Metformin rescues Parkinson's disease phenotypes caused by hyperactive mitochondria.

Metabolic dysfunction occurs in many age-related neurodegenerative diseases, yet its role in disease etiology remains poorly understood. We recently discovered a potential causal link between the branched-chain amino acid transferase BCAT-1 and the neurodegenerative movement disorder Parkinson's disease (PD). RNAi-mediated knockdown of Caenorhabditis elegans bcat-1 is known to recapitulate PD-like features, including progressive motor deficits and neurodegeneration with age, yet the underlying mechanisms have remained unknown. Using transcriptomic, metabolomic, and imaging approaches, we show here that bcat-1 knockdown increases mitochondrial respiration and induces oxidative damage in neurons through mammalian target of rapamycin-independent mechanisms. Increased mitochondrial respiration, or "mitochondrial hyperactivity," is required for bcat-1(RNAi) neurotoxicity. Moreover, we show that post-disease-onset administration of the type 2 diabetes medication metformin reduces mitochondrial respiration to control levels and significantly improves both motor function and neuronal viability. Taken together, our findings suggest that mitochondrial hyperactivity may be an early event in the pathogenesis of PD, and that strategies aimed at reducing mitochondrial respiration may constitute a surprising new avenue for PD treatment.

Happy, sad, or yucky? Parental emotion talk with infants in a book-sharing task.

While preschoolers consistently produce and use labels for happy and sad emotional states, labels for other emotional states (e.g., disgust) emerge much later in development. One explanation for these differences may lie in how parents first talk about these emotions with their children in infancy and toddlerhood. The current study examined parent talk about different emotions (i.e., happiness, sadness, anger, fear, and disgust) in a book-sharing task with their 12- to 24-month-old infants. Parental talk on each emotion page was coded for both quantity and quality of emotion talk. We found that, rather than labeling or asking questions about disgust emotional states, parents instead elaborated on and asked questions about the context of disgust pictures. In contrast, parents frequently labeled happy and sad emotional states and behaviors. Parental use of causal questions related to infants' productive emotion vocabularies. These different narrative styles may partly explain why older children acquire emotion labels for "happy" and "sad" much earlier than "disgust."

Cognitive reappraisal moderates the relationship between perfectionism and cognitive flexibility.

OBJECTIVE: Characterized by setting high standards for performance, perfectionism is a transdiagnostic process implicated in the development and maintenance of psychopathology. In contrast, cognitive flexibility is associated with enhanced mental health. Yet, the relationship between perfectionism and cognitive flexibility is understudied. We examined the relationship between perfectionism and cognitive flexibility, and whether emotion regulation strategies moderated the association between them. METHOD: Adult participants (N = 486) were recruited online and completed questionnaires on perfectionism, emotion regulation and cognitive flexibility. RESULTS: Perfectionism negatively correlated with one of the two aspects of cognitive flexibility assessed. Reappraisal, but not suppression, moderated the relationship between perfectionism and flexibility. CONCLUSIONS: Results indicate that perfectionism is associated with inflexible appraisal of everyday challenges. Additionally, cognitive reappraisal attenuates the negative relationship between perfectionism and cognitive flexibility; except in individuals with high narcissistic perfectionism for whom the debilitating relationship between the two variables is enhanced by reappraisal.

Expressive suppression mediates the relation between disordered eating and suicidal ideation.

OBJECTIVE: Although disordered eating is robustly associated with suicidal thoughts, it is not well understood why these conditions relate to each other. Emotion dysregulation is a shared risk factor for disordered eating and suicidal thoughts. Individuals with dysregulated emotions struggle to select appropriate strategies to modulate emotions and the strategies they use might explain some of the shared variances. Thus, we examined whether emotion regulation strategies mediated the relationship between disordered eating and suicidal ideation. METHOD: Adult participants (N = 230) completed questionnaires on current disordered eating symptoms, emotion regulation strategies, and current suicidal ideation. RESULTS: Disordered eating symptoms positively associated with suicidal ideation. In addition, expressive suppression mediated the relation between disordered eating symptoms and current suicidal ideation. No relation was found for cognitive reappraisal. CONCLUSIONS: The use of expressive suppression as an emotion regulation strategy may be related to increased suicidal ideation in individuals who express concerns about eating.

