DDT associations with granddaughters'(F2) measured obesity at a median age of 26 and self-reported age at menarche.MethodsF2 weight, height and waist circumference were measured by trained examiners. o,p'-DDT, p,p'-DDT and p,p'-DDE were measured in archived F0 perinatal serum. F0 DDT associations with F2 outcomes, accounting for F1 characteristics, were estimated in log-linear models adjusted for F0 and F1 body mass index (BMI), race, and menarche timing (N = 258 triads for obesity; N = 235 triads for early menarche). Interactions between F0 BMI and DDTs were estimated.ResultsF0 o,p'-DDT was associated with F2 obesity [Odds ratio (OR), 2.6; 95% confidence interval (CI), 1.3-6.7; tertile 3 vs. 1), among normal weight F0 (70%), but not among overweight and obese F0 (P interaction = 0.03), independent of other DDTs. F0 o,p'-DDT was also associated with F2 early menarche (OR, 2.1; 95% CI, 1.1-3.9, tertile 3 vs. 1) and this association was not modified by F0 BMI.ConclusionsAncestral exposure to environmental chemicals, banned decades ago, may influence the development of earlier menarche and obesity, which are established risk factors for breast cancer and cardiometabolic diseases.ImpactDiscovery of actionable biomarkers of response to ancestral environmental exposures in young women may provide opportunities for breast cancer prevention.See related commentary by Fenton and Boyles, p. 1459.

The advancement of high-resolution metabolomics (HRM) and metabolome-wide-association study (MWAS) enables the readout of environmental effects in human specimens. We used HRM to understand DDT-induced alterations of in utero environment and potential health effects. Endogenous metabolites were measured in 397 maternal perinatal serum samples collected during 1959-1967 in the Child Health and Development Studies (CHDS) and in 16 maternal postnatal serum samples of mice treated with or without DDT. MWAS was performed to assess associations between metabolites and p,p'-DDT, o,p'-DDT and p,p'-DDE levels, followed by pathway analysis. Distinct metabolic profiles were found with p,p'-DDT and p,p'-DDE. Amino acids such arginine had a strong association with p,p'-DDT and o,p'-DDT in both women and mice, whereas lipids and acyl-carnitine intermediates were found exclusively associated with p,p'-DDE in CHDS women indicating mitochondrial impairment. It suggests that the role of serine and fatty acid metabolism on the causal disease pathway should be examined.

The authors examined the relationship of prepregnancy body mass index (BMI) and gestational weight gain (GWG) with child neurodevelopment. Mother-child dyads were a subgroup (n = 2,084) of the Child Health and Development Studies from the Oakland, California, area enrolled during pregnancy from 1959 to 1966 and followed at child age 9 years. Linear regression was used to examine associations between prepregnancy BMI, GWG, and standardized Peabody Picture Vocabulary Test and Raven Progressive Matrices scores and to evaluate effect modification of GWG by prepregnancy BMI. Before pregnancy, 77% of women were normal weight, 8% were underweight, 11% were overweight, and 3% were obese. Associations between GWG and child outcomes did not vary by prepregnancy BMI, suggesting no evidence for interaction. In multivariable models, compared to normal prepregnancy BMI, prepregnancy overweight and obesity were associated with lower Peabody scores (b: -1.29; 95% CI [-2.6, -0.04] and b: -2.7; 95% CI [-5.0, -0.32], respectively). GWG was not associated with child Peabody score [b: -0.03 (95% CI: -0.13, 0.07)]. Maternal BMI and GWG were not associated with child Raven score (all P >0.05). Maternal prepregnancy overweight and obesity were associated with lower scores for verbal recognition in mid-childhood. These results contribute to evidence linking maternal BMI with child neurodevelopment. Future research should examine the role of higher prepregnancy BMI values and the pattern of pregnancy weight gain in child cognitive outcomes.

