Critical Windows Of Susceptibility Research Articles

Breast composition during and after puberty: the Chilean Growth and Obesity Cohort Study

BackgroundBreast density (BD) is a strong risk factor for breast cancer. Little is known about how BD develops during puberty. Understanding BD trajectories during puberty and its determinants could be crucial for promoting preventive actions against breast cancer (BC) at early ages. The objective of this research is to characterize % fibroglandular volume (%FGV), absolute fibroglandular volume (AFGV), and breast volume (BV) at different breast Tanner stages until 4-year post menarche in a Latino cohort and to assess determinants of high %FGV and AFGV during puberty and in a fully mature breast.MethodsThis is a longitudinal follow-up of 509 girls from low-middle socioeconomic status of the Southeast area of Santiago, recruited at a mean age of 3.5 years. The inclusion criteria were singleton birth born, birthweight between 2500 and 4500 g with no medical or mental disorder. A trained dietitian measured weight and height since 3.5 years old and sexual maturation from 8 years old (breast Tanner stages and age at menarche onset). Using standardized methods, BD was measured using dual-energy X-ray absorptiometry (DXA) in various developmental periods (breast Tanner stage B1 until 4 years after menarche onset).ResultsIn the 509 girls, we collected 1,442 breast DXA scans; the mean age at Tanner B4 was 11.3 years. %FGV increased across breast Tanner stages and peaked 250 days after menarche. AFGV and BV peaked 2 years after menarche onset. Girls in the highest quartiles of %FGV, AFGV, and BV at Tanner B4 and B5 before menarche onset had the highest values thereafter until 4 years after menarche onset. The most important determinants of %FGV and AFGV variability were BMI z-score (R2 = 44%) and time since menarche (R2 = 42%), respectively.ConclusionWe characterize the breast development during puberty, a critical window of susceptibility. Although the onset of menarche is a key milestone for breast development, we observed that girls in the highest quartiles of %FGV and AFGV tracked in that group afterwards. Following these participants in adulthood would be of interest to understand the changes in breast composition during this period and its potential link with BC risk.

Role of antenatal anxiety in the relationship between maternal exposure to nitrogen dioxide and small for gestational age: A birth cohort study

BackgroundBoth Nitrogen dioxide (NO2) exposure and antenatal anxiety have individually been associated with small for gestational age (SGA). Little is known, however, about whether there is effect modification of antenatal anxiety on NO2-related SGA. MethodsThe prospective birth cohort study included 1823 mother-newborn pairs in Guangzhou, China, from January 2017 to April 2020. Exposure to NO2 during the pre-conceptional and prenatal periods was estimated using an inverse distance weighted method. Antenatal anxiety was assessed by Trait Anxiety Inventory. SGA was determined by the Chinese gestational age- and sex-specific birthweight standards. Cox proportional hazards regression models was used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for SGA as per 10 μg/m3 increase in NO2. Modifying effects of trait anxiety on NO2-related SGA were identified by stratified analyses, and three-dimensional response surface plots and two-dimensional heat maps. ResultsEach 10 μg/m3 increase in NO2 exposure during the third trimester was significantly associated with SGA risk among overall participants (HR = 1.221, 95 % CI: 1.014–1.471) and primipara (HR = 1.271, 95 % CI: 1.023–1.579). We found significant effect modification of anxiety level for NO2-related SGA in the third trimester (Pinteraction < 0.05). Pregnant women with higher levels of trait anxiety were more likely to deliver SGA newborns, particularly for those with high trait anxiety (HR = 1.781, 95 % CI: 1.007–2.945). Primiparous women were more susceptible. ConclusionsThis study provides evidence that antenatal trait anxiety may modify the effects of maternal NO2 exposure on SGA risk. The third trimester could be a critical window of susceptibility.

