Chris Gennings

Fetal and postnatal metal dysregulation in autism

Genetic and environmental factors contribute to the etiologies of autism spectrum disorder (ASD), but evidence of specific environmental exposures and susceptibility windows is limited. Here we study monozygotic and dizygotic twins discordant for ASD to test whether fetal and postnatal metal dysregulation increases ASD risk. Using validated tooth-matrix biomarkers, we estimate pre- and post-natal exposure profiles of essential and toxic elements. Significant divergences are apparent in metal uptake between ASD cases and their control siblings, but only during discrete developmental periods. Cases have reduced uptake of essential elements manganese and zinc, and higher uptake of the neurotoxin lead. Manganese and lead are also correlated with ASD severity and autistic traits. Our study suggests that metal toxicant uptake and essential element deficiency during specific developmental windows increases ASD risk and severity, supporting the hypothesis of systemic elemental dysregulation in ASD. Independent replication in population-based studies is needed to extend these findings.

Early-life metal exposure and schizophrenia: A proof-of-concept study using novel tooth-matrix biomarkers.

BACKGROUNDnDespite evidence for the effects of metals on neurodevelopment, the long-term effects on mental health remain unclear due to methodological limitations. Our objective was to determine the feasibility of studying metal exposure during critical neurodevelopmental periods and to explore the association between early-life metal exposure and adult schizophrenia.nnnMETHODSnWe analyzed childhood-shed teeth from nine individuals with schizophrenia and five healthy controls. We investigated the association between exposure to lead (Pb(2+)), manganese (Mn(2+)), cadmium (Cd(2+)), copper (Cu(2+)), magnesium (Mg(2+)), and zinc (Zn(2+)), and schizophrenia, psychotic experiences, and intelligence quotient (IQ). We reconstructed the dose and timing of early-life metal exposures using laser ablation inductively coupled plasma mass spectrometry.nnnRESULTSnWe found higher early-life Pb(2+) exposure among patients with schizophrenia than controls. The differences in log Mn(2+) and log Cu(2+) changed relatively linearly over time to postnatal negative values. There was a positive correlation between early-life Pb(2+) levels and psychotic experiences in adulthood. Moreover, we found a negative correlation between Pb(2+) levels and adult IQ.nnnCONCLUSIONSnIn our proof-of-concept study, using tooth-matrix biomarker that provides direct measurement of exposure in the fetus and newborn, we provide support for the role of metal exposure during critical neurodevelopmental periods in psychosis.

Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis.

ImportancenThere is growing interest in the role of nutrition in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS).nnnObjectivenTo evaluate the associations between nutrients, individually and in groups, and ALS function and respiratory function at diagnosis.nnnDesign, Setting, and ParticipantsnA cross-sectional baseline analysis of the Amyotrophic Lateral Sclerosis Multicenter Cohort Study of Oxidative Stress study was conducted from March 14, 2008, to February 27, 2013, at 16 ALS clinics throughout the United States among 302 patients with ALS symptom duration of 18 months or less.nnnExposuresnNutrient intake, measured using a modified Block Food Frequency Questionnaire (FFQ).nnnMain Outcomes and MeasuresnAmyotrophic lateral sclerosis function, measured using the ALS Functional Rating Scale-Revised (ALSFRS-R), and respiratory function, measured using percentage of predicted forced vital capacity (FVC).nnnResultsnBaseline data were available on 302 patients with ALS (median age, 63.2 years [interquartile range, 55.5-68.0 years]; 178 men and 124 women). Regression analysis of nutrients found that higher intakes of antioxidants and carotenes from vegetables were associated with higher ALSFRS-R scores or percentage FVC. Empirically weighted indices using the weighted quantile sum regression method of good micronutrients and good food groups were positively associated with ALSFRS-R scores (β [SE], 2.7 [0.69] and 2.9 [0.9], respectively) and percentage FVC (β [SE], 12.1 [2.8] and 11.5 [3.4], respectively) (all Pu2009<u2009.001). Positive and significant associations with ALSFRS-R scores (β [SE], 1.5 [0.61]; Pu2009=u2009.02) and percentage FVC (β [SE], 5.2 [2.2]; Pu2009=u2009.02) for selected vitamins were found in exploratory analyses.nnnConclusions and RelevancenAntioxidants, carotenes, fruits, and vegetables were associated with higher ALS function at baseline by regression of nutrient indices and weighted quantile sum regression analysis. We also demonstrated the usefulness of the weighted quantile sum regression method in the evaluation of diet. Those responsible for nutritional care of the patient with ALS should consider promoting fruit and vegetable intake since they are high in antioxidants and carotenes.

