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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.

D(2)-like dopamine receptors mediate functional changes via activation of inhibitory G proteins, including those that affect adenylate cyclase activity, and potassium and calcium channels. Although it is assumed that the binding of a drug to a single isoform of a D(2)-like receptor will cause similar changes in all receptor-mediated functions, it has been demonstrated in brain that the dopamine agonists dihydrexidine (DHX) and N-n-propyl-DHX are "functionally selective". The current study explores the underlying mechanism using transfected MN9D cells and D(2)-producing anterior pituitary lactotrophs. Both dopamine and DHX inhibited adenylate cyclase activity in a concentration-dependent manner in both systems, effects blocked by D(2), but not D(1), antagonists. In the MN9D cells, quinpirole and R-(-)-N-propylnorapomorphine (NPA) also inhibited the K(+)-stimulated release of [(3)H]dopamine in a concentration-responsive, antagonist-reversible manner. Conversely, neither DHX, nor its analogs, inhibited K(+)-stimulated [(3)H]dopamine release, although they antagonized the effects of quinpirole. S-(+)-NPA actually had the reverse functional selectivity profile from DHX (i.e., it was a full agonist at D(2L) receptors coupled to inhibition of dopamine release, but a weak partial agonist at D(2L) receptor-mediated inhibition of adenylate cyclase). In lactotrophs, DHX had little intrinsic activity at D(2) receptors coupled to G protein-coupled inwardly rectifying potassium channels, and actually antagonized the effects of dopamine at these D(2) receptors. Together, these findings provide compelling evidence for agonist-induced functional selectivity with the D(2L) receptor. Although the underlying molecular mechanism is controversial (e.g., "conformational induction" versus "drug-active state selection"), such data are irreconcilable with the widely held view that drugs have "intrinsic efficacy".

Dihydrexidine (DHX), the first high-affinity D 1 dopamine receptor full agonist, is only 10-fold selective for D 1 versus D 2 receptors, having D 2 affinity similar to the prototypical agonist quinpirole. The D 2 functional properties of DHX and its more D 2 selective analog N - n -propyl-dihydrexidine (PrDHX) were explored in rat brain and pituitary. DHX and PrDHX had binding characteristics to D 2 receptors in rat striatum typical of D 2 agonists, binding to both high- and low-affinity sites and being sensitive to guanine-nucleotides. Consistent with these binding data, both DHX and PrDHX inhibited forskolin-stimulated cAMP synthesis in striatum with a potency and intrinsic activity equivalent to that of quinpirole. Unexpectedly, however, DHX and PrDHX had little functional effect at D 2 receptors expressed on dopaminergic neurons that mediate inhibition of cell firing, dopamine release, or dopamine synthesis. Quantitative receptor competition autoradiography demonstrated that DHX bound to D 2 receptors in striatum (predominantly postsynaptic receptor sites) with equal affinity as D 2 sites in the substantia nigra (autoreceptor sites). The data from these experiments, coupled with what is known about the location of specific dopamine receptor isoforms, lead to the hypothesis that DHX, after binding to D 2L and D 2S receptors, causes agonist-typical functional changes only at some of these receptors. This phenomenon (herein termed “functional selectivity”) suggests that drugs may be targeted not only at specific receptor isoforms but also at separate functions mediated by a single isoform, yielding novel approaches to drug discovery.