Trace analysis of per- and polyfluorinated alkyl substances (PFAS) in dried blood spots – Demonstration of reproducibility and comparability to venous blood samples

Per- and polyfluoroalkyl substances (PFAS) are a group of man-made chemicals that have been widely used in consumer, personal care, and household products for their stain- and water-repellent properties. PFAS exposure has been linked to various adverse health outcomes. Such exposure has commonly been evaluated in venous blood samples. While this sample type can be obtained from healthy adults, a less invasive method of blood collection is required when evaluating vulnerable populations. Dried blood spots (DBS) have gained attention as a biomatrix for exposure assessment given the relative ease of collection, transport, and storage. The objective of this study was to develop and validate an analytical method to measure PFAS in DBS. A workflow is presented for extracting PFAS from DBS, chemical analysis by liquid chromatography-high resolution mass spectrometry, normalization for blood mass, and blank correction to account for potential contamination. Over 80 % recovery was achieved for the 22 PFAS measured with an average coefficient of variation of 14 %. Comparison of PFAS concentrations detected in DBS and paired whole blood samples from six healthy adults was correlated (R2 > 0.9). Findings demonstrate trace levels of a broad range of PFAS in DBS can be reproducibly measured and are comparable to liquid whole blood samples. DBS can offer novel insights to environmental exposures, including during critical windows of susceptibility (i.e., in utero, early life), which have been largely uncharacterized.

Perinatal exposure to foodborne inorganic nanoparticles: A role in the susceptibility to food allergy?

Food allergy (FA) is an inappropriate immune response against dietary antigens. Various environmental factors during perinatal life may alter the establishment of intestinal homeostasis, thereby predisposing individuals to the development of such immune-related diseases. Among these factors, recent studies have emphasized the chronic dietary exposure of the mother to foodborne inorganic nanoparticles (NP) such as nano-sized silicon dioxide (SiO2), titanium dioxide (TiO2) or silver (Ag). Indeed, there is growing evidence that these inorganic agents, used as food additives in various products, as processing aids during food manufacturing or in food contact materials, can cross the placental barrier and reach the developing fetus. Excretion in milk is also suggested, hence continuing to expose the neonate during a critical window of susceptibility. Due to their immunotoxical and biocidal properties, such exposure may disrupt the host-intestinal microbiota's beneficial exchanges and may interfere with intestinal barrier and gut-associated immune system development in fetuses then the neonates. The resulting dysregulated intestinal homeostasis in the infant may significantly impede the induction of oral tolerance, a crucial process of immune unresponsiveness to food antigens. The current review focuses on the possible impacts of perinatal exposure to foodborne NP during pregnancy and early life on the susceptibility to developing FA.

Low and High Ambient Temperatures during Pregnancy and Birth Weight among 624,940 Singleton Term Births in Israel (2010–2014): An Investigation of Potential Windows of Susceptibility

Background:Exposure to heat during pregnancy has been associated with reduced fetal growth. Less is known about associations with cold and the potential for critical time windows of exposure.Objectives:We aimed to evaluate, in a national retrospective cohort, critical windows of susceptibility during pregnancy to extreme temperatures (low and high) and fetal growth, among 624,940 singleton term births in Israel during the period 2010–2014.Methods:Temperature exposures were estimated using a spatially refined gridded climate data set with a 1-h and resolution. Percentiles of temperature were categorized by climatic zone for the entire pregnancy and by trimesters and weeks. Generalized additive models with the distributed lag nonlinear model framework were used to estimate unadjusted and adjusted associations between percentiles and categories of temperature and fetal growth markers: term [births after 36 weeks of gestational age (GA)] mean birth weight and term low birth weight (tLBW, term infants with birth weight below ).Results:After adjustment, extreme temperatures (percentiles) during the entire pregnancy were associated with a lower mean birth weight { vs. 41st–50th percentile: [95% confidence interval (CI): , )]; vs. 41st–50th percentile: ; 95% CI: , }. Similar inverse U-shaped patterns were observed for all trimesters, with stronger associations for heat than for cold and for exposures during the third trimester. For heat, results suggest critical windows between 3–9 and 19–34 GA-weeks, with the strongest association estimated at 3 GA-weeks (temperature vs. 41st–50th percentiles: ; 95% CI: , ). For cold, there was a consistent trend of null associations early in pregnancy and stronger inverse associations over time, with the strongest association at 36 GA-week ( vs. 41st–50th percentiles: ; 95% CI: , ). For tLBW, U-shape patterns were estimated for the entire pregnancy and third trimester exposures, as well as nonsignificant associations with heat for 29–36 GA-weeks. Generally, the patterns of associations with temperatures during the entire pregnancy were consistent when stratified by urbanicity and geocoding hierarchy, when estimated for daily minimum and maximum temperatures, when exposures were classified based on temperature distributions in 49 natural regions, and when estimated for all live births.Discussion:Findings from our study of term live births in Israel (2010–2014) suggest that exposure to extreme temperatures, especially heat, during specific time windows may result in reduced fetal growth. https://doi.org/10.1289/EHP8117