Perceived Stress Mediates Associations Between Grit and Health-Related Quality of Life.

Grit, characterized by passion and perseverance in the pursuit of long-term goals, may be associated with enhanced quality of life and reduced levels of perceived chronic stress. We hypothesized that reduced levels of perceived stress may mediate the association between facets of grit (i.e., Perseverance and Consistency) and healthy functioning. We conducted two studies, one with college students and one with community adults, to test this hypothesis (cumulative N = 600). In both studies, facets of grit were assessed using the Short Grit Scale, levels of perceived chronic stress were assessed via the Perceived Stress Scale, and health-related quality of life was measured using selected questions from the Medical Outcome Study Short Form-36. Consistent with our hypothesis, perceived stress levels significantly mediated the relation between Grit-Perseverance and health-related quality of life in both college students and community adults. Our data suggest that individuals with high Grit-Perseverance experience lower perceived stress, which may result in improved health-related quality of life. Additionally, perceived stress partially mediated the relation between Grit-Consistency and health-related quality of life, but only in community adults. These novel findings suggest that the association between Grit-Perseverance and perceived chronic stress may differ for college students and community adults. Overall, our work indicates that perceived stress may be a key mediator through which facets of grit are related to healthy functioning in college students and community adults.

Rumination and Gender in the Relation Between Perceived Threat and State Anxiety During COVID-19.

OBJECTIVES: Perception of and subsequent responses to counter threats by disease, such as COVID-19, are essential for engagement in self-protective behaviors. But, associated increases in anxiety that accompany the threat of disease may negatively impact well-being. Therefore, identifying variables that may modulate the association between perceived threat from COVID-19 and anxiety is important. We conducted a study to examine the moderating roles of two subtypes of rumination (brooding and reflection) in the association between perceived threat from COVID-19 and state anxiety. Additionally, as both COVID-19 outcomes and the tendency to ruminate differ across genders, we explored gender as a second moderator. METHODS: Participants (N = 300; Men = 144) were recruited online in April 2020 and completed measures of state anxiety, brooding and reflective rumination, and perceived threat from COVID-19. RESULTS: Moderation regression analyses revealed that perceived threat and brooding were independently associated with increased state anxiety. Reflective rumination and gender, however, significantly moderated the relation between perceived threat and state anxiety. For men, reflective rumination strengthened the association between threat and anxiety. For women, reflective rumination weakened this association; women with the highest scores in reflective rumination also reported high state anxiety at low, medium, and high perceived threat levels. CONCLUSIONS: These findings illuminate gender differences in the relations between perceived threat, rumination, and experienced state anxiety during the pandemic.

Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer's Disease.

Background: We profiled circulating plasma metabolites to identify systemic biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD). Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure small molecule plasma metabolites from 150 clinically diagnosed AD patients and 567 age-matched healthy elderly of Caribbean Hispanic ancestry. Plasma biomarkers of AD were measured including P-tau181, Aß40, Aß42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-abundant modules of metabolites were tested with clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels. Results: Over 6000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR = 0.91 [0.89-0.96], p = 2e-04). Association was restricted to individuals without an APOE ε4 allele (OR = 0.89 [0.84-0.94], p = 8.7e-05). Among individuals carrying at least one APOE ε4 allele, PC4 of lysoPCs moderately increased risk of AD (OR = 1.37 [1.16-1.6], p = 1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with Aß42/Aß40 ratio. Conclusions: Unbiased metabolic profiling can identify critical metabolites and pathways associated with ß-amyloid and phosphotau pathology. We also observed an APOE-ε4 dependent association of lysoPCs with AD and biologically based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

INTRODUCTION: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact. METHODS: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes. RESULTS: AD pathology on biopsy correlates with CSF ß-amyloid-40/42, neurofilament light chain (NfL), and phospho-tau-181(p-tau181)/ß-amyloid-42, while several gene expression modules correlate with NfL. Proteomic analysis highlights 7 core proteins that correlate with pathology and gene expression changes on biopsy, and metabolomic analysis of CSF identifies disease-relevant groups that correlate with biopsy data.. DISCUSSION: As additional biomarkers are added to AD diagnostic panels, our work provides insight into the CNS pathophysiology these markers are tracking.

Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles.

Ocular retinoblastoma malignancies, which develop into metastatic phenotypes, result in poor prognosis and survival for infant and child patients. To improve the prognosis of metastatic retinoblastoma, it is important to identify novel compounds with less toxic side effects and higher therapeutic efficacy compared to existing chemotherapeutics. Piperlongumine (PL), a neuroprotective, plant-derived compound has been explored for its anticancer activities both in vitro and in vivo. Here, we analyze the potential efficacy of PL for metastatic retinoblastoma cell treatment. Our data reveal that PL treatment significantly inhibits cell proliferation in metastatic retinoblastoma Y79 cells compared to the commonly used retinoblastoma chemotherapeutic drugs carboplatin, etoposide, and vincristine. PL treatment also significantly increases cell death compared to treatment with other chemotherapeutic drugs. PL-induced cell-death signaling was associated with significantly higher caspase 3/7 activities and greater loss of mitochondrial membrane potential. PL was also internalized into Y79 cells with an estimated concentration of 0.310pM and expression analysis revealed reduced MYCN oncogene levels. We next examined extracellular vesicles derived from PL-treated Y79 cells. Extracellular vesicles in other cancers are pro-oncogenic, mediating systemic toxicities via the encapsulation of chemotherapeutic drugs. Within metastatic Y79 EV samples, an estimated PL concentration of 0.026pM was detected. PL treatment significantly downregulated Y79 EV cargo of the oncogene MYCN transcript. Interestingly, non-PL-treated Y79 cells incubated with EVs from PL-treated cells exhibited significantly reduced cell growth. These findings indicate that in metastatic Y79 cells, PL exhibits potent anti-proliferation effects and oncogene downregulation. Importantly, PL is also incorporated into extracellular vesicles released from treated metastatic cells with measurable anti-cancer effects on target cells at a distance from the site of primary treatment. The use of PL in the treatment of metastatic retinoblastoma may reduce primary tumor proliferation and inhibit metastatic cancer activity systemically via extracellular vesicle circulation.

Metabolomic changes associated with chronic arsenic exposure in a Bangladeshi population.

Chronic exposure to arsenic (As) remains a global public health concern and our understanding of the biological mechanisms underlying the adverse effects of As exposure remains incomplete. Here, we used a high-resolution metabolomics approach to examine how As affects metabolic pathways in humans. We selected 60 non-smoking adults from the Folic Acid and Creatine Trial (FACT). Inorganic (AsIII, AsV) and organic (monomethylarsonous acid [MMAs], dimethylarsinous Acid [DMAs]) As species were measured in blood and urine collected at baseline and at 12 weeks. Plasma metabolome profiles were measured using untargeted high-resolution mass spectrometry. Associations of blood and urinary As with 170 confirmed metabolites and >26,000 untargeted spectral features were modeled using a metabolome-wide association study (MWAS) approach. Models were adjusted for age, sex, visit, and BMI and corrected for false discovery rate (FDR). In the MWAS screening of confirmed metabolites, 17 were associated with ≥1 blood As species (FDR<0.05), including fatty acids, neurotransmitter metabolites, and amino acids. These results were consistent across blood As species and between blood and urine As. Untargeted MWAS identified 423 spectral features associated with ≥1 blood As species. Unlike the confirmed metabolites, untargeted model results were not consistent across As species, with AsV and DMAs showing distinct association patterns. Mummichog pathway analysis revealed 12 enriched metabolic pathways that overlapped with the 17 identified metabolites, including one carbon metabolism, tricarboxylic acid cycle, fatty acid metabolism, and purine metabolism. Exposure to As may affect numerous essential pathways that underlie the well-characterized associations of As with multiple chronic diseases.

Metabolomic Evaluation of Air Pollution-related Bone Damage and Potential Mediation.

