Chronic Effects Research Articles

Chronic and Periodic Effects of Smoke from Crop Residue Combustion on Soil Enzymatic Activity

Wildfires lead to the emission of large volumes of toxic smoke, which is transported hundreds of kilometres away from the fires and can have a negative impact on soil, biota and humans. A series of modelling experiments on pyrogenic fumigation of soil were carried out to assess the effects of gaseous products from wildfires on soil biochemical parameters. The effects of chronic exposure to gaseous substances and periodic, repetitive effects of smoke exposure on soil were determined. The results were compared with a single intensive smoke exposure. It was found that pyrogenic impact significantly affected the change of enzymatic activity of ordinary chernozem. The degree of influence depended on the duration and periodicity of smoke exposure. In all experiments enzymes of oxidoreductase class (catalase, peroxidase, polyphenol oxidase) were more sensitive to fumigation than invertase from hydrolase class. The reason of suppression of enzymatic activity of soils is high concentrations of toxic gases. The following concentrations exceeded the maximum permissible concentrations for atmospheric air: CO 714 times, phenol (hydroxybenzene) 441 times, acetaldehyde 24100 times, formaldehyde 190 times. Accumulation of polycyclic aromatic hydrocarbons (PAHs) in soil after fumigation was revealed, the total content of PAHs was 377 ng/g. The highest values were recorded for naphthalene, where the concentration was 4.4 times higher than the maximum permissible and phenanthrene 2.8 times higher than the maximum permissible. It was found that 60-minute intensive smoke affects the soil to a lesser extent than chronic and periodic. Indicators of enzymatic activity of chernozem after such fumigation decreased by 15-33% depending on the enzyme, in chronic and periodic by 41-84 and 31-78%, respectively. The obtained data indicate a significant effect of smoke on enzymatic activity of soils under chronic and periodic exposure to gaseous products of combustion.

Long‐term effects of tagging fishes with electronic tracking devices

AbstractTagging fishes with internal or external electronic tracking devices (acoustic, radio, satellite, or archival tags) is invaluable to behavioural, ecological, and welfare research, but may have adverse effects on the animals studied. While short‐term responses to tagging (e.g., days to weeks) have often been investigated, less information is available on longer‐term impacts (e.g., months to years) and the potential chronic effects of tagging on basic biological needs such as foraging and reproduction. Here, we synthesize existing knowledge from peer‐reviewed acoustic, radio, satellite, and archival tagging articles (n = 149) and anecdotal accounts (n = 72) from 36 researchers to assess the effects of tagging over prolonged periods. We identified a dearth of research that has specifically measured or quantified the impacts of tagging over a period longer than a few weeks or months (e.g., median experimental study duration = 33 days; n = 120 articles). Nevertheless, there was limited evidence to support a net negative long‐term impact from the implantation or attachment of electronic devices. Considerations and future research directions are discussed with the goal of generating guidance to the research community and minimizing potentially detrimental impacts to study animals. Given the global application and relevance of electronic tagging research to inform conservation and management of fishes, it is imperative for scientists to continue evaluating how tagging procedures affect animal welfare, fate, and the interpretation of tracking data.

Acute and chronic effects of methanolic extract of Teucrium polium on blood parameters and histopathology of liver and kidney in Female Rats

Teucrium polium L. is commonly used as a medicinal plant in Algeria to fight various human diseases. In this study, extracting aerial parts of T. polium with methanol gave a dry matter yield of 8.24 %. The effects of methanolic extract of T. polium "TPME" were examined per os on female rats Albino Wistar for six weeks. Biochemical and hematological serum parameters and morphology and histopathology of organs of treated rats were studied. Acute toxicity showed low toxicity with a lethal dose of 50% LD50 > 2400 mg / Kg of body weight. These data can be used to classify these plants as slightly toxic. However, sub-acute treatment for six weeks of rats with 75, 150, and 300 mg of methanolic extract / Kg of body weight significantly increased the most studied hematological parameters. Biochemical analysis revealed a significant increase of renal parameters (urea, creatinine, uric acid, Na, and K), accompanied by an increase in the relative weight of kidney, lipidic (cholesterol), and hepatic glutamate oxaloacetate transaminase (GOT) values in all treated rats. Histopathological examination confirmed the biochemical tests by the observation of perilobular necrosis areas, bile duct and inflammatory infiltration of the liver, and the presence of marked intracytoplasmic vacuoles in the kidney with the dose 300 mg of TPME Kg of animal body weight. Use of Teucrium polium L. may cause hepatotoxicity and nephrotoxicity after prolonged herb administration. Keywords: Teucrium polium L, TPME, LD50, biochemical parameters, toxicity