Critical windows of susceptibility in the association between manganese and neurocognition in Italian adolescents living near ferro-manganese industry

IntroductionUnderstanding the neurodevelopmental effects of manganese (Mn) is complicated due to its essentiality for growth and development. While evidence exists for the harmful effects of excess Mn, pediatric epidemiologic studies have observed inconsistent associations between Mn and child cognition. ObjectiveWe sought to estimate prospective associations between Mn measured in three different early-life time windows with adolescent cognition using deciduous teeth biomarkers. MethodsDeciduous teeth were collected from 195 participants (ages 10–14 years) of the Public Health Impact of Manganese Exposure (PHIME) study in Brescia, Italy. Measurements of tooth Mn represented prenatal (∼14 weeks gestation – birth), early postnatal (birth – 1.5 years) and childhood (∼1.5 – 6 years) time windows. Neuropsychologists administered the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), to obtain composite IQ and subtest scores. Associations between tooth Mn at each time window and adolescent WISC-III scores were estimated using multivariable linear regression. We tested differences in associations between Mn and outcomes across time windows using multiple informant models. Sex-specific associations were explored in stratified models. ResultsAdjusted associations between tooth Mn and composite IQ scores were positive in the prenatal period and negative in the childhood period. Associations were strongest for subtest scores that reflect working memory, problem solving, visuospatial ability and attention: prenatal Mn was positively associated with Digits backward [SD change in score per interquartile range increase in Mn: β = 0.20 (95 % CI: 0.02, 0.38)] and Block design [β = 0.21 (0.01, 0.41)] and early postnatal Mn was positively associated with Digits forward [β = 0.24 (0.09, 0.40)], while childhood Mn was negatively associated with Coding [β = -0.14 (-0.28, -0.001)]. Sex-stratified analyses suggested different Mn-cognition associations for boys and girls and was also dependent on the time window of exposure. ConclusionOur results suggest that exposure timing is critical when evaluating Mn associations between Mn and cognition. Higher prenatal Mn was beneficial for adolescent cognition; however, these beneficial associations shifted towards harmful effects in later time windows. Cognitive domains most sensitive to Mn across time windows included visuospatial ability, working memory, attention and problem-solving.

The effect of prenatal temperature and PM2.5 exposure on birthweight: weekly windows of exposure throughout the pregnancy

BACKGROUND AND AIM: Birthweight is a strong predictor of normal growth, healthy development, and survival. Several studies have found associations between temperature, fine particulate matter (PM2.5), and birth weight. However, the relevant timing of exposures varies between studies and is yet unclear. Therefore, we assessed the difference in term birthweight (TBW) associated with weekly exposure to temperature and PM2.5 throughout 37 weeks of gestation. METHODS: We included all singleton live term births in Massachusetts, U.S between 2004 and 2015 (n=712,438). Weekly PM2.5 and temperature predictions were estimated on a 1 km grid from satellite-based models. We utilized a distributed lag nonlinear model (DLNM) to estimate the difference in TBW associated with weekly exposures to PM2.5 and temperature simultaneously from the last menstrual period to 37 weeks of gestation. RESULTS:We found a nonlinear association with temperature exposure. We observed positive differences in TBW associated with rises of colder temperatures (2.6g increase, 95% CI 0.1g; 5.1g, for one ºC increase from -4 ºC) and negative difference in TBW associated with rises of warmer temperatures (7.9g decrease, 95% CI -11.2g; -4.6g, for one ºC increase from 23 ºC). Temperature effects were larger in the first and final weeks of gestation. We observed a negative difference in TBW associated with PM2.5 exposure. Overall, one µg/m3 increase in prenatal exposure was associated with 3.9g lower TBW (95% CI -5.0g; -2.9g). PM2.5 effects were larger in the final weeks of gestation. CONCLUSIONS:We found heat and PM2.5 exposure to be related to lower TBW. Our findings suggest that women are more susceptible to both exposures towards the end of pregnancy. Susceptibility to heat was higher in the initial weeks of pregnancy as well. These critical windows of susceptibility can be communicated to pregnant women during routine prenatal visits to increase awareness and target interventions to reduce exposures. KEYWORDS: birthweight, temperature, air pollution, birth outcomes

The Hidden Danger of Environmental Chemicals during the “Windows of Susceptibility” in a Woman’s Life – How can we use Intermediate Biomarkers to Improve Breast Cancer Prevention?