ContextCurrently no direct evidence links in utero dichlorodiphenyltrichloroethane (DDT) exposure to human breast cancer. However, in utero exposure to another xenoestrogen, diethylstilbestrol, predicts an increased breast cancer risk. If this finding extends to DDT, it could have far-reaching consequences. Many women were heavily exposed in utero during widespread DDT use in the 1960s. They are now reaching the age of heightened breast cancer risk. DDT exposure persists and use continues in Africa and Asia without clear knowledge of the consequences for the next generation.HypothesisIn utero exposure to DDT is associated with an increased risk of breast cancer.DesignThis was a case-control study nested in a prospective 54-year follow-up of 9300 daughters in the Child Health and Development Studies pregnancy cohort (n = 118 breast cancer cases, diagnosed by age 52 y and 354 controls matched on birth year).Setting and participantsKaiser Foundation Health Plan members who received obstetric care in Alameda County, California, from 1959 to 1967, and their adult daughters participated in the study.Main outcome measureDaughters' breast cancer diagnosed by age 52 years as of 2012 was measured.ResultsMaternal o,p'-DDT predicted daughters' breast cancer (odds ratio fourth quartile vs first = 3.7, 95% confidence interval 1.5-9.0). Mothers' lipids, weight, race, age, and breast cancer history did not explain the findings.ConclusionsThis prospective human study links measured DDT exposure in utero to risk of breast cancer. Experimental studies are essential to confirm results and discover causal mechanisms. Findings support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk.

Menstrual irregularity has been associated with insulin resistance, type 2 diabetes mellitus and markers of metabolic dysfunction. This study aimed to determine whether irregular menstrual cycles (MCs) in reproductive-age women are associated with the weight of their daughters at birth and growth up to age five. We studied 4863 pregnant women with menstrual history data in a prospective cohort, recruited from the Kaiser Health Plan (1959-1966). Serial measures of their daughters' weight and height were abstracted from medical records. We used analysis of covariance, stratified by maternal body mass index, to explore the association between maternal MC and infant birth weight (BW). We included 4774 daughters in a repeated measures analysis to compare the effect of maternal MC on childhood weight through age five. Daughters of non-obese women with irregular MC had a statistically significant lower BW compared to daughters of women with regular MC; this difference was notably amplified among obese women. The daughters' weights were not statistically different when growth was assessed from birth to five years. We conclude that daughters of obese women with irregular MC, in particular, had significantly lower BW compared to daughters of women with regular MC, which did not persist over five years of follow-up.

BackgroundElevated 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.ObjectivesWe assessed whether prenatal exposure to the pesticide DDT increases risk of adult hypertension.MethodsWe 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.ResultsPrenatal 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.ConclusionsThese findings suggest that the association between DDT exposure and hypertension may have its origins early in development.

• Third trimester maternal serum estriol was directly associated with daughters' DHEAS in young adulthood • Rapid weight gain from ages 5–9 was also directly associated with DHEAS in young adulthood. • Adrenal function in young adulthood may be programmed in utero and middle childhood with adult health consequences Fetal adrenal-derived OH-DHEAS is the primary precursor for maternal estriol, an abundant, human, placental estrogen. We measured maternal pregnancy estriol as a marker of fetal adrenal function + placenta capacity to synthesize estriol. We hypothesized that maternal estriol is directly correlated with the adrenal hormone, DHEAS, in young adult women. We tested this hypothesis in a subset of women in the Child Health and Development Studies (351 of 470 eligible). 176 of these had serum samples collected at ages 27–30 for DHEAS assays, archived maternal pregnancy serum for estriol assays, and childhood growth data. In regression analyses, both maternal estriol and accelerated growth in middle childhood were independently, directly associated with DHEAS (+19% for quartile 4 versus quartile 1 of estriol, 95%CI=+ 2%, +36% and +12% for quartile 4 versus quartile 1 for middle childhood growth, 95%CI= +3%, +21%). Adrenal function may be programmed in utero and middle childhood with long-term consequences. [ABSTRACT FROM AUTHOR]