Ambient air pollution has been associated with bone damage. However, no studies have evaluated the metabolomic response to air pollutants and its potential influence on bone health in postmenopausal women. We analyzed data from WHI participants with plasma samples. Whole-body, total hip, femoral neck, and spine BMD at enrollment and follow-up (Y1, Y3, Y6). Daily particulate matter NO, NO2, PM10 and SO2 were averaged over 1-, 3-, and 5-year periods before metabolomic assessments. Statistical analyses included multivariable-adjusted linear mixed models, pathways analyses, and mediation modeling. NO, NO2, and SO2, but not PM10, were associated with taurine, inosine, and C38:4 phosphatidylethanolamine (PE), at all averaging periods. We found a partial mediation of C38:4 PE in the association between 1-year average NO and lumbar spine BMD (p-value: 0.032). This is the first study suggesting that a PE may partially mediate air pollution-related bone damage in postmenopausal women.

Linking Air Pollution Exposure to Blood-Based Metabolic Features in a Community-Based Aging Cohort with and without Dementia.

BACKGROUND: Long-term exposure to air pollution has been associated with changes in levels of metabolites measured in the peripheral blood. However, most research has been conducted in ethnically homogenous, young or middle-aged populations. OBJECTIVE: To study the relationship between the plasma metabolome and long-term exposure to three air pollutants: particulate matter (PM) less than 2.5µm in aerodynamic diameter (PM2.5), PM less than 10µm in aerodynamic diameter (PM10), and nitrogen dioxide (NO2) in an ethnically diverse, older population. METHODS: Plasma metabolomic profiles of 107 participants of the Washington Heights and Inwood Community Aging Project in New York City, collected from 1995-2015, including non-Hispanic white, Caribbean Hispanic, and non-Hispanic Black older adults were used. We estimated the association between each metabolic feature and predicted annual mean exposure to the air pollutants using three approaches: 1) A metabolome wide association study framework; 2) Feature selection using elastic net regression; and 3) A multivariate approach using partial-least squares discriminant analysis. RESULTS: 79 features associated with exposure to PM2.5 but none associated with PM10 or NO2. PM2.5 exposure was associated with altered amino acid metabolism, energy production, and oxidative stress response, pathways also associated with Alzheimer's disease. Three metabolites were associated with PM2.5 exposure through all three approaches: cysteinylglycine disulfide, a diglyceride, and a dicarboxylic acid. The relationship between several features and PM2.5 exposure was modified by diet and metabolic diseases. CONCLUSIONS: These relationships uncover the mechanisms through which PM2.5 exposure can lead to altered metabolic outcomes in an older population.

Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer's Disease.

Background: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD. Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aß40, Aß42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels. Results: Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without an APOE ε4 allele (OR=0.89 [0.84-0.94], p= 8.7e-05), the association remained. Among individuals carrying at least one APOE ε4 allele, PC4 of lysoPCs moderately increased risk of AD (OR=1.37 [1.16-1.6], p=1e-04). Essential amino acids including tyrosine metabolism pathways were enriched among metabolites associated with P-tau181 levels and heparan and keratan sulfate degradation pathways were associated with Aß42/Aß40 ratio reflecting different pathways enriched in early and middle stages of disease. Conclusions: Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with ß-amyloid and phosphotau pathology. We also observed an APOE ε4 dependent association of lysoPCs with AD and that biologically-based diagnostic criteria may aid in the identification of unique pathogenic mechanisms.

Seminar: Extracellular Vesicles as Mediators of Environmental Stress in Human Disease.

BACKGROUND: Extracellular vesicles (EVs), membrane-bound particles containing a variety of RNA types, DNA, proteins, and other macromolecules, are now appreciated as an important means of communication between cells and tissues, both in normal cellular physiology and as a potential indicator of cellular stress, environmental exposures, and early disease pathogenesis. Extracellular signaling through EVs is a growing field of research for understanding fundamental mechanisms of health and disease and for the potential for biomarker discovery and therapy development. EVs are also known to play important roles in mediating the effects of exposure to environmental stress. OBJECTIVES: This seminar addresses the application of new tools and approaches for EV research, developed in part through the National Institutes of Health (NIH) Extracellular RNA Communication Program, and reflects presentations and discussions from a workshop held 27-28 September 2021 by the National Institute of Environmental Health Sciences (NIEHS) and the National Center for Advancing Translational Sciences (NCATS) on "Extracellular Vesicles, Exosomes, and Cell-Cell Signaling in Response to Environmental Stress." The panel of experts discussed current research on EVs and environmental exposures, highlighted recent advances in EV isolation and characterization, and considered research gaps and opportunities toward identifying and characterizing the roles for EVs in environmentally related diseases, as well as the current challenges and opportunities in this field. DISCUSSION: The authors discuss the application of new experimental models, particularly organ-on-chip (OOC) systems and in vitro approaches and how these have the potential to extend findings in population-based studies of EVs in exposure-related diseases. Given the complex challenges of identifying cell-specific EVs related to environmental exposures, as well as the general heterogeneity and variability in EVs in blood and other accessible biological samples, there is a critical need for rigorous reporting of experimental methods and validation studies. The authors note that these efforts, combined with cross-disciplinary approaches, would ensure that future research efforts in environmental health studies on EV biomarkers are rigorous and reproducible. https://doi.org/10.1289/EHP12980.