Introduction: It has been observed that many toxic environmental agents increase risk, accelerate development, or deteriorate the course of breast cancer (BC). In particular, endocrine-disrupting chemicals (EDC) are harmful to endocrine receptor actions and signaling in the breast tissue. Usually, there is a long interval of time between the exposure to EDC and BC incidence, and this often represents a serious obstacle for effective BC prophylaxis. Notably, during certain periods of a woman’s life cycle, the BC risk is particularly elevated due to increased susceptibility to some EDC. These windows of susceptibility (WOS) include prenatal, puberty, pregnancy, and menopausal transition stages of a female’s life course. Four WOS have been considered as the most vulnerable periods for BC since the mammary gland undergoes the main anatomical and physiological transformations at those intervals. This means that during specific WOS, the EDC from the environment can have the most dangerous impact on BC risk and possible BC development later in a woman’s life. However, most clinical BC studies related to toxic environmental exposures have not been connected to the specific WOS. Therefore, the goal of this article is to briefly describe some important research results, focused on the links between EDC and BC, within four critical WOS. In addition, this mini-review outlines some useful biomarkers for further research and prophylaxis of BC and also for both the research community and the medical professionals. Conclusion: To bridge the gap in BC prevention, it is essential to recognize the links between EDC and BC within the critical WOS. Moreover, an integrative model of BC research, applying intermediate biomarkers, is necessary to determine the mechanisms of action of various EDC during critical periods in a woman’s lifespan. Hopefully, this will lead to progress in BC prevention.

The effect of prenatal temperature and PM2.5 exposure on birthweight: Weekly windows of exposure throughout the pregnancy

BackgroundBirthweight is a strong predictor of normal growth, healthy development, and survival. Several studies have found associations between temperature, fine particulate matter (PM2.5), and birth weight. However, the relevant timing of exposures varies between studies and is yet unclear. Therefore, we assessed the difference in term birthweight (TBW) associated with weekly exposure to temperature and PM2.5 throughout 37 weeks of gestation. MethodsWe included all singleton live term births in Massachusetts, U.S between 2004 and 2015 (n = 712,438). Weekly PM2.5 and temperature predictions were estimated on a 1 km grid from satellite-based models. We utilized a distributed lag nonlinear model (DLNM) to estimate the difference in TBW associated with weekly exposures from the last menstrual period to 37 weeks of gestation. ResultsWe found a nonlinear association with prenatal temperature exposure. Larger effects were observed in warmer temperatures, where higher temperatures were negatively associated with TBW. Temperature effects were larger in the first and final weeks of gestation. We observed a negative difference in TBW associated with PM2.5 exposure. Overall, a 1 µg/m3 increase in prenatal exposure was associated with 3.9 g lower TBW (95% CI −5.0 g; −2.9 g). PM2.5 effects were larger in the final weeks of gestation. ConclusionWe found heat and PM2.5 exposure to be related to lower TBW. Our findings suggest that women are more susceptible to both exposures towards the end of pregnancy. Susceptibility to heat was higher in the initial weeks of pregnancy as well. These critical windows of susceptibility can be communicated to pregnant women during routine prenatal visits to increase awareness and target interventions to reduce exposures.

Recommendations for Assessment of Environmental Exposures in Longitudinal Life Course Studies Such as the National Children's Study.