Role of sex and training characteristics on exercise effects on cardiovascular aging: protocol for a systematic review with meta-analysis of randomized trials

BackgroundCardiovascular diseases remain a leading global cause of mortality worldwide especially in older adults. Although it is known that regular exercise reduces cardiovascular diseases incidence, its effects on specific cardiovascular aging parameters considering the influence of sex and different exercise designs are still not fully understood. Therefore, this systematic review and meta-analysis aims to evaluate the effects of different physical exercise protocols on age-related cardiovascular outcomes in older adults.MethodsThis systematic review and meta-analysis will be reported in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Articles will be eligible if they are randomized controlled trials with a primary objective of evaluating the chronic effects of exercise interventions on cardiovascular aging parameters. Search strategy will be performed from the inception to September 30th, 2023, in the following electronic databases: MEDLINE (Ovid), SCOPUS (Elsevier), Embase, Sport Discus (EBSCO), Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection (Clarivate Analytics). Data will be extracted and managed through Research Electronic Data Capture (REDCap) software. The Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX) will be used to assess the methodological quality of included studies. Additionally, the quality of the findings will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) profiler. Meta-analysis based on the random-effects model will be performed (if deemed suitable, considering the methodological and clinical heterogeneity of the studies) to estimate the effects of exercise training on cardiovascular aging variables (i.e., cardiac output; arterial stiffness; stroke volume; endothelial function; and carotid intima-media thickness). Heterogeneity will be assessed with the I2 statistics, while the publication bias will be assessed based on Egger’s test.DiscussionTo the best of our knowledge, this will be the first systematic review and meta-analysis to investigate the impact of sex and training protocols on the cardiovascular aging parameters. Moreover, the findings of this systematic review and meta-analysis will provide evidence for health professionals in the management of elderly patients in order to optimize the exercise prescription to face the cardiovascular alterations related to the aging process, considering the effects of different protocols according to sex.Systematic review registrationPROSPERO CRD42023441015 .

The Chronic Toxicity of Endocrine-Disrupting Chemical to Daphnia magna: A Transcriptome and Network Analysis of TNT Exposure.

Endocrine-disrupting chemicals (EDCs) impair growth and development. While EDCs can occur naturally in aquatic ecosystems, they are continuously introduced through anthropogenic activities such as industrial effluents, pharmaceutical production, wastewater, and mining. To elucidate the chronic toxicological effects of endocrine-disrupting chemicals (EDCs) on aquatic organisms, we collected experimental data from a standardized chronic exposure test using Daphnia magna (D. magna), individuals of which were exposed to a potential EDC, trinitrotoluene (TNT). The chronic toxicity effects of this compound were explored through differential gene expression, gene ontology, network construction, and putative adverse outcome pathway (AOP) proposition. Our findings suggest that TNT has detrimental effects on the upstream signaling of Tcf/Lef, potentially adversely impacting oocyte maturation and early development. This study employs diverse bioinformatics approaches to elucidate the gene-level toxicological effects of chronic TNT exposure on aquatic ecosystems. The results provide valuable insights into the molecular mechanisms of the adverse impacts of TNT through network construction and putative AOP proposition.