Background: In a previous Child Health and Development Studies report, p, p'-DDT was associated with a fivefold increased risk of premenopausal (before age 50 years) breast cancer for women first exposed before puberty. Here we extend our observation to breast cancer diagnosed during early postmenopause (ages 50-54 years) to determine whether age at diagnosis modifies the interaction of DDT with age at exposure.Methods: We conducted a second prospective, nested case-control study in the Child Health and Development Studies (153 incident breast cancer cases diagnosed at ages 50-54 years and 432 controls matched to cases on birth year). These were analyzed separately and pooled with our previous study (129 breast cancer cases diagnosed at ages 31-49 years and 129 controls matched on birth year). Blood samples were obtained during pregnancy (median age, 26 years), 1-3 days after delivery from 1959 to 1967 in Oakland, California. Serum was assayed for p, p'-DDT, o, p'-DDT, and p, p'-DDE. Odds ratios (ORs) below are given for doubling of serum p, p'-DDT. All statistical tests were two-sided.Results: For early postmenopausal breast cancer, p, p'-DDT was associated with risk for all women (ORDDT 50-54 = 1.99, 95% CI = 1.48 to 2.67). This association was accounted for by women first exposed to DDT after infancy (ORDDT 50-54 for first exposure after infancy = 2.83, 95% CI = 1.96 to 4.10 vs ORDDT 50-54 for first exposure during infancy = 0.56, 95% CI = 0.26 to 1.19; Pinteraction DDT x age at first exposure = .01). In contrast, for premenopausal breast cancer, p, p'-DDT was associated with risk among women first exposed during infancy through puberty, but not after (ORDDT<50 for first exposure during infancy = 3.70, 95% CI = 1.22 to 11.26, Pinteraction DDT x age at first exposure x age at diagnosis = .03).Conclusions: p, p'-DDT was associated with breast cancer through age 54 years. Risk depended on timing of first exposure and diagnosis age, suggesting susceptibility windows and an induction period beginning in early life. DDT appears to be an endocrine disruptor with responsive breast targets from in utero to menopause. [ABSTRACT FROM AUTHOR]

Observational evidence suggests that adult body size has its roots earlier in life, yet few life-course studies have data on siblings with which to control for family-level confounding. Using prospective data from the Early Determinants of Mammographic Density Study (n = 1,108; 1959-2008), we examined the association of maternal prepregnancy body mass index (BMI; weight (kg)/height (m)²), gestational weight gain (GWG), birth size, and childhood growth factors with adult BMI in daughters at midlife using quantile, linear, and logistic regression models. We compared overall cohort findings (n = 1,108) with sibling differences (n = 246 sibling sets). Results derived by all 3 regression methods supported positive and independent associations of prepregnancy BMI, GWG, and percentile change in early childhood growth with BMI in daughters at midlife. Sibling analyses demonstrated that higher GWG was independently related to a higher adult BMI in daughters, particularly for the highest 90th quantile of adult BMI (β = 0.64 (standard error, 0.26) BMI units). Greater increases in weight percentiles between 1 and 4 years of age within siblings were also associated with higher adult BMI in the 75th quantile (β = 0.06 (standard error, 0.03) kg). Thus, even after consideration of the role of family-level fixed effects, maternal GWG and childhood weight gain are associated with adult body size in midlife. body mass index; catch-up growth; gestational weight gain; life course; obesity [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated the combination of pregnancy complications that predict risk for cardiovascular disease (CVD) death and how risk changes with age. This report presents a comprehensive investigation of the relation of the occurrence of multiple pregnancy complications to CVD death over 5 decades in a large pregnancy cohort.Methods and Results: We examined pregnancy events (1959-1967) and CVD death through 2011 in 14 062 women from the Child Health and Development Studies. CVD death was determined by linkage to California Vital Statistics and National Death Index. Women were a median age of 26 years at enrollment and 66 years in 2011. Preexisting hypertension (hazard ratio, 3.5; 95% confidence interval, 2.4-5.1); glycosuria (hazard ratio, 4.2; confidence interval, 1.3-13.1); late-onset preeclampsia (after week 34, hazard ratio, 2.0; confidence interval, 1.2-3.5); and hemoglobin decline over the second and third trimesters (hazard ratio, 1.7; confidence interval, 1.2-2.7) predicted CVD death. Delivery of a small-for-gestation or preterm infant and early-onset preeclampsia (by week 34) significantly predicted premature CVD death (P<0.05 for age dependence). Preterm birth combined with hemorrhage, gestational hypertension, or preexisting hypertension identified women with a 4- to 7-fold increased risk of CVD death. Preeclampsia in combination with preexisting hypertension conferred a significant nearly 6-fold risk in comparison with a 4-fold risk for preexisting hypertension alone.Conclusions: We observed combinations of pregnancy complications that predict high risk of death and 2 new risk markers, glycosuria and hemoglobin decline. Obstetricians serve as primary care physicians for many young women and can readily use these complications to identify high-risk women to implement early prevention. [ABSTRACT FROM AUTHOR]

