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The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) funds a wide range of projects that span biomedical, environmental sciences, and engineering research and generate a wealth of data resulting from hypothesis-driven research projects. Combining or integrating these diverse data offers an opportunity to uncover new scientific connections that can be used to gain a more comprehensive understanding of the interplay between exposures and health. Integrating and reusing data generated from individual research projects within the program requires harmonization of data workflows, ensuring consistent and robust practices in data stewardship, and embracing data sharing from the onset of data collection and analysis. We describe opportunities to leverage data within the SRP and current SRP efforts to advance data sharing and reuse, including by developing an SRP dataset library and fostering data integration through Data Management and Analysis Cores. We also discuss opportunities to improve public health by identifying parallels in the data captured from health and engineering research, layering data streams for a more comprehensive picture of exposures and disease, and using existing SRP research infrastructure to facilitate and foster data sharing. Importantly, we point out that while the SRP is in a unique position to exploit these opportunities, they can be employed across environmental health research. SRP research teams, which comprise cross-disciplinary scientists focused on similar research questions, are well positioned to use data to leverage previous findings and accelerate the pace of research. Incorporating data streams from different disciplines addressing similar questions can provide a broader understanding and uncover the answers to complex and discrete research questions.

The etiologic pathways leading to neuropsychiatric diseases remain poorly defined. As genomic technologies have advanced over the past several decades, considerable progress has been made linking neuropsychiatric disorders to genetic underpinnings. Interest and consideration of nongenetic risk factors (e.g., lead exposure and schizophrenia) have, in contrast, lagged behind heritable frameworks of explanation. Thus, the association of neuropsychiatric illness to environmental chemical exposure, and their potential interactions with genetic susceptibility, are largely unexplored. In this review, we describe emerging approaches for considering the impact of chemical risk factors acting alone and in concert with genetic risk, and point to the potential role of epigenetics in mediating exposure effects on transcription of genes implicated in mental disorders. We highlight recent examples of research in nongenetic risk factors in psychiatric disorders that point to potential shared biological mechanisms—synaptic dysfunction, immune alterations, and gut–brain interactions. We outline new tools and resources that can be harnessed for the study of environmental factors in psychiatric disorders. These tools, combined with emerging experimental evidence, suggest that there is a need to broadly incorporate environmental exposures in psychiatric research, with the ultimate goal of identifying modifiable risk factors and informing new treatment strategies for neuropsychiatric disease.

Recent data indicate that approximately 12% of children in the United States are affected by neurodevelopmental disorders, including attention deficit hyperactivity disorder, learning disorders, intellectual disabilities, and autism spectrum disorders. Accumulating evidence indicates a multifactorial etiology for these disorders, with social, physical, genetic susceptibility, nutritional factors, and chemical toxicants acting together to influence risk. Exposure to endocrine-disrupting chemicals during the early stages of life can disrupt normal patterns of development and thus alter brain function and disease susceptibility later in life. This article highlights research efforts and pinpoints approaches that could shed light on the possible associations between environmental chemicals that act on the endocrine system and compromised neurodevelopmental outcomes.

