Metabolic alterations in the cortex of a mouse model with glutathione deficit - relevance to schizophrenia

Background: Glutathione (GSH) is a major redox regulator and antioxidant and is decreased in cerebrospinal fluid and prefrontal cortex of schizophrenia patients [Do et al. (2000) Eur J Neurosci 12:3721]. The genes of the key GSH-synthesizing enzyme, glutamate- cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits, are associated with schizophrenia, suggesting that the deficit in GSH synthesis is of genetic origin [Gysin et al. (2007) PNAS 104:16621]. GCLM knock-out (KO) mice, which display an 80% decrease in brain GSH levels, have abnormal brain morphology and function [Do et al. (2009) Curr Opin Neurobiol 19:220]. Developmental redox deregulation by impaired GSH synthesis and environmental risk factors generating oxidative stress may have a central role in schizophrenia. Here, we used GCLM KO mice to investigate the impact of a genetically dysregulated redox system on the neurochemical profile of the developing brain. Methods: The neurochemical profile of the anterior and posterior cortical areas of male and female GCLM KO and wild-type mice was determined by in vivo 1H NMR spectroscopy on postnatal days 10, 20, 30, 60 and 90, under 1 to 1.5% isoflurane anaesthesia. Localised 1H NMR spectroscopy was performed on a 14.1 T, 26 cm VNMRS spectrometer (Varian, Magnex) using a home-built 8 mm diameter quadrature surface coil (used both for RF excitation and signal reception). Spectra were acquired using SPECIAL with TE of 2.8 ms and TR of 4 s from VOIs placed in anterior or posterior regions of the cortex [Mlynárik et al. (2006) MRM 56:965]. LCModel analysis allowed in vivo quantification of a neurochemical profile composed of 18 metabolites. Results: GCLM KO mice displayed nearly undetectable GSH levels as compared to WT mice, demonstrating their drastic redox deregulation. Depletion of GSH triggered alteration of metabolites related to its synthesis, namely increase of glycine and glutamate levels during development (P20 and P30). Concentrations of glutamine and aspartate that are produced from glutamate were also increased in GCLM KO animals relative to WT. In addition, GCLM KO mice also showed higher levels of N-acetylaspartate that originates from the acetylation of aspartate. These metabolites are particularly implicated in neurotransmission processes and in mitochondrial oxidative metabolism. Their increase may indicate impaired mitochondrial metabolism with concomitant accumulation of lactate in the adult mice (P60 and P90). In addition, the GSH depletion triggers reduction of GABA concentration in anterior cortex of the P60 mice, which is in accordance with known impairment of GABAergic interneurons in that area. Changes were generally more pronounced in males than in females at P60, which is consistent with earlier disease onset in male patients. Discussion: In conclusion, the observed metabolic alterations in the cortex of a mouse model of redox deregulation suggest impaired mitochondrial metabolism and altered neurotransmission. The results also highlight the age between P20 and P30 as a sensitive period during the development for these alterations.

Sustainability, certification, and regulation of biochar

Biochar has a relatively long half-life in soil and can fundamentally alter soil properties, processes, and ecosystem services. The prospect of global-scale biochar application to soils highlights the importance of a sophisticated and rigorous certification procedure. The objective of this work was to discuss the concept of integrating biochar properties with environmental and socioeconomic factors, in a sustainable biochar certification procedure that optimizes complementarity and compatibility between these factors over relevant time periods. Biochar effects and behavior should also be modelled at temporal scales similar to its expected functional lifetime in soils. Finally, when existing soil data are insufficient, soil sampling and analysis procedures need to be described as part of a biochar certification procedure.

The global carbon budget:a conflicting claims problem

Despite global environmental governance has traditionally couched global warming in terms of annual CO2 emissions (a flow), global mean temperature is actually determined by cumulative CO2 emissions in the atmosphere (a stock). Thanks to advances of scientific community, nowadays it is possible to quantify the \global carbon budget", that is, the amount of available cumulative CO2 emissions before crossing the 2oC threshold (Meinshausen et al., 2009). The current approach proposes to analyze the allocation of such global carbon budget among countries as a classical conflicting claims problem (O'Neill, 1982). Based on some appealing principles, it is proposed an efficient and sustainable allocation of the available carbon budget from 2000 to 2050 taking into account different environmental risk scenarios. Keywords: Carbon budget, Conflicting claims problem, Distribution, Climate change. JEL classification: C79, D71, D74, H41, H87, Q50, Q54, Q58.