An important step toward understanding the relationship between the environment and child health and development is the comprehensive cataloging of external environmental factors that may modify health and development over the life course. Our understanding of the environmental influences on health is growing increasingly complex. Significant key questions exist as to what genes, environment, and life stage mean to defining normal variations and altered developmental trajectories throughout the life course and also across generations. With the rapid advances in genetic technology came large-scale genomic studies to search for the genetic etiology of complex diseases. While genome-wide association studies (GWAS) have revealed genetic factors and networks that advance our understanding to some extent, it is increasingly recognized that disease causation is largely non-genetic and reflects interactions between an individual's genetic susceptibility and his or her environment. Thus, the full promise of the human genome project to prevent or treat disease and promote good health arguably depends on a commitment to understanding the interactions between our environment and our genetic makeup and requires a design with prospective environmental data collection that considers critical windows of susceptibility that likely correspond to the expression of specific genes and gene pathways. Unlike the genome, which is static, relevant exposures as well as our response to exposures, change over time. This has fostered the complementary concept of the exposome ideally defined as the measure of all exposures of an individual over a lifetime and how those exposures relate to health. The exposome framework considers multiple external exposures (e.g., chemical, social) and behaviors that may modify exposures (e.g., diet), as well as consequences of environmental exposures indexed via biomarkers of physiological response or measures of behavioral response throughout the lifespan. The exposome concept can be applied in prospective developmental studies such as the National Children's Study (NCS) with the practical understanding that even a partial characterization will bring major advances to health. Lessons learned from the NCS provide an important opportunity to inform future studies that can leverage these evolving paradigms in elucidating the role of environment on health across the life course.

Abstract A15: Prenatal exposure to polycyclic aromatic hydrocarbons and breast tissue composition in adolescent girls

Abstract Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that result from incomplete combustion of biomass and fossil fuels. PAH have endocrine-disrupting properties and are known animal carcinogens. Evidence from case-control studies suggests an association between PAH and breast cancer risk, but longitudinal research on PAH exposure during critical windows of susceptibility, such as prenatally and in early life, is limited. The purpose of this study was to prospectively examine whether prenatal exposure to PAH is associated with breast tissue composition, an intermediate marker of breast cancer risk, in adolescent girls. We studied 105 adolescent girls in the Columbia Center for Children’s Environmental Health (CCCEH) birth cohort, which recruited nonsmoking African American and Dominican American pregnant women living in three low-income neighborhoods in New York City from 1998-2006. Women wore a small backpack holding a personal air monitor for 2 consecutive days during the 3rd trimester of pregnancy, which measured concentrations of pyrene and 8 other carcinogenic PAH (summed and categorized into tertiles for analysis). Girls completed a follow-up clinic visit in adolescence (ages 11.2-19.6 years, median=15.8), at which time breast tissue composition was measured by optical spectroscopy (OS). OS is a novel and noninvasive tool that provides a broad compositional view of the breast by capturing variation in the amount of water, lipid, oxy-hemoglobin, deoxy-hemoglobin, and collagen, as well as overall cellular and connective tissue density. OS measured red and near-infrared light transmission of 7 wavelengths (650-1060 nm) at 4 source-detector distances in each breast quadrant, resulting in 16 overlapping tissue volumes. Principal component analysis was used to reduce spectral data and generate principal component (PC) scores for each participant, which were averaged over both breasts. We used multivariable linear regression to examine associations of prenatal PAH measures (pyrene and Σ8 PAH) with each of the first 4 OS PCs, which explained &amp;gt;99% of the spectral variation in the sample. Models were adjusted for age, ethnicity, body mass index (BMI) at time of OS measurement, age at breast development, and mothers’ prepregnancy BMI. After adjusting for covariates, PC1 scores were significantly lower on average in the highest compared to lowest tertile of prenatal ambient Σ8 PAH (β = -0.42, 95% CI = -0.81 to -0.02, p = 0.04). PC1 covered 91.8% of the spectral variations and represents overall light attenuation from higher scattering due to higher cellularity and connective tissues. PC1 also mapped to multiple chromophores including hemoglobin and collagen. No associations were found between prenatal ambient Σ8 PAH and PCs 2-4, and no associations with OS PCs were found for pyrene. To conclude, we found evidence suggesting that prenatal exposure to PAH is associated with breast tissue composition in adolescent girls. Citation Format: Rebecca D. Kehm, Lothar Lilge, E. Jane Walter, Nur Zeinomar, Jasmine A. McDonald, Parisa Tehranifar, Julie B. Herbstman, Rachel L. Miller, Mary Beth Terry. Prenatal exposure to polycyclic aromatic hydrocarbons and breast tissue composition in adolescent girls [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A15.