Background Exposure to ambient air pollution is widespread and may be detrimental to human brain development and a potential risk factor for Autism Spectrum Disorder (ASD). We conducted a systematic review of the human evidence on the relationship between ASD and exposure to all airborne pollutants, including particulate matter air pollutants and others (e.g. pesticides and metals). Objective To answer the question: “is developmental exposure to air pollution associated with ASD?” Methods We conducted a comprehensive search of the literature, identified relevant studies using inclusion/exclusion criteria pre-specified in our protocol (registered in PROSPERO, CRD # 42015017890), evaluated the potential risk of bias for each included study and identified an appropriate subset of studies to combine in a meta-analysis. We then rated the overall quality and strength of the evidence collectively across all air pollutants. Results Of 1,158 total references identified, 23 human studies met our inclusion criteria (17 case-control, 4 ecological, 2 cohort). Risk of bias was generally low across studies for most domains; study limitations were related to potential confounding and accuracy of exposure assessment methods. We rated the quality of the body of evidence across all air pollutants as “moderate.” From our meta-analysis, we found statistically significant summary odds ratios (ORs) of 1.07 (95% CI: 1.06, 1.08) per 10-μg/m3 increase in PM10 exposure (n = 6 studies) and 2.32 (95% CI: 2.15, 2.51) per 10-μg/m3 increase in PM2.5 exposure (n = 3 studies). For pollutants not included in a meta-analysis, we collectively evaluated evidence from each study in rating the strength and quality of overall evidence considering factors such as inconsistency, imprecision, and evidence of dose-response. All included studies generally showed increased risk of ASD with increasing exposure to air pollution, although not consistently across all chemical components. Conclusion After considering strengths and limitations of the body of research, we concluded that there is “limited evidence of toxicity” for the association between early life exposure to air pollution as a whole and diagnosis of ASD. The strongest evidence was between prenatal exposure to particulate matter and ASD. However, the small number of studies in the meta-analysis and unexplained statistical heterogeneity across the individual study estimates means that the effect could be larger or smaller (including not significant) than these studies estimate. Our research supports the need for health protective public policy to reduce exposures to harmful airborne contaminants among pregnant women and children and suggests opportunities for optimizing future research.

Accumulating evidence suggests that outdoor air pollution may have a significant impact on central nervous system (CNS) health and disease. To address this issue, the National Institute of Environmental Health Sciences/National Institute of Health convened a panel of research scientists that was assigned the task of identifying research gaps and priority goals essential for advancing this growing field and addressing an emerging human health concern. Here, we review recent findings that have established the effects of inhaled air pollutants in the brain, explore the potential mechanisms driving these phenomena, and discuss the recommended research priorities/approaches that were identified by the panel.

Background: Despite increasing availability of environmental health science (EHS) data, development, and implementation of relevant semantic standards, such as ontologies or hierarchical vocabularies, has lagged. Consequently, integration and analysis of information needed to better model environmental influences on human health remains a significant challenge. Objectives: We aimed to identify a committed community and mechanisms needed to develop EHS semantic standards that will advance understanding about the impacts of environmental exposures on human disease. Methods: The National Institute of Environmental Health Sciences sponsored the “Workshop for the Development of a Framework for Environmental Health Science Language” hosted at North Carolina State University on 15–16 September 2014. Through the assembly of data generators, users, publishers, and funders, we aimed to develop a foundation for enabling the development of community-based and data-driven standards that will ultimately improve standardization, sharing, and interoperability of EHS information. Discussion: Creating and maintaining an EHS common language is a continuous and iterative process, requiring community building around research interests and needs, enabling integration and reuse of existing data, and providing a low barrier of access for researchers needing to use or extend such a resource. Conclusions: Recommendations included developing a community-supported web-based toolkit that would enable a) collaborative development of EHS research questions and use cases, b) construction of user-friendly tools for searching and extending existing semantic resources, c) education and guidance about standards and their implementation, and d) creation of a plan for governance and sustainability. Citation: Mattingly CJ, Boyles R, Lawler CP, Haugen AC, Dearry A, Haendel M. 2016. Laying a community-based foundation for data-driven semantic standards in environmental health sciences. Environ Health Perspect 124:1136–1140; http://dx.doi.org/10.1289/ehp.1510438

Studies examining maternal infection as a risk factor for neurological disorders in the offspring have suggested that altered maternal immune status during pregnancy can be considered as an adverse event in prenatal development. Infection occurring in the mother during the gestational period has been implicated in multiple neurological effects. The current manuscript will consider the issue of immune/inflammatory conditions during prenatal development where adverse outcomes have been linked to maternal systemic infection. The discussions will focus primary on white matter and oligodendrocytes as they have been identified as target processes. This white matter damage occurs in very early preterm infants and in various other human diseases currently being examined for a linkage to maternal or early developmental immune status. The intent is to draw attention to the impact of altered immune status during pregnancy on the offspring for the consideration of such contributing factors to the general assessment of developmental neurotoxicology.