Extending the Distributed Lag Model framework to handle chemical mixtures

ABSTRACT Distributed Lag Models (DLMs) are used in environmental health studies to analyze the time‐delayed effect of an exposure on an outcome of interest. Given the increasing need for analytical tools for evaluation of the effects of exposure to multi‐pollutant mixtures, this study attempts to extend the classical DLM framework to accommodate and evaluate multiple longitudinally observed exposures. We introduce 2 techniques for quantifying the time‐varying mixture effect of multiple exposures on an outcome of interest. Lagged WQS, the first technique, is based on Weighted Quantile Sum (WQS) regression, a penalized regression method that estimates mixture effects using a weighted index. We also introduce Tree‐based DLMs, a nonparametric alternative for assessment of lagged mixture effects. This technique is based on the Random Forest (RF) algorithm, a nonparametric, tree‐based estimation technique that has shown excellent performance in a wide variety of domains. In a simulation study, we tested the feasibility of these techniques and evaluated their performance in comparison to standard methodology. Both methods exhibited relatively robust performance, accurately capturing pre‐defined non‐linear functional relationships in different simulation settings. Further, we applied these techniques to data on perinatal exposure to environmental metal toxicants, with the goal of evaluating the effects of exposure on neurodevelopment. Our methods identified critical neurodevelopmental windows showing significant sensitivity to metal mixtures.

Maternal Lifetime Stress and Prenatal Psychological Functioning and Decreased Placental Mitochondrial DNA Copy Number in the PRISM Study

Psychosocial stress contributes to placental oxidative stress. Mitochondria are vulnerable to oxidative stress, which can lead to changes in mitochondrial DNA copy number (mtDNAcn). We examined associations of maternal lifetime stress, current negative life events, and depressive and posttraumatic-stress-disorder symptom scores with placental mtDNAcn in a racially/ethnically diverse sample (n = 147) from the Programming of Intergenerational Stress Mechanisms (PRISM) study (Massachusetts, March 2011 to August 2012). In linear regression analyses adjusted for maternal age, race/ethnicity, education, prenatal fine particulate matter exposure, prenatal smoking exposure, and the sex of the child, all measures of stress were associated with decreased placental mtDNAcn (all P values < 0.05). Weighted-quantile-sum (WQS) regression showed that higher lifetime stress and depressive symptoms accounted for most of the effect on mtDNAcn (WQS weights: 0.25 and 0.39, respectively). However, among white individuals, increased lifetime stress and posttraumatic stress disorder symptoms explained the majority of the effect (WQS weights: 0.20 and 0.62, respectively) while among nonwhite individuals, lifetime stress and depressive symptoms accounted for most of the effect (WQS weights: 0.27 and 0.55, respectively). These analyses are first to link increased maternal psychosocial stress with reduced placental mtDNAcn and add to literature documenting racial/ethnic differences in the psychological sequelae of chronic stress that may contribute to maternal-fetal health.

Lagged kernel machine regression for identifying time windows of susceptibility to exposures of complex mixtures

The impact of neurotoxic chemical mixtures on childrens health is a critical public health concern. It is well known that during early life, toxic exposures may impact cognitive function during critical time intervals of increased vulnerability, known as windows of susceptibility. Knowledge on time windows of susceptibility can help inform treatment and prevention strategies, as chemical mixtures may affect a developmental process that is operating at a specific life phase. There are several statistical challenges in estimating the health effects of time-varying exposures to multi-pollutant mixtures, such as: multi-collinearity among the exposures both within time points and across time points, and complex exposure-response relationships. To address these concerns, we develop a flexible statistical method, called lagged kernel machine regression (LKMR). LKMR identifies critical exposure windows of chemical mixtures, and accounts for complex non-linear and non-additive effects of the mixture at any given exposure window. Specifically, LKMR estimates how the effects of a mixture of exposures change with the exposure time window using a Bayesian formulation of a grouped, fused lasso penalty within a kernel machine regression (KMR) framework. A simulation study demonstrates the performance of LKMR under realistic exposure-response scenarios, and demonstrates large gains over approaches that consider each time window separately, particularly when serial correlation among the time-varying exposures is high. Furthermore, LKMR demonstrates gains over another approach that inputs all time-specific chemical concentrations together into a single KMR. We apply LKMR to estimate associations between neurodevelopment and metal mixtures in Early Life Exposures in Mexico and Neurotoxicology, a prospective cohort study of child health in Mexico City.

Big and disparate data: considerations for pediatric consortia

Purpose of review Increasingly, there is a need for examining exposure disease associations in large, diverse datasets to understand the complex determinants of pediatric disease and disability. Recognizing that childrens health research consortia will be important sources of big data, it is crucial for the pediatric research community to be knowledgeable about the challenges and opportunities that they will face. The present review will provide examples of existing childrens health consortia, highlight recent pooled analyses conducted by childrens health research consortia, address common challenges of pooled analyses, and provide recommendations to advance collective research efforts in pediatric research. Recent findings Formal consortia and other collective-science initiatives are increasingly being created to share individual data from a set of relevant epidemiological studies to address a common research topic under the concept that the joint effort of many individual groups can accomplish far more than working alone. There are practical challenges to the participation of investigators within consortia that need to be addressed in order for them to work. Summary Researchers who access consortia with data centers will be able to go far beyond their initial hypotheses and potentially accomplish research that was previously thought infeasible or too costly.