Unravelling bisphenol A-induced hepatotoxicity: Insights into oxidative stress, inflammation, and energy dysregulation

Bisphenol A (BPA), a prevalent plastic monomer and endocrine disruptor, negatively impacts metabolic functions. This study examines the chronic effects of eco-relevant BPA concentrations on hepatotoxicity, focusing on redox balance, inflammatory response, cellular energy sensors, and metabolic homeostasis in male Swiss albino mice. Chronic BPA exposure resulted in reactive oxygen species (ROS) accumulation, altered hepatic antioxidant defense, lipid peroxidation, and NOX4 expression, leading to reduced cell viability. Additionally, BPA exposure significantly upregulated hepatic pro-inflammatory cytokine genes (Tnf-α, Il-1β, Il-6), NOS2, and arginase II, correlating with increased TLR4 expression, NF-κB phosphorylation, and a dose-dependent decrease in IκBα levels. BPA-induced NF-κB nuclear localization and inflammasome activation (NLRP3, cleaved caspase-1, IL-1β) established an inflammatory milieu. Perturbations in hepatic AMPKα phosphorylation, SIRT1, and PGC-1α, along with elevated p38 MAPK phosphorylation and ERα expression, indicated BPA-induced energy dysregulation. Furthermore, increased PLA2G4A, COX1, COX2, and PTGES2 expression in BPA-treated liver correlated with hyperlipidemia, hepatic FASN expression, steatosis, and visceral adiposity, likely due to disrupted energy sensors, oxidative stress, and inflammasome activation. Elevated liver enzymes (ALP, AST, ALT) and apoptotic markers indicated liver damage. Notably, N-acetylcysteine (NAC) priming reversed BPA-induced hepatocellular ROS accumulation, NF-κB-inflammasome activation, and intracellular lipid accumulation, while upregulating cellular energy sensors and attenuating ERα expression, suggesting NAC's protective effects against BPA-induced hepatotoxicity. Pharmacological inhibition of the NF-κB/NLRP3 cascade in BAY11-7082 pretreated, or NLRP3 immunodepleted hepatocytes reversed BPA's negative impact on SIRT1/p-AMPKα/PGC-1α and intracellular lipid accumulation, providing mechanistic insights into BPA-induced metabolic disruption.

Acute and chronic response of supervised band-elastic resistance exercise in systemic cytokines levels of bipolar disorders and schizophrenia individuals: A pilot study

Despite earlier research demonstrating the immunomodulatory effects of acute and chronic exercise in many medical illnesses, there is a lack of literature evaluating the acute and chronic effects of exercise on the cytokine levels in individuals with bipolar disorder (BD) or schizophrenia (SCH). This study aims to examine the acute effects of resistance exercise on cytokines and the chronic effects of resistance exercise by 10 weeks on cytokine levels, symptoms of disease, and muscular strength in individuals with BD and SCH. The included individuals (N=10) performed a single session of band-elastic resistance exercises (six exercises, 3 sets of 12–15 repetitions, 60 seconds of interval between sets). A sub-sample (N=6) of individuals performed a supervised band-elastic resistance exercise program (2 times a week, for 10 weeks, 6 exercises, 3 sets of 12–15 repetitions, 60 seconds of interval). We verified for acute effects: IL-2 (P=0.0085) and IL-4 (P=0.0253) levels increased, while IL-6 decreased (P=0.0435), and for chronic effects: increased IL-2 and IL-4 levels (significant effect size - Pre vs Post), a decrease in disease symptoms, and an increase in muscular strength. This study adds to what is already known about how resistance exercises affect people with BD and SCH in both short-term (systemic cytokines levels) and long-term (symptoms of disease, muscular strength, and systemic cytokines levels).

Brain and Serum Membrane Vesicle (Exosome) Profiles in Experimental Alcohol-Related Brain Degeneration: Forging the Path to Non-Invasive Liquid Biopsy Diagnostics