The recent resurgence of interest in the use of intravital microscopy in lung research is a manifestation of extraordinary progress in visual imaging and optical microscopy. This review evaluates the tools and instrumentation available for a number of imaging modalities, with particular attention to recent technological advances, and addresses recent progress in use of optical imaging techniques in basic pulmonary research. 1 Limitations of existing methods and anticipated future developments are also identified. Although there have also been major advances made in the use of magnetic resonance imaging, positron emission tomography, and X-ray and computed tomography to image intact lungs and while these technologies have been instrumental in advancing the diagnosis and treatment of patients, the purpose of this review is to outline developing optical methods that can be evaluated for use in basic research in pulmonary biology.

Striatal enlargement has been consistently reported in schizophrenics receiving chronic neuroleptic treatment although the results following atypical antipsychotic treatment have been equivocal. In order to disentangle patient illness from a possible drug effect on brain structure, young adult rats were administered either haloperidol, risperidone, clozapine, olanzapine, or vehicle daily for four or eight months via drinking water. Significant increases in caudate-putamen volumes were seen in animals receiving either haloperidol or clozapine when compared with control animals following eight months of drug administration. Conversely, olanzapine-treated animals showed significant decreases in caudate-putamen volumes when compared with control animals after eight months of drug. Thus, converging evidence indicates that the neuroplastic response of the striatum following neuroleptic exposure causes volumetric increases, whereas atypical antipsychotics affect the basal ganglia differentially. The current data suggests that such differential responses may be due to both the pharmacological properties and the relative doses of the atypical agents.

Perturbations in the developmental regulation of the dopaminergic system have been hypothesized to participate in the age-dependent onset of schizophrenia. Although data from studies of non-human primates suggest that dopamine D1-like receptors decrease during adolescence, less information is available concerning changes in human brain. The present study employed quantitative receptor autoradiography to measure D1-like receptor density and affinity in human caudate and putamen. Samples were obtained postmortem from 15 subjects (9 weeks to 49 years), and grouped a priori into three classes: infants, adolescents, and adults. Receptor density and affinity were assessed by saturation binding with [3H]-SCH23390, a D1 receptor antagonist. A decrease in D1 receptor density was observed from infancy to adulthood, with no change in receptor affinity. The temporal pattern of D1-like receptor expression during maturation may play a role in the interaction of dopamine with other neurotransmitter systems, and in the occurrence and pharmacotherapy of neurological and neuropsychiatric disorders.

OPC-14597 {aripiprazole; 7-(-4(4-(2,3-dichlorophenyl)-1-piperazinyl) butyloxy)-3,4-dihydro-2(1H)-quinolinone} is a novel candidate antipsychotic that has high affinity for striatal dopamine D2-like receptors, but causes few extrapyramidal effects. These studies characterized the molecular pharmacology of OPC-14597, DM-1451 (its major rodent metabolite), and the related quinolinone derivative OPC-4392 at each of the cloned dopamine receptors, and at serotonin 5HT6 and 5HT7 receptors. All three compounds exhibited highest affinity for D2L and D2S receptors relative to the other cloned receptors examined. Both OPC-4392 and OPC-14597 demonstrated dual agonist/antagonist actions at D2L receptors, although the metabolite DM-1451 behaved as a pure antagonist. These data suggest that clinical atypicality can occur with drugs that exhibit selectivity for D2L/D2S rather than D3 or D4 receptors, and raise the possibility that the unusual profile of OPC-14597 in vivo (presynaptic agonist and postsynaptic antagonist) may reflect different functional consequences of this compound interacting with a single dopamine receptor subtype (D2) in distinct cellular locales.

Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967

Children entering classrooms for the first time this fall can be seen carrying backpacks filled with school supplies, yet each new student brings something less obvious but more important—a legacy of their earlier experiences and environment. Three studies published in this issue of Environmental Health Perspectives (Bouchard et al. 2011; Engel et al. 2011; Rauh et al. 2011) deliver compelling new data linking one aspect of a child’s history—in utero exposure to organophosphates (OP), a commonly used class of pesticides—and early cognitive development. Working memory, perceptual reasoning, and IQ were among the measures of intellectual development associated with prenatal OP exposure. Bouchard et al. (2011) found that children in the category corresponding to the highest 20% of maternal urinary levels of OP metabolites during pregnancy showed a 7-point decrease in full scale IQ compared with children of mothers in the lowest 20%, an association of magnitude similar to that observed with an increase in blood lead concentrations from 1 to 10 µg/dL (Canfield et al. 2003). The strength of evidence arising from these studies reflects, in part, their rigorous study design. Each used a longitudinal birth cohort, a design well suited to detect the evolution of exposure effects over time. Accordingly, the latest findings build on previous data from these birth cohorts showing relationships between prenatal OP pesticide exposure levels and developmental end points in the first 3 years of life (e.g., Engel et al. 2007; Eskenazi et al. 2004; Rauh et al. 2006). Decrements in full-scale IQ, working memory, and perceptual reasoning showed the most consistent associations with prenatal exposure biomarkers across studies. Comparability of these results, despite differences in populations and exposure metrics, underscores the robustness of this latest group of findings. Two of the birth cohorts represent multiethnic inner city populations in New York City, while the third cohort comprises low-income families living in California’s Salinas Valley, an agricultural area. Rauh et al. (2011) measured chlorpyrifos in cord blood, whereas Engel et al. (2011) and Bouchard et al. (2011) relied on measurement of nonspecific OP metabolites in maternal urine samples collected during pregnancy. A primary limitation of these three studies relates to exposure assessment. One study measured chlorpyrifos and diazinon in blood (Rauh et al. 2011), but the other studies (Bouchard et al. 2011; Engel et al. 2011) measured OP pesticide breakdown products in urine. Some of these breakdown products can also be found pre-formed in food; thus, measurements in urine do not show how much exposure was due to the parent pesticide compounds or the preformed breakdown product. Another complication is that measurement of the breakdown products reflects exposure to many different OP pesticides, some that are much more toxic than others. For many OP pesticides, however, there are no laboratory methods to measure the parent pesticides in blood or specific breakdown products in urine at levels needed for epidemiologic research. The National Institute of Environmental Health Sciences (NIEHS), through the Exposure Biology Program, is supporting efforts to improve exposure assessment for epidemiological research. The three birth cohort studies highlighted here were initiated in the first phase of the Children’s Centers for Environmental Health and Disease Prevention Research Program. This program was developed jointly by the NIEHS and the U.S. Environmental Protection Agency (EPA) in response to a 1997 Executive Order that charged agencies to prioritize the identification and assessment of environmental health risks to children and to ensure that policies, programs, activities, and standards address these risks (Clinton 1997). At present, six full centers and six developmental/formative Children’s Centers, each comprised of interdisciplinary research teams, receive support through this program. Collectively, these centers are addressing a range of established and emerging priority issues in the environmental health of children, including neurodevelopment, respiratory health, and endocrine function. An important component of these NIEHS/U.S. EPA Children’s Centers is meaningful engagement of affected communities. Although not the focus of the articles in this issue of EHP, all three research teams have community outreach and translation cores whose primary objective is to rapidly and effectively translate the center study findings at local, state, and national levels to communities and stakeholders. These efforts have taken various forms, from hosting town hall meetings, developing community advisory boards, and encouraging integrated pest management solutions in New York City to outreach efforts to reduce take home exposures among farm workers in the Salinas Valley. The present findings in young children are likely to have implications for longer-term learning and academic success. Determining the persistence of these associations, and their generalizability to other populations, requires additional study. The U.S. EPA began a phase-out of the residential use of chlorpyrifos and diazinon in 2001 and 2004, respectively, which led to a marked reduction of markers of chlorpyrifos exposure in the United States, yet exposure to children continues due to use of organophosphate pesticides on crops and residues on foods. Spurred by recent advances in mechanistic toxicology and exposure science, efforts to improve identification of neurodevelopmental toxicity of new and existing industrial compounds are under way (e.g., U.S. Senate Committee on Environment & Public Works 2009). The findings of Bouchard et al. (2011), Engel et al. (2011), and Rauh et al. (2011) should stimulate renewed efforts to develop and fully implement measures that can identify threats before widespread exposure occurs and harms pregnant women and children.