The Lexical Stroop Sort (LSS) picture-word task: a computerized task for assessing the relationship between language and executive functioning in school-aged children.

The relationship between language development and executive function (EF) in children is not well understood. The Lexical Stroop Sort (LSS) task is a computerized EF task created for the purpose of examining the relationship between school-aged children's oral language development and EF. To validate this new measure, a diverse sample of school-aged children completed standardized oral language assessments, the LSS task, and the widely used Dimensional Change Card Sort (DCCS; Zelazo, 2006) task. Both EF tasks require children to sort stimuli into categories based on predetermined rules. While the DCCS largely relies on visual stimuli, the LSS employs children's phonological loop to access their semantic knowledge base. Accuracy and reaction times were recorded for both tasks. Children's scores on the LSS task were correlated with their scores on the DCCS task, and a similar pattern of relationships emerged between children's vocabulary and the two EF tasks, thus providing convergent validity for the LSS. However, children's phonological awareness was associated with their scores on the LSS, but not with those on the DCCS. In addition, a mediation model was used to elucidate the predictive relationship between phonological awareness and children's performance on the LSS task, with children's vocabulary fully mediating this relationship. The use of this newly created and validated LSS task with different populations, such as preschoolers and bilinguals, is also discussed.

Differential Associations between Strategies of Emotion Regulation and Facets of Grit in College Students and Adults.

According to socioemotional selectivity theory, motivation influences emotion regulation. Grit is a motivation orientation defined by the passionate pursuit of long-term goals. We conducted two studies to determine the relation between facets of grit and two emotion regulation strategies: cognitive reappraisal and expressive suppression. In Study 1, we examined the relation between these variables in college students (20-24 year olds), and Study 2 focused on community adults (25-72 year olds). Facets of grit were assessed using the Short Grit Scale and habitual use of emotion regulation strategies was assessed using the Emotion Regulation Questionnaire. We combined data from both studies and conducted regression analyses to examine the role of each facet of grit, participant's age, and the interaction between age and facets of grit in the habitual use of either reappraisal or suppression as strategies to regulate emotions. The regression analyses revealed that both facets of grit were positively associated with reappraisal regardless of age. However, the facets of grit differed in their associations with expressive suppression. Grit-Consistency was negatively associated with expressive suppression, regardless of age. But, a significant interaction effect with participant's age emerged for Grit-Perseverance. Specifically, Grit-Perseverance was positively associated with expressive suppression only in individuals below the age of 31. Overall, the data suggest that the relations between facets of grit and habitual use of emotion regulation strategy may vary with age. Additionally, our work indicates adults with high levels of grit may experience healthy emotional functioning, particularly later in adulthood.

An exposomic framework to uncover environmental drivers of aging.

The exposome, the environmental complement of the genome, is an omics level characterization of an individual's exposures. There is growing interest in uncovering the role of the environment in human health using an exposomic framework that provides a systematic and unbiased analysis of the non-genetic drivers of health and disease. Many environmental toxicants are associated with molecular hallmarks of aging. An exposomic framework has potential to advance understanding of these associations and how modifications to the environment can promote healthy aging in the population. However, few studies have used this framework to study biological aging. We provide an overview of approaches and challenges in using an exposomic framework to investigate environmental drivers of aging. While capturing exposures over a life course is a daunting and expensive task, the use of historical data can be a practical way to approach this research.