The anticancer drug metabolites endoxifen and 4-hydroxy-tamoxifen induce toxic effects on Daphnia pulex in a two-generation study.

Although pharmaceutical metabolites are found in the aquatic environment, their toxicity on living organisms is poorly studied in general. Endoxifen and 4-hydroxy-tamoxifen (4OHTam) are two metabolites of the widely used anticancer drug tamoxifen for the prevention and treatment of breast cancers. Both metabolites have a high pharmacological potency in vertebrates, attributing prodrug characteristics to tamoxifen. Tamoxifen and its metabolites are body-excreted by patients, and the parent compound is found in sewage treatment plan effluents and natural waters. The toxicity of these potent metabolites on non-target aquatic species is unknown, which forces environmental risk assessors to predict their toxicity on aquatic species using knowledge on the parent compounds. Therefore, the aim of this study was to assess the sensitivity of two generations of the freshwater microcrustacean Daphnia pulex towards 4OHTam and endoxifen. Two chronic tests of 4OHTam and endoxifen were run in parallel and several endpoints were assessed. The results show that the metabolites 4OHTam and endoxifen induced reproductive and survival effects. For both metabolites, the sensitivity of D. pulex increased in the second generation. The intrinsic rate of natural increase (r) decreased with increasing 4OHTam and endoxifen concentrations. The No-Observed Effect Concentrations (NOECs) calculated for the reproduction of the second generation exposed to 4OHTam and endoxifen were <1.8 and 4.3μg/L, respectively, whereas the NOECs that were calculated for the intrinsic rate of natural increase were <1.8 and 0.4μg/L, respectively. Our study raises questions about prodrug and active metabolites in environmental toxicology assessments of pharmaceuticals. Our findings also emphasize the importance of performing long-term experiments and considering multi-endpoints instead of the standard reproduction outcome.

Early adversity and 5-HTT-BDNF genes: new evidences of gene-environment interactions on depressive symptoms in a general population

Adverse childhood experiences have been described as one of the major environmental risk factors for depressive disorder. Likewise, the deleterious impact of early traumatic experiences on depression seems to be moderated by individual genetic variability. Serotonin transporter (5-HTT) and the Brain-Derived Neurotrophic Factor (BDNF) seem to modulate the effect of childhood adversity on adult depression, although inconsistencies across studies have been found. Moreover, the GxE interaction concerning the different types of childhood adversity remains poorly understood. The aim of this study is to analyse the putative interaction between the 5-HTT gene (5-HTTLPR polymorphism), BDNF gene (Val66Met polymorphism) and childhood adversity in accounting for adult depressive symptoms.

Tien rakentajan ja kunnossapitäjän ympäristöriskit ja -vastuut moottoritien elinkaarihankkeessa

Diplomityössä on tarkasteltu moottoritien rakentajan ja kunnossapitäjän ympäristöriskejä ja -vastuita moottoritien elinkaarihankkeessa. Työssä esitellään malli ympäristöriskien analysoimiseksi. Mallin avulla tuotetun tiedon pohjalta yrityksessä on mahdollista päättää ympäristöriskien hallintastrategiasta. Työssä on tutustuttu keskeiseen ympäristölainsäädäntöön ja sen yrityksen ympäristövastuulle asettamiin vaatimuksiin. Imagotekijöitä on käsitelty osana ympäristövastuuseen liittyvää yrityskohtaista päätöksentekoa. Hankekohtainen ympäristöriskien tunnistaminen ja arviointi on tehty E18 Muurla – Lohja moottoritiehankkeen tarjouslaskentavaiheessa. Tarjousvaiheessa tehty riskianalyysi palvelee päätöksentekoa yrityksessä valittaessa ympäristöriskien hallintastrategiaa. Analyysillä tuotetun tiedon avulla voidaan ohjata suunnittelua, tarjouksen hinnoittelua ja tarjouksen liitteeksi tuotettavan ympäristömateriaalin sisältöä. Tien rakentamisen ja kunnossapidon aikana materiaalia voidaan edelleen hyödyntää ympäristöasioiden hallinnassa.