Abstract A30: Single-cell RNA-sequencing analysis of estrogen and the endocrine-disrupting chemical induced mouse mammary gland reorganization after surgical menopause

Abstract Menopause is considered a critical window of susceptibility (WOS) for its sensitivity to endocrine-disrupting chemicals due to decline of endogenous estrogen. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary gland tissue was affected by both 17β-estradiol (E2) and polybrominated diphenyl ethers (PBDEs). These endocrine-disrupting chemicals have been used as flame retardants in common household products since the 1970s and are vastly detected in human serum. During physiologically relevant exposure to E2, PBDEs enhanced E2-mediated regrowth of mammary glands with terminal end budlike structures. To better elucidate the effects of E2 and PBDEs, single-cell RNA sequencing (scRNAseq) analysis was performed. In a definitive manner, E2 was found to induce Pgr expression in both Esr1+ and Esr1- cells. We identified PBDE-impacted cell populations, Esr1+/Pgr+ and Esr1-/Pgr+ cells, in both mature luminal epithelial and progenitor cells, as well as the mammary gland population of M2 macrophages. Significantly, scRNAseq data show gene expression differences among cells with differential expression of Esr1 and Pgr. The results help clarify how exposure to both E2 and endocrine-disrupting chemicals like PBDEs after menopause impacts mammary gland structure. Ultimately, the findings advance understanding of how such exposure can increase the risk of developing breast cancer through the expansion of estrogen-responsive cells. (Supported by NIH U01ES026137.) Citation Format: Shiuan Chen, Noriko Kanaya, Gregory Chang, Xiwei Wu, Kohei Saeki, Lauren Bernal, Timothy Dynold, Susan L. Neuhausen. Single-cell RNA-sequencing analysis of estrogen and the endocrine-disrupting chemical induced mouse mammary gland reorganization after surgical menopause [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A30.

Abstract 026: Early Life Exposure to Green Areas and Diabetes Risk, an Assessment From Infancy to Early Teens

Background: Increasing empirical evidence suggests that exposure to nature (natural vegetation, or “greenness”) influences health. Studies have shown that greenness is related to lower diabetes risk possibly through mediation of physical activity, harmful environmental exposures, or mental health. However, to our knowledge, no previous study has reported on associations between greenness and insulin resistance in children. We hypothesize that children are more sensitive to environmental exposures particularly during critical windows of susceptibility. Our research aims to evaluate the early life association between greenness and insulin resistance and assess vulnerable life-periods in which individuals are more susceptible to their surroundings. Methods: We use data from Project Viva, a longitudinal cohort study designed to study prenatal factors, pregnancy outcomes, and child health. From 1999 to 2002, we recruited pregnant women from a multispecialty group practice in Massachusetts. Of the 1,036 who attended the early teen research visit, we considered 460 participants who provided fasting blood and had complete data for all covariates and exposure at infancy (less than one year), early childhood (median age 3.3 years), mid-childhood (median age 7.7 years) and early teens (median age 13.2). We defined greenness exposure surrounding each participant’s address using 30m resolution Landsat satellite imagery [Normalized Difference Vegetation Index] at infancy (under one year of age), early childhood, mid-childhood, and early teens. Our main outcome measurement was the homeostatic model assessment to estimate insulin resistance (HOMA-IR) at the early teen visit. Results: In models adjusted for age, race, sex, mother’s education, father’s education, household income and median household income from the census tract at delivery, living in the highest quintile of greenness in the 90-m area at the early teen visit was associated with 0.65 lower HOMA-IR (95%CI: -1.52, -0.40) than those in the lowest quintile. The observed association between higher greenness exposure and lower HOMA-IR in early teens was consistent for the 270-m area, although slightly attenuated, and no longer significant for the 1230-m area (mean HOMA-IR was 3.06, SD=2.08). We found no associations of exposure to greenness in the 90-m, 270-m or 1230-m areas around participants’ home at infancy, early childhood, or mid-childhood with early teenage HOMA-IR. Conclusions: Higher levels of green vegetation, especially closer to the home, at the early teen visit were associated with lower insulin resistance at the same time period. Early exposure to green space during infancy, early childhood and mid-childhood was not associated with HOMA-IR as an early teenager. Early childhood longitudinal studies including geographic contextual factors across diverse populations are needed to confirm or refute these findings.

In Utero and Peripubertal Metals Exposure in Relation to Reproductive Hormones and Sexual Maturation in Girls

Metals occur naturally in the environment and are potential endocrine disrupting chemicals (EDCs). In utero development and adolescence are critical windows of susceptibility to EDC exposure. Few h...