Five rats were exposed to fixed-time food schedules, ranging from 30 to 480 sec. Three rats displayed a postfood pattern of schedule-induced drinking, with short latencies from food delivery to drinking at all interfood interval durations. In contrast, drinking for the other 2 subjects tended to occur at lower overall levels, and drinking bouts frequently began in the middle of the interfood interval, such that the latency from food delivery to drinking increased dramatically as the interfood interval increased. Observation of these 2 subjects revealed that another form of licking-pawgrooming-occurred reliably after food delivery and before drinking bouts. A between subject comparison of the 3 postfood drinkers and the 2 pawgroomers revealed that, in addition to a common topography (repetitive licking), pawgrooming and drinking were similar with respect to their temporal locus, relation to the interfood interval, and extinction baseline levels. These similarities suggest that drinking and pawgrooming are induced by a common mechanism. Cohen, Looney, Campagnoni, and Lawler’s (1985) two-state model of reinforcer-induced motivation provides a useful framework for the interpretation of these results.

Once thought to be rare, autism spectrum disorders (ASD) have gained increasing public attention as prevalence studies have revealed sharp increases over the past two decades. ASD now represents the second most common category of neurodevelopmental disorders. The prevalence data have been instrumental in mobilizing parents to act on behalf of their affected family members for better services and treatments and for greater research investments aimed at understanding what causes these disorders and how they can be prevented.

Parkinson disease (PD) continues to be a high research priority at the NIEHS. The institute currently supports a broad scope of research, from molecular epidemiology studies of environmental risk and protective factors for PD to basic laboratory investigations aimed at developing new animal models, understanding the role of mitochondrial oxidative damage in vulnerable cell populations, and defining transport mechanisms for toxicant entry to the brain. Taken together, results from these studies provide strong support for the idea that typical late-onset PD reflects joint effects of environmental factors and genetic susceptibility. The NIEHS has special interest in enabling the synthesis of findings emerging across disparate disciplines and research settings in the PD arena. The NIEHS Collaborative Centers for Parkinson’s Disease Environmental Research (CCPDER) Program was initiated in 2002 to strengthen the interchange among geneticists, clinicians, epidemiologists, and scientists engaged in fundamental laboratory research on PD. In June 2004, all NIEHS grantees in the area of neurodegeneration were brought together to share their most recent findings, and to identify and encourage new areas of collaboration among investigators. Most recently, the NIEHS partnered with the National Institute of Neurological Disorders and Stroke to support the development of a database, PD-DOC, that will enable sharing of clinical, pathological, biochemical, and risk factor information among researchers. A high-priority need that has been identified by PD researchers is for improved methodologies to facilitate data pooling, combined analysis, and comparison of results across epidemiologic studies. In response to this need, the NIEHS has provided support through the CCPDER Program for two meetings that will bring together PD epidemiologists and related experts to develop a series of methodologic recommendations. These will include guidelines for ascertainment and case definition in epidemiologic field studies, and recommendations for both exposure assessment methods and a minimal data set of high-importance exposures to be collected in future investigations. Materials produced through this mechanism will be made widely available through venues such as the CCPDER website, and will be used to guide the development of the epidemiologic component of PD-DOC. Collectively, these efforts are intended to improve the ability of epidemiologic researchers to identify novel genetic and environmental risk factors for PD, and to inform and be informed by mechanistic laboratory-based research. Ultimately, these data will provide a basis for devising strategies to prevent disease by avoiding or ameliorating harmful exposures and exploiting those exposures that confer protection.