Background: Polychlorinated biphenyls (PCBs), known endocrine disruptors, were banned in 1979 but persist in the environment. Previous studies are inconsistent regarding prenatal exposure to PCBs and pregnancy outcomes. We investigated associations between prenatal exposure to PCBs and gestational length and birth weight. Methods: In a sample of 600 infants (born between 1960 and 1963) randomly selected from Child Health and Development Studies participants followed through adolescence we measured 11 PCB congeners in maternal post partum sera (within three days of delivery). Length of gestation was computed from the reported first day of the last menstrual period (LMP) and delivery date. Linear regression was used to estimate associations between PCB exposure and gestational age and birth weight, adjusting for potential confounders. PCBs were grouped according to hypothesized biological action (1b (sum of weak phenobarbital inducers), 2b (sum of limited dioxin activity), and 3 (sum of CYP1A and CYP2b inducers)) or degree of ortho- substitution (mono, di, tri). Secondary analyses examined associations between total PCB exposure and exposure to individual congeners. Results: Each unit increase in mono-ortho substituted PCBs was associated with a 0.30 week decrease (95% confidence interval (CI) -0.59, -0.016), corresponding to a 2.1 (95% CI −4.13, -0.11) day decrease in length of gestation. Similar associations were estimated for di-ortho substituted PCBs, (1.4 day decrease; (95% CI −2.9, 0.1)) and group 3 PCBs (0.84 day decrease; (95% CI −1.8, 0.11). We found similar associations in congener specific analyses and for the sum of congeners. Conclusions: Our study provides new evidence that PCB exposure shortens length of gestation in humans. This may have public health implications for population exposures. [ABSTRACT FROM AUTHOR]

Abstract: More than 20 studies of serum “DDT” and breast cancer have found little support for the hypothesis that exposure influences risk of breast cancer. However, studies share common limitations including the inability to account for exposure in early life when the breast may be most vulnerable and the inability to measure exposure to the primary components of commercial DDT. This paper (1) summarizes evidence regarding critical windows of exposure for breast cancer (2) summarizes lessons learned from initial efforts to study DDT and breast cancer (3) reviews evidence from the Child Health and Development Studies (CHDS) where exposure was measured in young women using blood samples obtained during active exposure, 1–3 days after delivery and (4) suggests approaches for human studies that might advance understanding of environmental stressors in the developmental origins of disease. [Copyright &y& Elsevier]

Abstract: Developmental exposure to polychlorinated biphenyls (PCBs) disrupts reproduction in animals. Human data are lacking. We measured PCBs in preserved mothers’ serum samples collected during 1960–1963, 1–3 days after their daughters’ birth. We recorded time to pregnancy (TTP) in 289 daughters 28–31 years later. PCB congeners 187, 156, and 99 in mother''s serum were associated with longer TTP in their daughters while PCB congeners 105, 138 and 183 were associated shorter TTP. Probability of pregnancy fell by 38% (95% CI 17–53%) and infertility was higher (30% not pregnant after 13 cycles versus 11% not pregnant after 13 cycles) among women whose mothers had a higher proportion of PCB congeners associated with longer TTP (75th percentile versus 25th percentile). This study demonstrates, for the first time, that developmental exposure to PCBs may disrupt pregnancy in humans. [Copyright &y& Elsevier]