Early adversity and 5-HTT-BDNF genes: New evidences of Gene-Environment interactions on depressive symptoms in a general population

Background Adverse childhood experiences have been described as one of the major environmental risk factors for depressive disorder. Similarly, the deleterious impact of early traumatic experiences on depression seems to be moderated by individual genetic variability. Serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) modulate the effect of childhood adversity on adult depression, although inconsistencies across studies have been found. Moreover, the gene×environment (G×E) interaction concerning the different types of childhood adversity remains poorly understood. The aim of this study was to analyse the putative interaction between the 5-HTT gene (5-HTTLPR polymorphism), the BDNF gene (Val66Met polymorphism) and childhood adversity in accounting for adult depressive symptoms. Method A sample of 534 healthy individuals filled in self-report questionnaires of depressive symptomatology [the Symptom Check List 90 Revised (SCL-90-R)] and different types of childhood adversities [the Childhood Trauma Questionnaire (CTQ)]. The 5-HTTLPR polymorphism (5-HTT gene) and the Val66Met polymorphism (BDNF gene) were genotyped in the whole sample. Results Total childhood adversity (β=0.27, p<0.001), childhood sexual abuse (CSA; β=0.17, p<0.001), childhood emotional abuse (β=0.27, p<0.001) and childhood emotional neglect (β=0.22, p<0.001) had an impact on adult depressive symptoms. CSA had a greater impact on depressive symptoms in Met allele carriers of the BDNF gene than in the Val/Val group (F=5.87, p<0.0001), and in S carriers of the 5-HTTLPR polymorphism (5-HTT gene) (F=5.80, p<0.0001). Conclusions Childhood adversity per se predicted higher levels of adult depressive symptoms. In addition, BDNF Val66Met and 5-HTTLPR polymorphisms seemed to moderate the effect of CSA on adult depressive symptoms.

Avaliação do risco ambiental em sedimento dos lagos do Riacho Cambé, em Londrina, pela distribuição de metais

The proposal of this study was to obtain the profile of these metals distribution Al, Co, Cu, Pb, Cr, Ni, Co and Zn in sediments from lakes in the city of Londrina-PR and evaluate the environmental risk resulting from such distribution. The parameters of comparison were the values of geological occurrence of these metals in soil from this region, the concentrations of metals in soil samples in the surroundings of the sediments collection points, the guiding values from CETESB and resulting rate risk from RAC criterion application. The result shows that the numerical scale RAC alone is incomplete to this evaluation.

Poluição por mercúrio em aterros urbanos do período colonial no extremo sul do Brasil

Land reclamation fills in the city of Rio Grande (RS) are polluted by mercury with concentrations ranging from 0.3 to 18.7 mg kg-1. The level of Hg pollution decreases from the oldest landfills of 18th century to recent ones. Mercury distribution along vertical profiles resembles the same for copper, lead, and zinc, what allow supposing that mercury distribution has an autochthonous character. It is suggested that the principal source of mercury pollution was the activities related to animal skin and fair hair treatment, using ancient technology known as "carroting". Similar scenario of environmental risk could be met in other Brazilian cities with similar colonization history.

Sorção de atrazina e de mesotriona em latossolos e estimativa do potencial de contaminação

Following application herbicides usually reach the soil and undergo several dissipation processes which determine their effects on target organisms and on the environment. This work aimed to evaluate atrazine and mesotrione sorption in Oxisols and estimate their potential impact on the environment. We observed that atrazine sorption was influenced by soil organic matter content and its hydrophobic character. Clay fraction was the main factor influencing mesotrione sorption followed in a lesser extent by soil organic matter content. In contrast to atrazine, mesotrione retention was favored by the higher carboxylic substitution in the aliphatic chains of soil organic matter. Atrazine and mesotrione were considered compounds that are likely to pose an appreciable risk of causing deleterious effects on the environment.