Background: Alcohol-related brain degeneration (ARBD) is associated with cognitive–motor impairments that can progress to disability and dementia. White matter (WM) is prominently targeted in ARBD due to chronic neurotoxic and degenerative effects on oligodendrocytes and myelin. Early detection and monitoring of WM pathology in ARBD could lead to therapeutic interventions. Objective: This study examines the potential utility of a non-invasive strategy for detecting WM ARBD using exosomes isolated from serum. Comparative analyses were made with paired tissue (Tx) and membrane vesicles (MVs) from the temporal lobe (TL). Methods: Long Evans rats were fed for 8 weeks with isocaloric liquid diets containing 37% or 0% caloric ethanol (n = 8/group). TL-Tx, TL-MVs, and serum exosomes (S-EVs) were used to examine ethanol’s effects on oligodendrocyte glycoprotein, astrocyte, and oxidative stress markers. Results: Ethanol significantly decreased the TL-Tx expression of platelet-derived growth factor receptor alpha (PDGFRA), 2′,3′-cyclic nucleotide 3′ phosphodiesterase (CNPase), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG), glial fibrillary acidic protein (GFAP), and 8-OHdG, whereas in the TL-MVs, ethanol increased CNPase, PDGFRA, and 8-OHdG, but decreased MOG and GFAP concordantly with TL-Tx. Ethanol modulated the S-EV expression by reducing PLP, nestin, GFAP, and 4-hydroxynonenal (HNE). Conclusion: Chronic ethanol exposures differentially alter the expression of oligodendrocyte/myelin, astrocyte, and oxidative stress markers in the brain, brain MVs, and S-EVs. However, directionally concordant effects across all three compartments were limited. Future studies should advance these efforts by characterizing the relationship between ABRD and molecular pathological changes in brain WM-specific exosomes in serum.

The importance of the role of T-cell immunity in the development of modern tick-borne encephalitis vaccines

The tick-borne encephalitis (TBE) virus is highly pathogenic and can affect the central nervous system, leading to severe chronic effects or death. The only effective measure to combat TBE is vaccine prophylaxis. Vaccines that are currently used for mass immunization are based on inactivated TBE virus, they provide a protective immune response, but such vaccines require multiple administrations. A possible reason for short-term immunity is an incomplete functional T-cell response to these types of vaccines. The aim of this review is to analyze the literature on the role of the T-cell immune response in protecting the body from tick-borne encephalitis, its importance for vaccine development, and to consider approaches to the development of new TBE vaccines based on different platforms. When preparing the review, we analyzed the literature presented in scientific databases — PubMed, Scopus, Elsevier, Google Scholar as of April 2024. The following keywords were used for the search: vaccine, tick-borne encephalitis virus, T-cell immune response, flaviviruses. A several publications have demonstrated that T-cell responses following natural infection with TBE virus and after vaccination with inactivated virus are different. During viral infection, both Th1- and Th2-type CD4+ T cells and CD8+ T cells are activated and play an important role in the elimination of viral infection. After vaccination, the only Th2-type CD4+ T-cell response predominates, which may be the reason for the short-lived immune response. To date, a number of different types of experimental TBE vaccines are being studied, such as live-attenuated vaccines, viral vector vaccines, subunit vaccines, virus-like particles, DNA and mRNA vaccines, and polyepitope immunogens. In our opinion, the most promising in terms of T-cell response activation are vaccines based on T-cell polyepitope immunogens delivered in the form of DNA or mRNA.