The unavailability of selective D1A (D1) or D1B (D5) dopamine receptor ligands has prevented the direct localization of binding sites for these receptors. Thus, receptor autoradiography with long exposure times was used to detect minor D1-like binding sites in the brains of D1A null mutants. Coronal brain sections were prepared from the caudal portion of the prefrontal cortex of homozygous or heterozygous D1A knockout mice or wildtype mice, and labeled with the D1 receptor antagonist [3H]-SCH23390. Slides were dried, and apposed to film with polymer-calibrated standards for 90 days to allow visualization of any low abundance binding sites. No binding was detected in most regions of homozygote (−/−) mouse brains that have high densities of D1 binding in wildtype mice (e.g., the striatum, nucleus accumbens, olfactory tubercles or amygdala). Conversely, small, but detectable amounts of D1-binding were measured in the hippocampus, albeit with a density less than the lowest standard (ca. 20 fmol/mg). Saturation binding of [3H]-SCH23390 in hippocampal homogenates from homozygous mice confirmed a Bmax of 12.3 fmol/mg protein with a KD of 0.57 nM. The current work demonstrates directly the presence of D1B (D5) receptors in hippocampus, and also shows that the loss of functional D1A gene products almost completely eliminates detectable D1-binding sites in striatum, as well as in some regions (e.g., the amygdala) where a non-adenylyl cyclase coupled D1 receptor has been reported. This indicates that these non-adenylyl cyclase coupled D1-like receptors represent alternate signaling pathways rather than novel gene products(s). Synapse 39:319–322, 2001. © 2001 Wiley-Liss, Inc.

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.

A novel phenylaminotetralin (PAT) radioligand, [ 3 H ]-(1R,3S)-(−)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene ([ 3 H ]-[−]-trans-H2-PAT), is shown here to label a saturable (Bmax=39±6 fmol/mg protein) population of sites with high affinity (Kd=0.13±0.03 nM) in guinea pig brain. Consistent with previous studies which showed that PATs stimulate catecholamine (dopamine) synthesis in rat striatum, autoradiographic brain receptor mapping studies here indicate that [ 3 H ]-(−)-trans-H2-PAT-labeled sites are highly localized in catecholaminergic nerve terminal fields in hippocampus, nucleus accumbens, and striatum in guinea pig brain. Competition binding studies with a broad range of CNS receptor-active ligands and CNS radioreceptor screening assays indicate that the pharmacological binding profile of brain [ 3 H ]-(−)-trans-H2-PAT sites closely resembles histamine H1-type receptors. Comparative studies using the histamine H1 antagonist radioligand, [ 3 H ]mepyramine, indicate that the H1 ligand binding profile and guinea pig brain distribution of H1 receptors and [ 3 H ]-(−)-trans-H2-PAT sites are nearly identical; moreover, both sites have about 40-fold stereoselective affinity for (−)- over (+)-trans-H2-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (σ3) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H1 receptors that can be stereoselectively labeled with [ 3 H ]-(−)-trans-H2-PAT.

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.

Dopamine D 1A receptor-deficient mice were assessed in a wide variety of tasks chosen to reflect the diverse roles of this receptor subtype in behavioural regulation. The protocol included examination of exploration and locomotor activity in an open field, a test of sensorimotor orienting, both place and cue learning in the Morris water maze, and assessment of simple associative learning in an olfactory discrimination task. Homozygous mice showed broad-based impairments that were characterized by deficiencies in initiating movement and/or reactivity to external stimuli. Data obtained from flash evoked potentials indicated that these deficits did not reflect gross visual impairments. The partial reduction in D 1A receptors in the heterozygous mice did not affect performance in most tasks, although circumscribed deficits in some tasks were observed (e.g., failure to develop a reliable spatial bias in the water maze). These findings extend previous behavioural studies of null mutant mice lacking D 1A receptors and provide additional support for the idea that the D 1A receptor participates in a wide variety of behavioural functions. The selective impairments of heterozygous mice in a spatial learning task suggest that the hippocampal/cortical dopaminergic system may be uniquely vulnerable to the partial loss of the D 1A receptor.

