Susceptible windows of exposure to fine particulate matter and fetal growth trajectories in the Spanish INMA (INfancia y Medio Ambiente) birth cohort.

While prior studies report associations between fine particulate matter (PM2.5) exposure and fetal growth, few have explored temporally refined susceptible windows of exposure. We included 2328 women from the Spanish INMA Project from 2003 to 2008. Longitudinal growth curves were constructed for each fetus using ultrasounds from 12, 20, and 34 gestational weeks. Z-scores representing growth trajectories of biparietal diameter, femur length, abdominal circumference (AC), and estimated fetal weight (EFW) during early (0-12 weeks), mid- (12-20 weeks), and late (20-34 weeks) pregnancy were calculated. A spatio-temporal random forest model with back-extrapolation provided weekly PM2.5 exposure estimates for each woman during her pregnancy. Distributed lag non-linear models were implemented within the Bayesian hierarchical framework to identify susceptible windows of exposure for each outcome and cumulative effects [ßcum, 95% credible interval (CrI)] were aggregated across adjacent weeks. For comparison, general linear models evaluated associations between PM2.5 averaged across multi-week periods (i.e., weeks 1-11, 12-19, and 20-33) and fetal growth, mutually adjusted for exposure during each period. Results are presented as %change in z-scores per 5 µg/m3 in PM2.5, adjusted for covariates. Weeks 1-6 [ßcum = -0.77%, 95%CrI (-1.07%, -0.47%)] were identified as a susceptible window of exposure for reduced late pregnancy EFW while weeks 29-33 were positively associated with this outcome [ßcum = 0.42%, 95%CrI (0.20%, 0.64%)]. A similar pattern was observed for AC in late pregnancy. In linear regression models, PM2.5 exposure averaged across weeks 1-11 was associated with reduced late pregnancy EFW and AC; but, positive associations between PM2.5 and EFW or AC trajectories in late pregnancy were not observed. PM2.5 exposures during specific weeks may affect fetal growth differentially across pregnancy and such associations may be missed by averaging exposure across multi-week periods, highlighting the importance of temporally refined exposure estimates when studying the associations of air pollution with fetal growth.

Susceptible windows of prenatal and postnatal fine particulate matter exposures and attention-deficit hyperactivity disorder symptoms in early childhood.

Few prior studies have explored windows of susceptibility to fine particulate matter (PM2.5) in both the prenatal and postnatal periods and children's attention-deficit/hyperactivity disorder (ADHD) symptoms. We analyzed data from 1416 mother-child pairs from the Spanish INMA (INfancia y Medio Ambiente) Study (2003-2008). Around 5 years of age, teachers reported the number of ADHD symptoms (i.e., inattention, hyperactivity/impulsivity) using the ADHD Diagnostic and Statistical Manual of Mental Disorders. Around 7 years of age, parents completed the Conners' Parent Rating Scales, from which we evaluated the ADHD index, cognitive problems/inattention, hyperactivity, and oppositional subscales, reported as age- and sex-standardized T-scores. Daily residential PM2.5 exposures were estimated using a two-stage random forest model with temporal back-extrapolation and averaged over 1-week periods in the prenatal period and 4-week periods in the postnatal period. We applied distributed lag non-linear models within the Bayesian hierarchical model framework to identify susceptible windows of prenatal or postnatal exposure to PM2.5 (per 5-µg/m3) for ADHD symptoms. Models were adjusted for relevant covariates, and cumulative effects were reported by aggregating risk ratios (RRcum) or effect estimates (ßcum) across adjacent susceptible windows. A similar susceptible period of exposure to PM2.5 (1.2-2.9 and 0.9-2.7 years of age, respectively) was identified for hyperactivity/impulsivity symptoms assessed ~5 years (RRcum = 2.72, 95% credible interval [CrI] = 1.98, 3.74) and increased hyperactivity subscale ~7 years (ßcum = 3.70, 95% CrI = 2.36, 5.03). We observed a susceptibility period to PM2.5 on risk of hyperactivity/impulsivity symptoms ~5 years in gestational weeks 16-22 (RRcum = 1.36, 95% CrI = 1.22, 1.52). No associations between PM2.5 exposure and other ADHD symptoms were observed. We report consistent evidence of toddlerhood as a susceptible window of PM2.5 exposure for hyperactivity in young children. Although mid-pregnancy was identified as a susceptible period of exposure on hyperactivity symptoms in preschool-aged children, this association was not observed at the time children were school-aged.