Extrapolation factors for calculating ecotoxicity effects in LCA

Abstract Purpose This study focuses on updating, improving, and expanding the extrapolation factors needed to convert various acute or chronic effect concentration indicators into consistent chronic EC10eq (effect concentration inducing a 10% response over background) for use in life cycle assessment (LCA). Our main objectives include (1) to present a detailed approach for the harmonization of ecotoxicity data, with a focus on deriving extrapolation factors, and (2) to estimate both generic and species group-specific extrapolation factors, facilitating the conversion of effect concentration indicator groups (EC10eq and EC50eq) into chronic EC10eq. Methods Experimental ecotoxicity data were sourced from CompTox Version 2.1.1, which integrates toxicity information from ToxValDB v9.1.1, and the information from REACH registration dossiers. We developed a framework for harmonizing ecotoxicity data, ensuring uniformity and high quality of aquatic ecotoxicity information from these sources. Through linear regression analysis, both generic and species group-specific extrapolation factors were then derived. Results and discussion Harmonization of ecotoxicity data yielded a streamlined dataset with 339,729 datapoints for 10,668 chemicals, reflecting a 54% reduction in raw datapoints. The geometric mean-based aggregation process produced 79,001 aggregated effect concentration datapoints at the species level, 41,303 at the species group level, and 23,215 at the effect concentration indicator level for these chemicals. This process facilitated the derivation of 3 generic and 24 species group-specific extrapolation factors, allowing for the conversion of effect concentration indicator groups (EC10eq and EC50eq) to a chronic EC10eq across two exposure classes (acute vs. chronic) and species groups, as defined in the US EPA ECOTOX knowledgebase, including algae, amphibians, fish, crustaceans, insects/spiders, invertebrates, molluscs, and worms. Conclusions The harmonization of ecotoxicity data and the derived extrapolation factors permit the integration of diverse datapoints with varying effect concentration indicators and exposure durations into USEtox ecotoxicity characterization factors. This has the potential to enhance substance coverage for characterizing ecotoxicity effects across chemicals in LCA frameworks by permitting wider species coverage. More generally, this is part of global efforts to extend the potential for quantitative assessment of environmental impacts of chemicals in an LCA framework.

Dyeing waters: Does indiscriminate dye use threaten aquatic ecosystems?

Aquatic ecosystem conservation is imperative to reaching global biodiversity and sustainability targets. However, the ecological status of waters has been continuously eroded through mismanagement in the face of existing and emerging anthropogenic stressors, such as pollutants. There has been an emerging trend towards the use of dyes to manage algae and plants as well as to alter aesthetics within various aquatic environments. This artificial colouring has potential ecological implications through reductions in light levels and disruptions to thermoclines (i.e., temperature regime changes with depth). Abiotic regime shifts could in turn drive ecological cascades by depowering primary production, hampering top-down trophic interactions, and affecting evolved animal behaviours. Despite commercial dyes being marketed as acutely non-toxic, very little is known about the chronic effects of these dyes across ecological scales and contexts. We thus call for greater research efforts to understand the ecological consequences of dye usage in aquatic environments, as well as the socio-cultural drivers for its application. This emerging research area could harness approaches such as biological assays, community module experiments, remote sensing, culturomics, and social surveys to elucidate dye effects, trends, and perspectives under a pollution framework. A greater understanding of the potential effects of dye in aquatic ecosystems under relevant contexts would help to inform management decisions and regulation options, while helping to mediate ecocentric and anthropocentric perspectives.

The effects of chronic, continuous β-funaltrexamine pre-treatment on lipopolysaccharide-induced inflammation and behavioral deficits in C57BL/6J mice

BackgroundInflammation and neuroinflammation are integral to the progression and severity of many diseases and are strongly associated with cardiovascular disease, cancer, autoimmune disorders, neurodegenerative disease, and neuropsychiatric disorders. These diseases can be difficult to treat without addressing the underlying inflammation, and, as such, a growing need has arisen for pharmaceutical treatments that target inflammatory mediators and signaling pathways. Our lab has investigated the therapeutic potential of the irreversible µ-opioid antagonist β-funaltrexamine (β-FNA) and discovered that acute treatment ameliorates inflammation in astrocytes in vitro and inhibits central and peripheral inflammation and reduces anxiety- and sickness-like behavior in male C57BL/6J mice. Now, our investigation has expanded to investigate the chronic pre-treatment effects of β-FNA on lipopolysaccharide (LPS)-induced inflammation and behavior in male C57BL/6J mice.ResultsMicro-osmotic drug pumps were surgically inserted into the subcutaneous intrascapular space of male C57BL/6J mice. β-FNA or saline vehicle was continuously administered for seven days. On the sixth day, mice were given intraperitoneal injections of LPS or saline. An elevated plus maze test, followed by a forced swim test, were administered 24 h post-injection to measure sickness-, anxiety- and depressive-like behavior. Immediately after testing, frontal cortex, hippocampus, spleen, and plasma were collected. Levels of inflammatory chemokines C–C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) were measured in tissues by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to assess expression of the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) and the NLR family pyrin domain-containing protein 3 (NRLP3) inflammasome in frontal cortex and spleen tissues. Chronic pre-treatment robustly decreased inflammation in the hippocampus, frontal cortex, and spleen and reduced or abolished anxiety- and sickness-like behavior (e.g., increased time spent motionless, increased time spent in a contracted position, and reduced distance moved). However, treatment with β-FNA alone increased both inflammation in the frontal cortex and anxiety-like behavior.ConclusionThese findings provide novel insights into the anti-inflammatory and behavior-modifying effects of chronic β-FNA pre-treatment and continue to support the therapeutic potential of β-FNA under inflammatory conditions.