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

A critical assumption in the unilateral 6-hydroxydopamine (6-OHDA) model is that interactions between the intact and denervated hemispheres do not influence the response to insult. The present study examined this issue by assessing the effects of unilateral substantia nigra 6-OHDA lesions in rats that previously had received corpus callosum transections, a treatment designed to minimize interhemispheric influences. Quantitative autoradiography in the caudate-putamen ipsilateral to the lesion revealed that corpus callosum transection did not alter the increase in D2-like receptors ([125I]-epidepride-labeled sites) that is induced by unilateral 6-OHDA lesion. There were no effects of either 6-OHDA lesion or transection on D1 receptor density ([l25I]-SCH23982 autoradiography). As a functional endpoint, dopamine-stimulated cAMP efflux was measured in superfused striatal slices. In this paradigm, the net effect of dopamine (DA) represents a combination of D1 receptor-mediated stimulation and D2 receptor-mediated inhibition. 6-OHDA lesion increased cAMP efflux induced by exposure to 100 p.M DA alone; corpus callosum transection did not alter this effect. An interaction between 6-OHDA lesion and transection status was revealed, however, by comparison of results obtained with DA alone vs. DA plus the D2 antagonist sulpiride (to block the D2 inhibitory effects of 100 p.M DA). This comparison revealed two important effects of 6-OHDA lesion in rats with an intact corpus callosum: (1)a moderate decrease in dopamine Dl receptor-mediated stimulation; and (2) a dramatic decrease in the ability of D2 receptors to inhibit this stimulation. Corpus callosum transection prevented these effects of 6-OHDA. These results provide a biochemical demonstration of D1:D2 receptor uncoupling in unilateral 6-OHDA lesioned rats, and suggest that interhemispheric influences (e.g., contralateral cortico-striatal glutamatergic projections) may contribute to lesion-induced alterations in D1:D2 receptor interactions. © 1995 Wiley-Liss, Inc.

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.

The effects of postmortem interval on dopamine D1 mRNA and D1 receptors were assessed in rat striatum under conditions simulating the handling of human brain tissue at 0, 6, 12, and 24 h postmortem. The amount of D1 mRNA was measured by both in situ hybridization film and emulsion autoradiography with [35S]dATP-labeled oligonucleotide probes. D1 receptor density was determined by autoradiography with [125I]SCH 23982. Neither the total amount of D1 mRNA in the striatum nor the frequency distribution of striatal cells expressing D1 mRNA varied with the postmortem interval. There was a modest but significant decrease (ca. 10%) in D1 receptors over the 24 h postmortem interval; this decrease occurred within the first 6 h postmortem, with no further decreases up to 24 h postmortem. These findings suggest that the effects of postmortem interval on D1 mRNA and receptors are minimal and should not limit an examination of possible alterations in dopamine D1 receptor mRNA and D1 receptors in the postmortem brains of humans with neuropsychiatric disease.

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.

The potential role of environmental factors in autism spectrum disorders (ASD) is an area of emerging interest within the public and scientific communities. The high degree of heritability of ASD suggests that environmental influences are likely to operate through their interaction with genetic susceptibility during vulnerable periods of development. Evaluation of the plausibility of specific neurotoxicants as etiological agents in ASD should be guided by toxicological principles, including dose-effect dependency and pharmacokinetic parameters. Clinical and epidemiological investigations require the use of sufficiently powered study designs with appropriate control groups and unbiased case ascertainment and exposure assessment. Although much of the existing data that have been used to implicate environmental agents in ASD are limited by methodological shortcomings, a number of efforts are underway that will allow more rigorous evaluation of the role of environmental exposures in the etiology and/or phenotypic expression of the disorder. Surveillance systems are now in place that will provide reliable prevalence estimates going forward in time. Anticipated discoveries in genetics, brain pathology, and the molecular/cellular basis of functional impairment in ASD are likely to provide new opportunities to explore environmental aspects of this disorder.