GAIT-GM integrative cross-omics analyses reveal cholinergic defects in a C. elegans model of Parkinson's disease.

Parkinson's disease (PD) is a disabling neurodegenerative disorder in which multiple cell types, including dopaminergic and cholinergic neurons, are affected. The mechanisms of neurodegeneration in PD are not fully understood, limiting the development of therapies directed at disease-relevant molecular targets. C. elegans is a genetically tractable model system that can be used to disentangle disease mechanisms in complex diseases such as PD. Such mechanisms can be studied combining high-throughput molecular profiling technologies such as transcriptomics and metabolomics. However, the integrative analysis of multi-omics data in order to unravel disease mechanisms is a challenging task without advanced bioinformatics training. Galaxy, a widely-used resource for enabling bioinformatics analysis by the broad scientific community, has poor representation of multi-omics integration pipelines. We present the integrative analysis of gene expression and metabolite levels of a C. elegans PD model using GAIT-GM, a new Galaxy tool for multi-omics data analysis. Using GAIT-GM, we discovered an association between branched-chain amino acid metabolism and cholinergic neurons in the C. elegans PD model. An independent follow-up experiment uncovered cholinergic neurodegeneration in the C. elegans model that is consistent with cholinergic cell loss observed in PD. GAIT-GM is an easy to use Galaxy-based tool for generating novel testable hypotheses of disease mechanisms involving gene-metabolite relationships.

Influences of climate change on long-term time series of persistent organic pollutants (POPs) in Arctic and Antarctic biota.

Time series of contaminants in the Arctic are an important instrument to detect emerging issues and to monitor the effectiveness of chemicals regulation, based on the assumption of a direct reflection of changes in primary emissions. Climate change has the potential to influence these time trends, through direct physical and chemical processes and/or changes in ecosystems. This study was part of an assessment of the Arctic Monitoring and Assessment Programme (AMAP), analysing potential links between changes in climate-related physical and biological variables and time trends of persistent organic pollutants (POPs) in Arctic biota, with some additional information from the Antarctic. Several correlative relationships were identified between POP temporal trends in freshwater and marine biota and physical climate parameters such as oscillation indices, sea-ice coverage, temperature and precipitation, although the mechanisms behind these observations remain poorly understood. Biological data indicate changes in the diet and trophic level of some species, especially seabirds and polar bears, with consequences for their POP exposure. Studies from the Antarctic highlight increased POP availability after iceberg calving. Including physical and/or biological parameters in the POP time trend analysis has led to small deviations in some declining trends, but did generally not change the overall direction of the trend. In addition, regional and temporary perturbations occurred. Effects on POP time trends appear to have been more pronounced in recent years and to show time lags, suggesting that climate-related effects on the long time series might be gaining importance.

Cross-species metabolomic analysis of tau- and DDT-related toxicity.

Exposure to the pesticide dichlorodiphenyltrichloroethane (DDT) has been associated with increased risk of Alzheimer's disease (AD), a disease also associated with hyperphosphorylated tau (p-tau) protein aggregation. We investigated whether exposure to DDT can exacerbate tau protein toxicity in Caenorhabditiselegans using a transgenic strain that expresses human tau protein prone to aggregation by measuring changes in size, swim behavior, respiration, lifespan, learning, and metabolism. In addition, we examined the association between cerebrospinal fluid (CSF) p-tau protein-as a marker of postmortem tau burden-and global metabolism in both a human population study and in C. elegans, using the same p-tau transgenic strain. From the human population study, plasma and CSF-derived metabolic features associated with p-tau levels were related to drug, amino acid, fatty acid, and mitochondrial metabolism pathways. A total of five metabolites overlapped between plasma and C. elegans, and four between CSF and C. elegans. DDT exacerbated the inhibitory effect of p-tau protein on growth and basal respiration. In the presence of p-tau protein, DDT induced more curling and was associated with reduced levels of amino acids but increased levels of uric acid and adenosylselenohomocysteine. Our findings in C. elegans indicate that DDT exposure and p-tau aggregation both inhibit mitochondrial function and DDT exposure can exacerbate the mitochondrial inhibitory effects of p-tau aggregation. Further, biological pathways associated with exposure to DDT and p-tau protein appear to be conserved between species.