Abstract: It has been suggested that increased risk for testicular cancer occurring worldwide may be due to exposures during fetal development. Lifestyle or environmental exposures may be the most important predictors of risk. However, few studies have directly examined these exposures prospectively. The Child Health and Development Studies is a 40-year follow-up of 20,530 pregnancies occurring between 1959 and 1967. There were 20 cases of testicular cancer diagnosed through 2003 among sons with a maternal interview in early pregnancy. Cases were matched to three controls on birth year and race. Odds ratios and 95% confidence intervals were calculated with exact conditional logistic regression. Compared to controls, mothers of testicular cancer cases were more likely to drink alcohol (unadjusted odds ratio, 3.2; 95% confidence interval, 0.83–15.48 for above vs. below the median for controls) and less likely to drink coffee (unadjusted odds ratio, 0.19; 95% confidence interval, 0.02–1.02 for above vs. below the median). Case mothers were neither more nor less likely to smoke. Although low power may limit interpretation of negative results, the prospective design minimizes bias. In this cohort, maternal serum testosterone in pregnancy was previously reported to be lower in women who drank alcohol. Because populations with high testicular cancer risk also have lower maternal testosterone, we suggest that testosterone could play a role in explaining the higher risk of son''s testicular cancer among mothers who drank alcohol during pregnancy. [Copyright &y& Elsevier]

Few empirical data exist on the characteristics of subjects who provide semen specimens in epidemiologic studies. The objective of this investigation was to determine participation rates and potential biases in a contemporary study of human semen quality. Subjects (n = 268) are a subset of the Child Health and Development Studies. Their mothers enrolled between 1960 and 1963 during pregnancy. Archived prenatal serum samples, prenatal and birth records, placental examinations, and follow-up for growth and development through adulthood are available. Sons were aged 36-39 years at the time of this study. Respondents to the initial mailing and nonrespondents, who were subsequently traced and recruited, differed in semen parameters, including sperm concentration (78.3 x 106/ml for respondents vs. 37.2; p = 0.003) and the percentage of normal morphology according to the 1987 criteria of the World Health Organization (58.7% for respondents vs. 53.3%; p = 0.04). The authors conclude that researchers designing population-based studies of semen parameters should expect nonrepresentative samples. Adaptation of the design to anticipate and mitigate bias and to maximize efficiency can yield scientifically sound information. Recommendations for study designs are discussed. Am J Epidemiol 2002;155:664-71. [ABSTRACT FROM AUTHOR]

• Lower childhood PPVT performance predicted higher adolescent depressive symptoms. • Higher T2 IL1-RA was associated with lower childhood PPVT performance. • Higher T2 IL-6 was associated with greater adolescent depressive symptoms. • Partial mediation of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT performance. • No T1 findings nor any significant associations with T2 sTNF-RII and IL-8. Accumulating evidence indicates that higher prenatal maternal inflammation is associated with increased depression risk in adolescent and adult-aged offspring. Prenatal maternal inflammation (PNMI) may increase the likelihood for offspring to have lower cognitive performance, which, in turn, may heighten risk for depression onset. Therefore, this study explored the potential mediating role of childhood cognitive performance in the relationship between PNMI and adolescent depressive symptoms in offspring. Participants included 696 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Biomarkers of maternal inflammation [interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptor-II (sTNF-RII)] were assayed from first (T1) and second trimester (T2) sera. Childhood (ages 9–11) cognitive performance was assessed via standardized Peabody Picture Vocabulary Test (PPVT), a measure of receptive vocabulary correlated with general intelligence. Adolescent (ages 15–17) depressive symptoms were assessed via self-report. There were no significant associations between T1 biomarkers and childhood PPVT or adolescent depressive symptoms. Higher T2 IL1-RA was directly associated with lower childhood PPVT (b = -0.21, SE = 0.08, t = -2.55, p = 0.01), but not with adolescent depressive symptoms. T2 IL-6 was not directly associated with childhood PPVT, but higher T2 IL-6 was directly associated at borderline significance with greater depressive symptoms in adolescence (b = 0.05, SE = 0.03, t = 1.96, p = 0.05). Lower childhood PPVT predicted significantly higher adolescent depressive symptoms (b = -0.07, SE = 0.02, t = -2.99, p < 0.01). There was a significant indirect effect of T2 IL-1RA on adolescent depressive symptoms via childhood PPVT (b = 0.03, 95 % CI = 0.002–0.03) indicating a partially mediated effect. No significant associations were found with T2 sTNF-RII nor IL-8. Lower childhood cognitive performance, such as that indicated by a lower PPVT score, represents a potential mechanism through which prenatal maternal inflammation contributes to adolescent depression risk in offspring. [ABSTRACT FROM AUTHOR]