Parkinson’s disease (PD) appears to arise from the interaction of three events—an individual’s inherited genetic susceptibility, their subsequent environmental exposures, and their age. We clearly need to intensify efforts to understand the environmental triggers of PD, the importance of the timing of exposure to these triggers, and the interplay between these exposures and a persons underlying genetic constitution and susceptibilities. This knowledge, once generated, will lead to better detection of the earliest stages of PD, to improved therapeutics, and most importantly, to viable prevention strategies so that people need not suffer from environmentally-caused PD. Many promising lines of investigation are already supported by the National Institute of Environmental Health Sciences (NIEHS), National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Aging (NIA) and other public and private organizations. In order to accelerate the pace of progress in this field, the NIEHS is developing a Consortium Centers Program that will provide a formal mechanism for “cross-talk” between PD clinicians, basic research scientists, and patient advocates. The Consortium will seek to identify and support novel approaches and research ventures that might not otherwise be pursued by scientists working in isolation. The NIEHS will also continue to explore ways to promote more mechanism-based research to understand putative environmental triggers for PD in concert with defined genetic susceptibilities.

In an analogy to the potent catechol dopamine D1 agonists dihydrexidine (1) and dinapsoline (2), benzo rings were fused onto the structures of the dopamine D2-selective agonists quinelorane (3) and quinpirole (4). Each of the phenyl ring-substituted derivatives had significant affinity for D2 receptors, albeit somewhat lower than the two parent compounds, 3 and 4. Compounds with N-propyl and N-allyl substituents (5b, 5c, 6c, and 6d) had higher affinity for the D2 dopamine receptor than did their corresponding secondary amines (5a and 6a). Slightly different effects on affinity of an n-propyl and an n-allyl group in the new analogues of 3 and 4 suggest that different binding orientations may be invoked at the receptor.

The N-n-propyl analog of dihydrexidine ((±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine) is a dopamine receptor agonist with high affinity for dopamine D2 and D3 receptors (K0.5=26 and 5 nM, respectively). Members of the hexahydrobenzo[a]phenanthridine structural class are atypical because they display high intrinsic activity at post-synaptic dopamine D2 receptors, but low intrinsic activity at dopamine D2 autoreceptors. The present study examined the effects of (±)-N-n-propyl-dihydrexidine on unconditioned behaviors in rats. The most striking results observed were large, dose-dependent decreases in locomotor activity (e.g., locomotor inhibition), and increases in vacuous chewing; yawning was also increased at the highest dose of (±)-N-n-propyl-dihydrexidine. The locomotor inhibition and yawning induced by (±)-N-n-propyl-dihydrexidine were blocked by pre-treatment with (−)-remoxipride (S(−)-3-bromo-N-((1-ethyl-2-pyrrolidinyl)-methyl)-2,6-dimethoxybenzamide), a dopamine D2 receptor antagonist, but not by the dopamine D1 receptor antagonist (+)-SCH23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). Vacuous chewing was decreased by both (−)-remoxipride and (+)-SCH23390. These data support the hypothesis that a subpopulation of post-synaptic dopamine D2 receptors has a critical role in decreases in locomotor activity and induction of vacuous chewing and yawning. © 1997 Elsevier Science B.V. All rights reserved.

The intrinsic activities of selected dopamine D1 receptor agonists were compared in three distinct molecular expression systems, C-6, Ltk, and GH4, cells transfected with primate D1A receptors. The influence of the cell expression system on intrinsic activity varied markedly among agonists. Dihydrexidine (DHX), a potent full agonist with dramatic antiparkinsonian actions, displayed intrinsic activity similar to dopamine in all three cell lines. In contrast, SKF82958 and SKF38393 (full and partial agonists, respectively, in rat striatum) had intrinsic activities equal to dopamine in GH4, cells that expressed a high density of D1 receptors, yet were of lower intrinsic activity in C-6 cells having 15-fold fewer receptors. The idea that spare receptors are one important determinant of observed intrinsic activity was explored directly by “receptor titration”, in which ca. 90% of D1 receptors in Ltk cells were inactivated using EEDQ, an irreversible antagonist. Whereas EEDQ pretreatment decreased the potency of all agonists, it changed the intrinsic activity of some, but not all, drugs. A 40% decrease was seen with the partial agonist SKF38393, and, surprisingly, a 30% decrease was seen with the purported full agonist SKF82958. Conversely, the intrinsic activity of DHX and A68930 were unaffected by the EEDQ treatment. The data demonstrate that significant and biologically meaningful differences in intrinsic efficacy (e.g., DHX vs. SKF82958) may be obscured in test systems that have sufficient receptor reserve (e.g., the striatum). Such differences in intrinsic efficacy may be an important predictor of the clinical utility of D1 agonists. © 1995 Wiley-Liss, Inc.