Avaliação de risco ambiental de ambientes aquáticos afetados pelo uso de agrotóxicos

Ecological risk assessment is a process evaluating the likelihood that adverse ecological effects may occur or are occurring as a result of exposure to one or more substances. Relevant information needed to predict risks from pesticides includes their physical chemical properties, mobility in soil, persistence in the environment, and bioaccumulation and toxicity in relevant organisms. Although currently a requirement for pesticide registration in Brazil, this process is not yet fully implemented in the country. This review aims to outline the principles of environmental risk assessment for pesticides, focusing on aquatic organisms, and to discuss the studies and efforts conducted in Brazil in this area.

Juvan kunnan jätevedenpuhdistamon ympäristöasioiden parantaminen

Diplomityö on osa Mikkelin ammattikorkeakoulun YTI:ssä vuosina 2005 - 2008 toteutettua ”Yritysten ympäristöriskit” EU-osarahoitteista hanketta. Työn tarkoituksena oli tunnistaa, arvioida ja luokittaa Etelä-Savossa, Juvalla toimivan yhdyskuntajätevedenpuhdistamon ympäristöriskit sekä antaa neuvoja löytyneiden riskien hallintaan. Jätevedenpuhdistamon toiminnasta syntyvät mahdolliset ympäristöriskitekijät tunnistettiin kirjallisuusselvitysten sekä haastattelujen avulla. Riskien tunnistamisen jälkeen riskien kartoittamiseen, arviointiin ja luokittamiseen käytettiin osia eri riskianalyysimenetelmistä. Riskit jaettiin viiteen eri riskiluokkaan; vakavasta riskistä merkityksettömään riskiin. Juvan kunnan jätevedenpuhdistamolla esiintyi neljän pienimmän riskiluokan riskejä, ja vakavia riskejä ei kartoituksessa tullut esille lainkaan. Riskejä arvioitiin niin sanotuissa normaalioloissa. Merkittävin yksittäinen riskitekijä jätevedenpuhdistamolla oli haitallisen tai poikkeavan aineen kulkeutuminen jäteveden mukana puhdistamolle. Tämä voisi heikentää puhdistamon puhdistustulosta merkittävästi. Kun laitosta ajetaan ympäristöluvassa asetettujen vaatimusten mukaisesti ja alueella sijaitsevat teollisuuslaitokset noudattavat heille annettuja määräyksiä, ei Juvan jätevedenpuhdistamolta aiheudu merkittäviä päästöjä maa-perään tai pohjavesiin.

Biogeochemistry in acid sulphate soil landscapes and small urban centres in Western Finland