Dentine biomarkers of prenatal and early childhood exposure to manganese, zinc and lead and childhood behavior

BackgroundMetal exposure alters neurodevelopmental outcomes; little is known about critical windows of susceptibility when exposure exerts the strongest effect. ObjectiveTo examine associations between dentine biomarkers of manganese (Mn), zinc (Zn) and lead (Pb) and later childhood behaviors. MethodsSubjects enrolled in a longitudinal birth cohort study in Mexico City provided naturally shed deciduous teeth. We estimated weekly prenatal and postnatal dentine Mn, Zn and Pb concentrations in teeth using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and measured behavior at ages 8–11 years of age using the Behavior Assessment System for Children, 2nd edition (BASC-2). We used distributed lag models and lagged weighted quantile sum regression to identify the role of individual and combined dentine biomarkers of Mn, Zn and Pb on behavioral outcomes controlling for maternal education and gestational age. ResultsAmong the 133 subjects included in this study, prenatal and early postnatal dentine Mn appeared protective against childhood behavioral problems, specifically hyperactivity and attention. Postnatal dentine Mn was associated with increased reporting of internalizing problems, specifically anxiety. At 6 months, a 1-unit increase (unit = 1 SD of log concentration) in Mn was associated with a 0.18-unit (unit = 1 SD of BASC-2 score) increase in internalizing symptoms score and a 0.25-unit increase in anxiety. Postnatal Pb was associated with increasing anxiety symptoms; at 12 months, a 1-unit increase in Pb was associated with a 0.4 unit increase in anxiety symptoms. When examined as a metal mixture, we observed two potential windows of susceptibility to increased anxiety symptoms: the first window (0–8 months) appeared driven by Mn, the second window (8–12 months) was driven by the metal mixture and dominated by Pb. A 1-unit increase in the mixture index was associated with a 0.7-unit increase in SD of anxiety symptoms. ConclusionsChildhood behaviors may demonstrate postnatal windows of susceptibility to individual and mixed metal concentrations measured in deciduous teeth. Prenatal dentine Mn may be protective, while excessive early postnatal Mn may increase risk for adverse behaviors. In combination, higher concentrations of Mn, Zn and Pb may have an adverse impact on behavior.

The Association Between Unconventional Gas Development and Preterm Birth: Evaluating Drilling Phases and Critical Windows of Susceptibility

The Association Between Unconventional Gas Development and Preterm Birth: Evaluating Drilling Phases and Critical Windows of Susceptibility

The Critical Hormone-Sensitive Window for the Development of Delayed Effects Extends to 10 Days after Birth in Female Rats Postnatally Exposed to 17alpha-Ethynylestradiol.

Neonatal exposure to estrogens is known to cause delayed effects, a late-occurring adverse effect on adult female reproductive functions, such as early onset of age-matched abnormal estrous cycling. However, the critical period in which neonates are sensitive to delayed effects inducible by exogenous estrogen exposure has not been clearly identified. To clarify this window, we examined the intensity and timing of delayed effects using rats exposed to ethynylestradiol (EE) at various postnatal ages. After subcutaneous administration of a single dose of EE (20 μg/kg, which induces delayed effects) on Postnatal Day (PND) 0, 5, 10, or 14 in Wistar rats, hypothalamic and hormonal alterations in young adults and long-term estrous cycling status were investigated as indicators of delayed effects. In young adults, peak luteinizing hormone concentrations at the time of the luteinizing hormone surge showed a decreasing trend, and KiSS1 mRNA expression of the anterior hypothalamus and number of KiSS1-positive cells in the anteroventral periventricular nucleus were significantly decreased in the PND 0, 5, and 10 groups. The reduction in KiSS1 mRNA and KiSS1-postive cells was inversely correlated with age at time of exposure. These groups also exhibited early onset of abnormal estrous cycling, starting from 17 wk of age in the PND0 group and 19 wk of age in the PND5 and 10 groups. These indicators were not apparent in the PND14 group. Our results suggest that PND0-PND10 is the critical window of susceptibility for delayed effects, and PND14 is presumed to be the provisional endpoint of the window.