How similar is similar enough? A sufficient similarity case study with Ginkgo biloba extract

Botanical dietary supplements are complex mixtures that can be highly variable in composition and quality, making safety evaluation difficult. A key challenge is determining how diverse products in the marketplace relate to chemically and toxicologically characterized reference samples (i.e., how similar must a product be in order to be well-represented by the tested reference sample?). Ginkgo biloba extract (GBE) was used as a case study to develop and evaluate approaches for determining sufficient similarity. Multiple GBE extracts were evaluated for chemical and biological-response similarity. Chemical similarity was assessed using untargeted and targeted chemistry approaches. Biological similarity was evaluated using in vitro liver models and short-term rodent studies. Statistical and data visualization methods were then used to make decisions about the similarity of products to the reference sample. A majority of the 26 GBE samples tested (62%) were consistently determined to be sufficiently similar to the reference sample, while 27% were different from the reference GBE, and 12% were either similar or different depending on the method used. This case study demonstrated that approaches to evaluate sufficient similarity allow for critical evaluation of complex mixtures so that safety data from the tested reference can be applied to untested materials.

Prenatal exposure to PM2.5 and birth weight: A pooled analysis from three North American longitudinal pregnancy cohort studies

A common practice when analyzing multi-site epidemiological data is to include a term for site to account for unmeasured effects at each location. This practice should be carefully considered when site can have complex relationships with important demographic and exposure variables. We leverage data from three longitudinal North American pregnancy cohorts to demonstrate a novel method to assess study heterogeneity and potential combinability of studies for pooled analyses in order to better understand how to consider site in analyses. Results from linear regression and fixed effects meta-regression models run both prior to and following the proposed combinability analyses were compared. In order to exemplify this approach, we examined associations between prenatal exposure to particulate matter and birth weight. Analyses included mother-child dyads (N=1966) from the Asthma Coalition on Community Environment and Social Stress (ACCESS) Project and the PRogramming of Intergenerational Stress Mechanisms (PRISM) study in the northeastern United States, and the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study in Mexico City. Mothers daily third trimester exposure to particulate matter≤2.5μm in diameter (PM2.5) was estimated using a validated satellite-based spatio-temporally resolved model in all studies. Fenton birth weight for gestational age z-scores were calculated. Linear regression analyses within each cohort separately did not find significant associations between PM2.5 averaged over the third trimester and Fenton z-scores. The initial meta-regression model also did not find significant associations between prenatal PM2.5 and birthweight. Next, propensity scores and log linear models were used to assess higher order interactions and determine if sites were comparable with regard to sociodemographics and other covariates; these analyses demonstrated that PROGRESS and ACCESS were combinable. Adjusted linear regression models including a 2-level site variable according to the pooling indicated by the log linear models (ACCESS and PROGRESS as one level and PRISM as another) revealed that a 5μg/m3 increase in PM2.5 was associated with a 0.075 decrease in Fenton z-score (p<0.0001); linear models including a 3-level site variable did not reveal significant associations. By assessing the combinability of heterogeneous populations prior to combining data using a method that more optimally accounts for underlying cohort differences, we were able to identify significant associations between prenatal PM2.5 exposure and birthweight that were not detected using standard methods.

Neonatal intensive care unit phthalate exposure and preterm infant neurobehavioral performance

Every year in the United States, more than 300,000 infants are admitted to neonatal intensive care units (NICU) where they are exposed to a chemical-intensive hospital environment during a developmentally vulnerable period. The neurodevelopmental impact of environmental exposure to phthalates during the NICU stay is unknown. As phthalate exposure during the third trimester developmental window has been implicated in neurobehavioral deficits in term-born children that are strikingly similar to a phenotype of neurobehavioral morbidity common among children born premature, the role of early-life phthalate exposure on the neurodevelopmental trajectory of premature infants may be clinically important. In this study, premature newborns with birth weight <1500g were recruited to participate in a prospective environmental health cohort study, NICU-HEALTH (Hospital Exposures and Long-Term Health), part of the DINE (Developmental Impact of NICU Exposures) cohort of the ECHO (Environmental influences on Child Health Outcomes) program. Seventy-six percent of eligible infants enrolled in the study. Sixty-four of 81 infants survived and are included in this analysis. 164 urine specimens were analyzed for phthalate metabolites using high-performance liquid chromatography/tandem mass spectrometry. The NICU Network Neurobehavioral Scale (NNNS) was performed prior to NICU discharge. Linear and weighted quantile sum regression quantified associations between phthalate biomarkers and NNNS performance, and between phthalate biomarkers and intensity of medical intervention. The sum of di(2-ethylhexyl) phthalate metabolites (∑DEHP) was associated with improved performance on the Attention and Regulation scales. Specific mixtures of phthalate biomarkers were also associated with improved NNNS performance. More intense medical intervention was associated with higher ∑DEHP exposure. NICU-based exposure to phthalates mixtures was associated with improved attention and social response. This suggests that the impact of phthalate exposure on neurodevelopment may follow a non-linear trajectory, perhaps accelerating the development of certain neural networks. The long-term neurodevelopmental impact of NICU-based phthalate exposure needs to be evaluated.