The overall purpose of this thesis was to increase the knowledge on the biogeochemistry of rural acid sulphate (AS) soil environments and urban forest ecosystems near small towns in Western Finland. In addition, the potential causal relationship between the distribution of AS soils and geographical occurence of multiple sclerosis (MS) disease was assessed based on a review of existing literature and data. Acid sulphate soils, which occupy an area of approximately 17–24 million hectare worldwide, are regarded as the nastiest soils in the world. Independent of the geographical locality of these soils, they pose a great threat to their surrounding environment if disturbed. The abundant metal-rich acid drainage from Finnish AS soils, which is a result of sulphide oxidation due to artificial farmland drainage, has significant but spatially and temporally variable ecotoxicological impacts on biodiversity and community structure of fish, benthic invertebrates and macrophytes. This has resulted in mass fish kills and even eradication of sensitive fish species in affected waters. Moreover, previous investigations demonstrated significantly enriched concentrations of Co, Ni, Mn and Al, metals which are abundantly mobilised in AS soils, in agricultural crops (timothy grass and oats) and approximately 50 times higher concentrations of Al in cow milk originating from AS soils in Western Finland. Nevertheless, the results presented here demonstrate, in general, relatively moderate metal concentrations in oats and cabbage grown on AS soils in Western Finland, although some of the studied fields showed anomalous values of metals (e.g. Co and Ni) in both the soil and target plants (especially oats), similar to that of the previous investigations. The results indicated that the concentrations of Co, Ni, Mn and Zn in oats and Co and Zn in cabbage were governed by soil geochemistry as these metals were correlated with corresponding concentrations extracted from the soil by NH4Ac-EDTA and NH4Ac, respectively. The concentrations of Cu and Fe in oats and cabbage were uncorrelated to that of the easily soluble concentrations in the soils, suggesting that biological processes (e.g. plant-root processes) overshadow geochemical variation. The concentrations of K and Mg in cabbage, which showed a low spread and were strongly correlated to the NH4Ac extractable contents in the soil, were governed by both the bioavailable fractions in the topsoil and plant-uptake mechanisms. The plant´s ability to regulate its uptake of Ca and P (e.g. through root exudates) seemed to be more important than the influence of soil geochemistry. The distribution of P, K, Ca, Mg, Mn and S within humus, moss and needles in and around small towns was to a high degree controlled by biological cycling, which was indicated by the low correlation coefficients for P, K, Ca, Mg and S between humus and moss, and the low spread of these nutrients in moss and needles. The concentration variations of elements in till are mainly due to natural processes (e.g. intrusions, weathering, mineralogical variations in the bedrock). There was a strong spatial pattern for B in humus, moss and needles, which was suggested to be associated with anthropogenic emissions from nearby town centres. Geogenic dust affected the spatial distribution of Fe and Cr in moss, while natural processes governed the Fe anomaly found in the needles. The spatial accumulation patterns of Zn, Cd, Cu, Ni and Pb in humus and moss were strong and diverse, and related to current industry, the former steel industry, coal combustion, and natural geochemical processes. An intriguing Cu anomaly was found in moss. Since it was located close to a main railway line and because the railway line´s electric cables are made of Cu, it was suggested that the reason for the Cu anomaly is corrosion of these cables. In Western Finland, where AS soils are particularly abundant and enrich the metal concentrations of stream waters, cow milk and to some extent crops, an environmental risk assessment would be motivated to elucidate if the metal dispersion affect human health. Within this context, a topic of concern is the distribution of multiple sclerosis as high MS prevalence rates are found in the main area of AS soils. Regionally, the AS soil type in the Seinäjoki area has been demonstrated to be very severe in terms of metal leaching, this area also shows one of the highest MS rates reported worldwide. On a local scale, these severe AS soil types coincide well with the corresponding MS clustering along the Kyrönjoki River in Seinäjoki. There are reasons to suspect that these spatial correlations are causal, as multiple sclerosis has been suggested to result from a combination of genetic and environmental factors.

Fetal alcohol spectrum disorders in Finnish children and adolescents : diagnosis, cognition, behavior, adaptation and brain metabolic alterations