Recent data indicate that full D1 dopamine agonists have greater antiparkinsonian effects in the MPTP primate model than do partial agonists, suggesting that the intrinsic activity of D1 agonists may affect their utility in the treatment of Parkinson's disease. It is unclear, however, whether human D1 receptors in situ are similar to D1 receptors in other species or in molecular expression systems. For this reason, the binding affinity and functional activity of a series of D1 dopamine receptor agonists [dihydrexidine (DHX), SKF82958, and A68930] were determined in postmortem human caudate. Results from in vitro binding studies with membranes from human caudate indicate that these D1 agonists competed for [3H]SCH23390 labeled sites with a rank order similar to that found in rat striatum [K50 = 36.8 nM (DHX); 18.6 nM (SKF82958); 3.9 nM (A68930)]. The ability of these compounds and the partial agonist SKF38393 to stimulate the enzyme adenylyl cyclase in tissue homogenates of human caudate was also examined. DHX and A68930 are full agonists compared to dopamine, whereas SKF82958 and SKF38393 are partial agonists. These differences in biochemical intrinsic activity are consistent with the profound antiparkinsonian effects caused by DHX, but not by SKF82958 and SKF38393, in the MPTP-monkey model. This suggests that DHX and A68930 may be of greater utility in treating disorders where a full efficacy D1 agonist may be required.

Changes in the mesostriatal dopamine system associated with normal aging are observed in both human and laboratory animals, but the specific behavioral consequences of these nonpathological changes are largely unexplored. The present study (a) assessed the effects of normal aging on markers for the mesostriatal dopamine system, and (b) examined the relationship of age-related changes in this system to decline in reaction time performance. Decreased levels of midbrain dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were observed in the aged rats as compared to young, but there was no evidence for age-related changes in the density of D1 or D2 receptor binding or the density of dopamine uptake sites. Some differences were observed when the aged rats were grouped according to reaction time performance. Aged RT-unimpaired rats exhibited higher density of D1 binding in rostrodorsal striatal patch areas, but lower overall levels of DA. In caudal striatum, aged RT-unimpaired rats exhibited lower DA and higher DOPAC levels.

Although partial efficacy dopamine D1 receptor agonists have little therapeutic benefit in parkinsonism, the first high potency, full efficacy dopamine D1 receptor agonist dihydrexidine recently has been shown to have profound antiparkinsonian effects. One reason for the greater antiparkinsonian effects of dihydrexidine vs. SKF38393 might be that SKF38393, while a partial dopamine D1 receptor agonist in rodent striatal preparations, has virtually no agonist activity in monkey striatum (Pifl et al., 1991, Eur. J. Pharmacol. 202, 273). To explore this hypothesis, we compared the dopamine D1 receptor affinity and efficacy of dihydrexidine and SKF38393 in striatum from rat and monkey. In vitro binding studies using membranes from putamen of adult rhesus monkeys demonstrated that dihydrexidine competed for dopamine D1 receptors (labeled with [3H]SCH23390) with high potency (IC50 = 20 nM vs. ca. 10 nM in rat brain). SKF38393 was about 4-fold less potent than dihydrexidine in both monkey and rat brain. The in vitro functional activity of these drugs was assessed by their ability to stimulate adenylate cyclase activity in tissue homogenates. Dihydrexidine was of full efficacy (relative to dopamine) in stimulating cAMP synthesis in both monkey and rat. SKF38393 was only a partial efficacy agonist in both rat striatum and monkey putamen, but contrary to the original hypothesis, it had the same efficacy (ca. 40% relative to dihydrexidine) in membranes from both species. Interestingly, greater between-subject variation was found in the stimulation produced by SKF38393 in primate compared to rat brain, although the basis for this variation is unclear.(ABSTRACT TRUNCATED AT 250 WORDS)