Environmental exposures in utero and microRNA

Purpose of reviewUnderstanding the effects of in-utero exposures to environmental agents is of great importance as the resulting deregulation of biological processes can affect both fetal development and health outcomes that manifest later in life. Due to their established role in developmental processes and inherent stability ex vivo, microRNAs (miRNAs) have emerged as attractive candidates to explore the impact of such exposures during this critical window of susceptibility. In this review, we summarize the findings of studies assessing miRNAs as markers of in-utero environmental exposures and as candidates for the molecular basis through which these exposures exert their influence on children's health.Recent findingsTo date, miRNA expression profiles due to various in-utero environmental exposures, including xenochemicals, endogenous factors, and nutritional status, have been reported.SummaryWhile the validity of the identified exposure-specific miRNA profiles remains to be established, the findings thus far do raise interesting questions worth addressing in future studies. Gaps that remain to be addressed include linking specific in-utero exposures to subsequent health outcomes based on established miRNA expression profiles and experimentally validating putative downstream targets of the deregulated miRNAs.

Identifying Opportunities for Cancer Prevention During Preadolescence and Adolescence: Puberty as a Window of Susceptibility

Early life exposures during times of rapid growth and development are recognized increasingly to impact later life. Epidemiologic studies document an association between exposures at critical windows of susceptibility with outcomes as diverse as childhood and adult obesity, timing of menarche, and risk for hypertension or breast cancer. This article briefly reviews the concept of windows of susceptibility for providers who care for adolescent patients. The theoretical bases for windows of susceptibility is examined, evaluating the relationship between pubertal change and breast cancer as a paradigm, and reviewing the underlying mechanisms, such as epigenetic modification. The long-term sequela of responses to early exposures may impact other adult morbidities; addressing these exposures represents an important challenge for contemporary medicine.

POPs vs. Fat: Persistent Organic Pollutant Toxicity Targets and Is Modulated by Adipose Tissue

Research over the last decade indicates that adipose (fat) tissue serves as more than an energy depot. The tissue has a dynamic role in maintaining normal carbohydrate and lipid levels as well as in regulating metabolic and other physiologic functions. Persistent organic pollutants (POPs), including certain organochlorine pesticides and numerous industrial chemicals, are highly attracted to lipids and accumulate in adipose tissue. A new review examines how adipose tissue both modulates and serves as a target of POP toxicity and highlights knowledge gaps [EHP 121(2):162–169, La Merrill et al.]. Adipose tissue contains diverse cell types, including adipocytes (fat cells), preadipocytes (immature fat cells), and immune cells. The cells not only respond to various metabolic signals, such as insulin from the pancreas, but also direct the activities of other cell types within the tissue and throughout the body. Adipocytes alone have multiple roles, including lipid storage, production of hormones that regulate appetite and metabolic functions, and secretion of molecules involved in inflammation, which triggers other metabolic and immune system cascades. Adipose tissue readily accumulates POPs, environmental contaminants associated with disruption of the endocrine, reproductive, and immune systems, impaired neurobehavioral development, and cancer. In the short term, adipose tissue sequesters POPs, limiting the exposure of other tissues. However, storage capacity and duration are not uniform and may vary by adipose tissue subtype. These factors complicate the task of predicting bodywide distribution of POPs, exposure of other tissues, and the compounds’ eventual metabolism and excretion. Over the long term, adipose tissue could serve as an internal source for chronic POP exposure, particularly with weight loss. Figure 1 Adipose tissue in lean people is characterized by M2 macrophages and CD4+ T cells. In obese people, the tissue accumulates M1 macrophages and CD8+ T cells, signs of inflammation. POPs may also contribute to inflammation in adipose tissue. Adipose tissue itself may experience toxic effects, especially if exposure occurs within critical windows of susceptibility, such as during prenatal, early postnatal, or pubertal development. Developmental exposure could redirect gene expression, with effects that may not become apparent until later in life. This mechanism, among other possibilities, could explain how several POPs may act as obesogens, compounds that increase the risk of obesity, itself a risk factor for diabetes, liver and cardiovascular diseases, and cancer. Furthermore, recent studies show that POPs provoke an inflammatory state in adipose tissue, a condition associated with the metabolic side effects of obesity. POPs also appear to have a role in lipotoxicity, the accumulation of lipids in nonadipose tissues, leading to metabolic dysfunction characteristic of cardiovascular disease and heart disease. Ample research points to adipose tissue being a central factor in POP toxicity, but significant knowledge gaps remain with regard to obesogens’ mechanisms of action, POP distribution and dynamics in the body, and the molecular pathways disrupted by or involved in POP toxicity. Human studies, especially prospective longitudinal investigations, are also needed to validate experimental findings.