Relation of prenatal and postnatal PM2.5 exposure with cognitive and motor function among preschool-aged children.

The literature informing susceptible periods of exposure on children's neurodevelopment is limited. We evaluated the impacts of pre- and postnatal fine particulate matter (PM2.5) exposure on children's cognitive and motor function among 1303 mother-child pairs in the Spanish INMA (Environment and Childhood) Study. Random forest models with temporal back extrapolation were used to estimate daily residential PM2.5 exposures that we averaged across 1-week lags during the prenatal period and 4-week lags during the postnatal period. The McCarthy Scales of Children's Abilities (MSCA) were administered around 5 years to assess general cognitive index (GCI) and several subscales (verbal, perceptual-performance, memory, fine motor, gross motor). We applied distributed lag nonlinear models within the Bayesian hierarchical framework to explore periods of susceptibility to PM2.5 on each MSCA outcome. Effect estimates were calculated per 5 µg/m3 increase in PM2.5 and aggregated across adjacent statistically significant lags using cumulative ß (ßcum) and 95% Credible Intervals (95%CrI). We evaluated interactions between PM2.5 with fetal growth and child sex. We did not observe associations of PM2.5 exposure with lower GCI scores. We found a period of susceptibility to PM2.5 on fine motor scores in gestational weeks 1-9 (ßcum = -2.55, 95%CrI = -3.53,-1.56) and on gross motor scores in weeks 7-17 (ßcum = -2.27,95%CrI = -3.43,-1.11) though the individual lags for the latter were only borderline statistically significant. Exposure in gestational week 17 was weakly associated with verbal scores (ßcum = -0.17, 95%CrI = -0.26,-0.09). In the postnatal period (from age 0.5-1.2 years), we observed a window of susceptibility to PM2.5 on lower perceptual-performance (ß = -2.42, 95%CrI = -3.37,-1.46). Unexpected protective associations were observed for several outcomes with exposures in the later postnatal period. We observed no evidence of differences in susceptible periods by fetal growth or child sex. Preschool-aged children's motor function may be particularly susceptible to PM2.5 exposures experienced in utero whereas the first year of life was identified as a period of susceptibility to PM2.5 for children's perceptual-performance.

Environmental epigenetics and its implication on disease risk and health outcomes.

This review focuses on how environmental factors through epigenetics modify disease risk and health outcomes. Major epigenetic events, such as histone modifications, DNA methylation, and microRNA expression, are described. The function of dose, duration, composition, and window of exposure in remodeling the individual's epigenetic terrain and disease susceptibility are addressed. The ideas of lifelong editing of early-life epigenetic memories, transgenerational effects through germline transmission, and the potential role of hydroxylmethylation of cytosine in developmental reprogramming are discussed. Finally, the epigenetic effects of several major classes of environmental factors are reviewed in the context of pathogenesis of disease. These include endocrine disruptors, tobacco smoke, polycyclic aromatic hydrocarbons, infectious pathogens, particulate matter, diesel exhaust particles, dust mites, fungi, heavy metals, and other indoor and outdoor pollutants. We conclude that the summation of epigenetic modifications induced by multiple environmental exposures, accumulated over time, represented as broad or narrow, acute or chronic, developmental or lifelong, may provide a more precise assessment of risk and consequences. Future investigations may focus on their use as readouts or biomarkers of the totality of past exposure for the prediction of future disease risk and the prescription of effective countermeasures.