Noninvasive Therapies: A Forthcoming Approach to Parkinson's Treatment.

In this review, we have discussed the invasive and non-invasive treatment options for Parkinson's Disease (PD) following their safety, specificity, and reliability. Initially, this study has highlighted the invasive treatment options and the side effects they possess. A deep understanding of L-Dopa treatment, as oral or infusion, and the use of dopamine agonists has indicated that there is a need to acquire an alternative treatment for PD. The combined therapy with L-Dopa has been proven to affect PD, but with some limitations, such as mild to chronic side effects, with particular requirements of age and health of the patient and a large amount of expenditure. In the discussion of noninvasive methods to treat PD, we have found that this approach is comparatively slow and requires repetitive sessions, but is safe, effective, and reliable at any stage of PD. Electroconvulsive therapy has revealed its effectiveness in various neurological diseases, including PD. Transcranial current stimulation (direct or alternative) has already been shown to have an alleviative response to PD symptoms. Transcranial magnetic stimulations and other strategies of using the magnetic field for potential treatment options for PD need to be explored further imminently.

Acute effect of different types of moderate intensity physical exercise on affective response and mood state in individuals with substance use disorder

Substance use disorder (SUD) affects a significant percentage of people around the world, negatively influencing aspects of physical and mental health. Physical exercise can promote acute and chronic effects on the affective response and mood of individuals and has shown promising effects in all phases of rehabilitation. The objective of this study was to verify the acute effects of two types of physical exercises at moderate intensity on the mood state and on the affective response of individuals hospitalized for the treatment of SUD. For this purpose, 43 individuals (31 men and 12 women) underwent two physical exercise sessions (one aerobic and one functional) and a control session. Before and immediately after the sessions, subjects answered questionnaires about mood, affective valence, and perceived arousal. Generalized estimating equations (GEE) followed by the Bonferroni post hoc test were used to assess the effect of timing and session on the variables. The results showed significant improvements after both physical exercise sessions in mood (reduction in levels of tension, depression, anger, fatigue, and confusion) and in affective valences (feeling of pleasure and arousal perception), with no changes after the control session. It is observed that different types of physical exercises can positively impact the mental health of individuals undergoing treatment for SUD and should be used as a non-pharmacological strategy in the rehabilitation process.

Mock assessment: Chronic prospective cumulative risk assessment

Abstract This Mock assessment is a part of the Framework Partnership Agreement between ANSES and EFSA with the help of RIVM to investigate the feasibility of a tiered approach proposed by EFSA for prospective chronic cumulative risk assessment (CRA). Three tiers address successively (i) a need for prospective CRA (Tier 0) using a deterministic approach to estimate the foreground exposure based on IEDI equation, (ii) a first estimation of prospective CRA (Tier I) using a probabilistic approach to estimate the background exposure at P99.9 and a deterministic approach to estimate the foreground exposure at mean or P97.5 consumption and (iii) a second estimation of prospective CRA (Tier II) using a probabilistic approach to estimate the background and foreground exposure at P99.9. ANSES tested this approach with an MRL application for the active substance fenamidone (with chronic effects on the thyroid) on lettuce, based on a new intended use currently under assessment at national level. For each Tier, the Margin of Exposure (MOE) was calculated for 9 populations with MCRA software using input data provided by EFSA and settings according to EFSA protocol. Different combinations of settings were tested as part of sensitivity analyses (consumption data, adjustment for additional uncertainties, cycle of monitoring data, etc.) and were used as the basis for discussion of different open points (trigger value in Tier 0, use frequency for the focal combination in tier II, ad hoc uncertainty analysis to account for additional uncertainties, etc.) to be addressed before prospective CRA could be implemented as a routine exercise. Finally, based on these discussions, recommendations were made to consolidate the approach for chronic prospective CRA.