Alcohol consumption during pregnancy can potentially affect the developing fetus in devastating ways, leading to a range of physical, neurological, and behavioral alterations most accurately termed Fetal Alcohol Spectrum Disorders (FASD). Despite the fact that it is a preventable disorder, prenatal alcohol exposure today constitutes a leading cause of intellectual disability in the Western world. In Western countries where prevalence studies have been performed the rates of FASD exceed, for example, autism spectrum disorders, Down’s syndrome and cerebral palsy. In addition to the direct effects of alcohol, children and adolescents with FASD are often exposed to a double burden in life, as their neurological sequelae are accompanied by adverse living surroundings exposing them to further environmental risk. However, children with FASD today remain remarkably underdiagnosed by the health care system. This thesis forms part of a larger multinational research project, The Collaborative Initiative on Fetal Alcohol Spectrum Disorders (the CIFASD), initiated by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) in the U.S.A. The general aim of the present thesis was to examine a cohort of children and adolescents growing up with fetal alcohol-related damage in Finland. The thesis consists of five studies with a broad focus on diagnosis, cognition, behavior, adaptation and brain metabolic alterations in children and adolescents with FASD. The participants consisted of four different groups: one group with histories of prenatal exposure to alcohol, the FASD group; one IQ matched contrast group mostly consisting of children with specific learning disorder (SLD); and two typically-developing control groups (CON1 and CON2). Participants were identified through medical records, random sampling from the Finnish national population registry and email alerts to students. Importantly, the participants in the present studies comprise a group of very carefully clinically characterized children with FASD as the studies were performed in close collaboration with leading experts in the field (Prof. Edward Riley and Prof. Sarah Mattson, Center for Behavioral Teratology, San Diego State University, U.S.A; Prof. Eugene Hoyme, Sanford School of Medicine, University of South Dakota, U.S.A.). In the present thesis, the revised Institute of Medicine diagnostic criteria for FASD were tested on a Finnish population and found to be a reliable tool for differentiating among the subgroups of FASD. A weighted dysmorphology scoring system proved to be a valuable additional adjunct in quantification of growth deficits and dysmorphic features in children with FASD (Study 1). The purpose of Study 2 was to clarify the relationship between alcohol-related dysmorphic features and general cognitive capacity. Results showed a significant correlation between dysmorphic features and cognitive capacity, suggesting that children with more severe growth deficiency and dysmorphic features have more cognitive limitations. This association was, however, only moderate, indicating that physical markers and cognitive capacity not always go hand in hand in individuals with FASD. Behavioral problems in the FASD group proved substantial compared to the typically developing control group. In Study 3 risk and protective factors associated with behavioral problems in the FASD group were explored further focusing on diagnostic and environmental factors. Two groups with elevated risks for behavioral problems emerged: length of time spent in residential care and a low dysmorphology score proved to be the most pervasive risk factor for behavioral problems. The results underscore the clinical importance of appropriate services and care for less visibly alcohol affected children and highlight the need to attend to children with FASD being raised in institutions. With their background of early biological and psychological impairment compounded with less opportunity for a close and continuous caregiver relationship, such children seem to run an especially great risk of adverse life outcomes. Study 4 focused on adaptive abilities such as communication, daily living skills and social skills, in other words skills that are important for gradually enabling an independent life, maintain social relationships and allow the individual to become integrated into society. The results showed that adaptive abilities of children and adolescents growing up with FASD were significantly compromised compared to both typically-developing peers and IQ-matched children with SLD. Clearly different adaptive profiles were revealed where the FASD group performed worse than the SLD group, who in turn performed worse than the CON1 group. Importantly, the SLD group outperformed the FASD group on adaptive behavior in spite of comparable cognitive levels. This is the first study to compare adaptive abilities in a group of children and adolescents with FASD relative to both a contrast group of IQ-matched children with SLD and to a group of typically-developing peers. Finally, in Study 5, through magnetic resonance spectroscopic imaging (MRS) evidence of longstanding neurochemical alterations were observed in adolescents and young adults with FASD related to alcohol exposure in utero 14-20 years earlier. Neurochemical alterations were seen in several brain areas: in frontal and parietal cortices, corpus callosum, thalamus and frontal white matter areas as well as in the cerebellar dentate nucleus. The findings are compatible with neuropsychological findings in FASD. Glial cells seemed to be more affected than neurons. In conclusion, more societal efforts and resources should be focused on recognizing and diagnosing FASD, and supporting subgroups with elevated risk of poor outcome. Without adequate intervention children and adolescents with FASD run a great risk of marginalization and social maladjustment, costly not only to society but also to the lives of the many young people with FASD.

Sustainable Gold Mining- Life Cycle Assessment of Cyanidation and Thiosulphate Leaching

With the increasing concern of the sustainable approach of gold mining, thiosulphate has been researched as an alternative lixiviant to cyanide since cyanide is toxic to the environment. In order to investigate the possibility of thiosulphate leaching application in the coming future, life cycle assessment, is conducted to compare the environmental footprint of cyanidation and thiosulphate leaching. The result showed the most significant environmental impact of cyanidation is toxicity to human, while the ammonia of thiosulphate leaching is also a major concern of acidification. In addition, an ecosystem evaluation is also performed to indicate the potential damages caused by an example of cyanide spill at Kittilä mine, resulting in significant environmental risk cost that has to be taken into account for decision making. From the opinion collected from an online LinkedIn discussion forum, the anxiety of sustainability alone would not be enough to contribute a significant change of conventional cyanidation, until the tighten policy of cyanide use. International Cyanide Code, therefore, is crucial for safe gold production. Nevertheless, it is still thoughtful to consider the values of healthy ecosystem and the gold for long-term benefit.