Maternal infection during pregnancy has been associated with increased risk of offspring psychopathology, including depression. As most infections do not cross the placenta, maternal immune responses to infection have been considered as potentially contributing to this relationship. This study examined whether gestational timing of maternal inflammation during pregnancy is associated with offspring internalizing and/or externalizing symptoms during childhood and, further, whether fetal sex moderated this relationship. Participants were 737 pregnant women and their offspring who were continuously followed through late childhood. Archived first and second trimester sera were analyzed for markers of inflammation [interleukin 8 (IL-8), IL-6, IL-1 receptor antagonist (IL-1ra), and soluble tumor necrosis factor receptor-II (sTNF-RII)]. When offspring were aged 9–11, mothers completed a questionnaire assessing psychological symptoms. Multivariate regression analyses indicated that elevated IL-8 in the first trimester was associated with significantly higher levels of externalizing symptoms in offspring. Higher IL-1ra in the second trimester was associated with higher offspring internalizing symptoms. Further, second trimester IL-1ra was associated with increased internalizing symptoms in females only. These findings demonstrate that elevated maternal inflammation during pregnancy is associated with the emergence of separate psychological phenotypes and that timing of exposure and fetal sex matter for offspring outcomes. Given that internalizing and externalizing symptoms in childhood increase risk for a variety of mental disorders later in development, these findings potentially have major implications for early intervention and prevention work. [ABSTRACT FROM AUTHOR]

Breast cancer is now the most common cancer globally, accounting for 12% of all new annual cancer cases worldwide. Despite epidemiologic studies having established a number of risk factors, knowledge of chemical exposure risks is limited to a relatively small number of chemicals. In this exposome research study, we used non-targeted, high-resolution mass spectrometry of pregnancy cohort biospecimens in the Child Health and Development Studies to test for associations with breast cancer identified via the California Cancer Registry. Second and third trimester archival samples were analyzed from 182 women who subsequently developed breast cancer and 384 randomly selected women who did not develop breast cancer. Environmental chemicals were annotated with the Toxin and Toxin-Target Database for chemical signals that were higher in breast cancer cases and used with an exposome epidemiology analytic framework to identify suspect chemicals and associated metabolic networks. Network and pathway enrichment analyses showed consistent linkage in both second and third trimesters to inflammation pathways, including linoleate, arachidonic acid and prostaglandins, and identified new suspect environmental chemicals associated with breast cancer, i.e., an N-substituted piperidine insecticide and a common commercial product, 2,4-dinitrophenol, linked to variations in amino acid and nucleotide pathways in second trimester and benzo[a]carbazole and a benzoate derivative linked to glycan and amino sugar metabolism in third trimester. The results identify new suspect environmental chemical risk factors for breast cancer and provide an exposome epidemiology framework for discovery of suspect environmental chemicals and potential mechanistic associations with breast cancer. [ABSTRACT FROM AUTHOR]

Purpose: Studies suggests that intrauterine exposure to maternal smoking both accelerates or delays age at menarche. We hypothesize that these opposing findings relate to different infant and childhood growth patterns across cohorts.Methods: Using data from an adult follow-up study of the Child Health and Development Studies and the National Collaborative Perinatal Project, we examined, using generalized estimating linear regression models, whether intrauterine exposure to maternal smoking was associated with age at menarche in 1090 daughters before and after accounting for growth in weight.Results: Compared to the nonexposed, intrauterine exposure to maternal smoking was associated with a 4-month acceleration in menarche in the National Collaborative Perinatal Project (β = -0.35 years; 95% confidence interval [CI]: -0.63, -0.08), but a 6-month delay in menarche in the Child Health and Development Studies (β = 0.48 years; 95% CI: 0.13, 0.83), despite having a similar reduction in birth weight in both cohorts (∼300 g). The results were more consistent across cohorts when we stratified by postnatal growth patterns. For example, in those with rapid weight gain (increasing two growth references from 0 to 4 years), intrauterine exposure to maternal smoking was related to a 7-month acceleration in menarche (β = -0.56 years; 95% CI: -0.95, -0.17).Conclusions: These findings suggest that the association of intrauterine exposure to maternal smoking on age at menarche depends on postnatal growth patterns. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]