Acute and Chronic Ecotoxicity of Daphnia magna Exposed to Ash Leachate from the Cotopaxi Volcano, Ecuador.

Ecuador's wetlands and aquatic ecosystems are chronically exposed to ash contamination due to the frequent volcanoes' eruptions in the country. Still, the short and long-term effects of ash contamination on the aquatic biota are not well understood. We used ashes released by the Cotopaxi volcano in 2016 to investigate their acute and chronic effects in Daphna magna. We calculated the half maximal effective concentration (EC50) after 2 and 21 days of exposure, the non-observed effect concentration (NOEC), and the lowest observed effect concentration (LOEC) on offspring production. We also analyzed the metal concentration present in the ashes. The EC50 values at 2 and 21 days were found at 80% and 5% ash leachate concentrations, respectively. After 21 days of exposure, high mortality and low neonatal production were observed in all leachate concentrations (NOEC was at 15%, and LOEC was at 20% leachate concentration). Our results suggest that the ashes from the Cotopaxi volcano can cause acute and chronic toxicity to aquatic life and should be classified as hazardous waste, depending on the dose. There is an urgent need for further studies that assess toxicity caused by the intense volcanic activity in Ecuador.

Abstract P126: Exercise-Induced Changes in Skeletal Muscle of Patients with Chronic Kidney Disease on Maintenance Hemodialysis

Background: Chronic kidney disease (CKD) patients on maintenance hemodialysis (MHD) often experience sarcopenia and functional decline. The impact of exercise and inactivity on sarcopenia in CKD is poorly understood. We aimed to identify exercise-responsive genes that are differentially expressed between controls and patients on MHD. We also aim to investigate the changes in gene expression in skeletal muscle following a resistance exercise program in patients on MHD. Methods: In a cross-sectional study, we performed RNA sequencing analysis in skeletal muscle biopsies from two groups (matched for age, gender, body mass index, and history of diabetes): controls (n=13) and patients on maintenance hemodialysis (MHD, n=10). In a separate cohort, we conducted a 12-week intradialytic resistance training in seven patients on MHD. Skeletal muscle biopsies were collected pre- and post-intervention to assess the acute (before and after a single bout of exercise) and chronic (after 12 weeks) effects of exercise. Total RNA was extracted and used to construct libraries for RNA sequencing using the Illumina NovaSeq 6000 system. Differentially expressed genes (DEGs) were identified based on a false discovery rate (FDR) of less than 0.05 and a fold change greater than 1.5. Exercise and inactivity-responsive genes in non-CKD populations identified in the MetaMEx (www.metamex.eu) were used as reference. Results: We found significant DEGs between the control and MHD that were affected by exercise or inactivity according to MetaMEx. These genes and fold changes between control and MHD groups are depicted in Table 1. In the exercise intervention cohort, we observed no significant differences in the expression of these genes either acutely (Figure 1A) or 12 weeks after the exercise intervention (Figure 1B). Conclusion: We found many DEGs related to exercise and inactivity between patients on MHD and controls; however, resistance training does not significantly alter skeletal muscle gene expression. Future studies should explore alternative exercise interventions, such as HIIT exercise, aerobic training, combined aerobic and resistance training, or longer duration programs, to determine if these approaches can effectively modulate gene expression and improve sarcopenia and frailty in this population.