We report that certain substituted hexahydrobenzo[a]phenanthridines are novel high affinity ligands selective for the dopamine D3 receptor. These data demonstrate that substitutions on the heterocyclic nitrogen and the pendant phenyl ring of this nucleus cause a marked increase in both affinity and selectivity for dopamine D3 vs. D2 receptors. Thus, these compounds represent important new tools to study the pharmacology of dopamine D3 receptors, and may also provide an opportunity for the synthesis of new radioligands for dopamine D3 receptors.

The radiosynthesis of (1R)-(+)-1-phenyl-3-methyl-7-[125I]iodo-8-hydroxy- 2,3,4,5-tetrahydro-1H-3-benzazepine (commonly referred to as SCH23982) and its use as a high affinity D1 dopamine antagonist ligand have been reported previously. We now provide a simple and inexpensive protocol for the rapid and efficient synthesis of this radioligand based on the Cloramine-T-catalyzed reaction between the commercially available precursor (R)-(+)-1-phenyl-3-methyl- 8-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine and carrier-free sodium [125I]iodide. [125I]SCH23982 is separated rapidly (within 20 min) from the precursor and reaction byproducts (e.g., chlorinated precursor, SCH23390) by reverse-phase HPLC on a C-8 column. The major iodinated product has been identified as SCH23982 based on co-chromatography with authentic SCH23982, UV spectral characteristics, and biological activity. The chromatographic effluent containing the active product is adsorbed on a C-18 Sep-Pak cartridge to remove mobile-phase constituents and permit it to be eluted and diluted to the desired concentration; this technique is used also for periodic repurification. Our synthesis protocol results in final purified product that incorporates ca. 50% of the initial 125I (tested using starting quantities of 1-10 mCi Na125I); the final product has a specific activity of ca. 2500 +/- 350 Ci/mmol. Data from in vitro receptor autoradiographic and homogenate studies with this radioligand are consistent with previously reported values in terms of expected receptor distribution, affinity, and density (KD of 1.0 nM, Bmax of 1400 fmol/mg protein in rat striatal membranes).

Three White King pigeons were exposed to fixed-time schedules ranging from 60 to 240 sec. General activity and attack against a conspecific target were measured separately at each interreinforcer interval value. Comparison of the temporal distributions of activity and attack revealed significant differences in their temporal locus and overall distribution between reinforcer presentations. At all interval values, attack was localized to the postreinforcer period, and peaked at the same absolute time (5–10 sec) following each reinforcer presentation. General activity was more uniformly distributed between reinforcers, and the peak level occurred later in the interval. As the interval length increased, peak levels of activity shifted to later times following reinforcement. These differences question traditional accounts which posit a unitary process underlying induced behaviors, while supporting Cohen, Looney, Campagnoni and Lawler's recent two-state model of induced behaviors [8].

Schedule-induced polydipsia as a function of six water dipper sizes was examined in four food-deprived rats under Fixed Time 1- and 2-minute schedules. Increasing dipper size increased session water intake but did not affect the number of intervals containing at least one barpress (i.e., number of bouts), nor the number of barpresses per bout, nor the temporal distribution of barpressing within the interfood interval. Previous research showing polydipsic intake to be impervious to other types of restrictions on water availability have suggested the notion of a volume constancy mechanism. The present research raises questions about the operation of the volume constancy mechanism, questions about how to conceptualize the dipper size manipulation, and questions about variables which affect the temporal locus of drinking.