Anti-inflammatory effect of the mixture of Ageratum conyzoides L. extract and eggshell membrane hydrolysates and in silico active compound predictions

Context: Ageratum conyzoides L. and eggshell membrane have the potential to be used as medicine. The independent use of A. conyzoides extract or eggshell membrane hydrolysates independently as a natural medicine has been widely known, but the mixture of the two as an anti-inflammatory has not been studied. Aims: To evaluate both the in vivo and in vitro anti-inflammatory effects of A. conyzoides extract and eggshell membrane hydrolysates, independently and in combination. In silico testing was conducted to identify chemicals that have a key role in inflammation signaling pathways. Methods: The chronic anti-inflammatory effects of A. conyzoides extract and eggshell membrane hydrolysates were evaluated on cotton pellet-induced rats using diclofenac-Na as a control. In vitro anti-inflammatory effects were studied via protein denaturation, membrane stability, and antiprotease activity. Furthermore, molecular docking was performed on the p38-MAPK signaling pathway using compounds found in A. conyzoides extract and eggshell membrane hydrolysates. Results: A. conyzoides extract and eggshell membrane hydrolysates given separately or in combination can inhibit the formation of exudates and granulomas. Molecular docking simulations showed that the metabolites in the extract and hydrolysate interact with p38-MAPK. Nobiletin in the extract is the potential metabolite that interacts with the p38-MAPK receptor with a free energy of binding and inhibition constant of -8.92 kcal/mol and 260.80 nM. Amino acids in the hydrolysates showed weaker interactions compared to the compound in the extract. Conclusions: A. conyzoides extract and eggshell membrane hydrolysates work additively to inhibit the severity of chronic inflammation.

Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC).

Administration of a new drug candidate in a first-in-human (FIH) clinical trial is a particularly challenging phase in drug development and is especially true for immunomodulators, which are a diverse and complex class of drugs with a broad range of mechanisms of action and associated safety risks. Risk is generally greater for immunostimulators, in which safety concerns are associated with acute toxicity, compared to immunosuppressors, where the risks are related to chronic effects. Current methodologies for FIH dose selection for immunostimulators are focused primarily on identifying the minimum anticipated biological effect level (MABEL), which has often resulted in sub-therapeutic doses, leading to long and costly escalation phases. The Health and Environmental Sciences Institute (HESI) - Immuno-Safety Technical Committee (ITC) organized a project to address this issue through two complementary approaches: (i) an industry survey on FIH dose selection strategies and (ii) detailed case studies for immunomodulators in oncology and non-oncology indications. Key messages from the industry survey responses highlighted a preference toward more dynamic PK/PD approaches as in vitro assays are seemingly not representative of true physiological conditions for immunomodulators. These principles are highlighted in case studies. To address the above themes, we have proposed a revised decision tree, which expands on the guidance by the IQ MABEL Working Group (Leach et al. 2021). This approach facilitates a more refined recommendation of FIH dose selection for immunomodulators, allowing for a nuanced consideration of their mechanisms of action (MOAs) and the associated risk-to-benefit ratio, among other factors.

Opioid-environment interaction: Contrasting effects of morphine administered in a novel versus familiar environment on acute and repeated morphine induced behavioral effects and on acute morphine ERK activation in reward associated brain areas

We report that environmental context can have a major impact on morphine locomotor behavior and ERK effects. We manipulated environmental context in terms of an environmental novelty/ familiarity dimension and measured morphine behavioral effects in both acute and chronic morphine treatment protocols. Wistar rats (n=7 per group) were injected with morphine 10 mg/kg or vehicle (s.c.), and immediately placed into an arena for 5 min, and locomotor activity was measured after one or 5 days. The morphine treatments were initiated either when the environment was novel or began after the rats had been familiarized with the arena by being given 5 daily nondrug tests in the arena. The results showed that acute and chronic morphine effects were strongly modified by whether the environment was novel or familiar. Acute morphine administered in a novel environment increased ERK activity more substantially in several brain areas, particularly in reward-associated areas such as the VTA in comparison to when morphine was given in a familiar environment. Repeated morphine treatments initiated in a novel environment induced a strong locomotor sensitization, whereas repeated morphine treatments initiated in a familiar environment did not induce a locomotor stimulant effect but rather a drug discriminative stimulus dis-habituation effect. The marked differential effects of environmental novelty/familiarity and ongoing dopamine activity on acute and chronic morphine treatments may be of potential clinical relevance for opioid drug addiction.