Toxicity Research Articles

10.E. Scientific session: Confronting the hidden risks: unveiling the disease burden of chemicals in Europe

Abstract With increasing industrialization and globalization, Europe faces a complex landscape of chemical hazards, ranging from persistent organic pollutants like PFAS to foodborne chemicals and beyond. Understanding the extent of these exposures and their associated population health risks is crucial for environmental and health policy making across Europe. The burden of disease methodology, particularly through metrics such as Disability-Adjusted Life Years (DALYs), combined with economic costs, plays a crucial role in assessing and addressing the impacts of chemicals on population health. DALYs provide a comprehensive measure that quantifies both the years of life lost due to premature death and the years lived with disability, offering a holistic understanding of the disease burden caused by chemical exposures. Additionally, incorporating economic costs into the analysis enables the evaluation of the financial burden imposed by chemical-related illnesses on healthcare systems, productivity, and societal well-being. By leveraging the burden of disease methodology, stakeholders can make evidence-based decisions to protect health of populations and allocate resources effectively, ultimately promoting healthier environments and communities. Several global and European initiatives provide platforms for evidence generation, knowledge-sharing, and action to address the disease burden of chemicals. At the global level, the Foodborne Disease Burden Epidemiology Reference Group of the World Health Organization (WHO/FERG) has estimated the global burden of foodborne diseases, including those caused by chemical contaminants in foods. At European level, the health impact of PFAS and other chemicals of high concern is being spearheaded by the European Environment Agency’s European Topic Centre on Human Health and the Environment, and the European Partnership on the Assessment of Risks from Chemicals (PARC). Furthermore, the Organisation for Economic Cooperation and Development has established a project of an unprecedented scale to measure the economic value of the effects of chemicals on human health. Complementary to these international initiatives, various countries have started to unravel the burden of chemicals based on local data and contextual insights. In this workshop, we will present the state-of-the-art of the disease burden of chemicals, by bringing together insights from key international and national burden of disease initiatives, emphasizing the imperative of addressing the cost of policy inaction in safeguarding public health. We will also show how burden of disease estimates for chemicals can help to monitor the trends towards relevant environment and health goals such as those described in the EU’s zero pollution ambition. Through collaborative discussions and knowledge-sharing, we aspire to identify actionable strategies for policymakers, researchers, and stakeholders to effectively address these challenges and promote a healthier future for all. Key messages • Understanding the vital importance of chemical risks for European health, the utilization of DALY and economic costs reveals their true burden, guiding evidence-based policies. • Global, regional and national initiatives are examining the impacts of chemicals worldwide, contributing to evidence gathering and policy shaping.

High altitude exercise stress echocardiograph for identification of susceptibility to acute mountain sickness

Abstract Background Acute high-altitude exposure increases the risk of acute mountain disease (AMS) and high-altitude pulmonary edema. After the initial exposure to high altitude, mountain climbers are worried about whether they will develop AMS. At high altitudes, there are no accurate indicators to predict the near future occurrence of AMS. Objectives To investigate whether treadmill exercise stress echocardiography at high altitude can predict the occurrence of AMS, and to find out some powerful factors associated with the susceptibility to AMS. Methods 36 healthy lowlanders were taken by bus from sea level to an altitude of 3600 m the next morning, during which they rested overnight at an altitude of 2150 m. Treadmill exercise stress echocardiography was performed immediately upon arrival at 2150 m, and the 2018 Lake Louise Questionnaire Score was performed the next day when arrived at the altitude of 3600 m. Heart rate (HR) and blood pressure (BP) were monitored during stress echocardiography. Left ventricular (LV) ejection fraction and E/e’ were calculated at rest and immediately after exercise. Other right ventricular systolic function parameters and pulmonary artery pressure (PAP) were calculated at the same time, which included tricuspid regurgitation velocity (TRV), tricuspid annular peak systolic excursion (TAPSE), systolic PAP (SPAP), right ventricular (RV) dimension by 2D, RV fraction of area change (FAC), right ventricular outflow tract velocity time integral (RVOT VTI). Pulmonary vascular resistance (PVR) was calculated according to the formula: TRV/RVOT VTI*10+0.16. Mean PAP (mPAP) was calculated as the formula: sPAP*0.61+2. All subjects ascended to 3600m within 24 hours by bus. AMS was identified by 2018 Lake Louise Questionnaire Score. Univariable and multivariable logistic regression analysis assessed independent factors associated with AMS. Results At the altitude of 3600m, 13 of 36 subjects had AMS, which defined as AMS (+) group. And the rest was AMS (-) group. There were no significant differences in HR, BP, SO2 and LV systolic and diastolic function between the two groups (P > 0.05). No significant differences were noted at rest except for TV s' (P < 0.05). Immediately after exercise, TRV, TAPSE, SPAP, mPAP, PVR, and RV area at the end of systole were much higher in AMS (+) group (all P < 0.05). While FAC and TVs’/SPAP were much lower in AMS (+) group (P < 0.05). By multivariable logistic regression model, mPAP immediately after exercise was significantly correlated with AMS occurrence (OR =1.332, 95% CI: 0.669-0.993, P= 003). The cutoff value of mPAP to predict AMS was 32 mmHg (AUC: 0.831, specificity: 86.7%, sensitivity: 76.9%). Conclusions The mPAP immediately after exercise upon arrival at an altitude of 2150 m is a strong predictor of near future AMS, and treadmill exercise stress echocardiography is a simple and non-invasive tool to help mountain climbers avoid more severe mountain sickness.

1.Y.2. Children’s mental health problems explode. Can exposome research offer a solution?

Abstract Background A week-long, multidisciplinary workshop at the Lorentz Institute explored the expectations of exposome research on child health. Exposome research investigates how combined exposures affect health. Currently we see an increase in adolescent mental health problems in Europe. We explore at the workshop if and how exposome research can be part of the solution to tackle this health issue. Findings The workshop aims were to analyze how monitoring data from exposome research can be best used for improving health policy in relation to improving (environmental) health policy in relation to children’s health. By taking a deep dive into solution-finding, we explored creative solutions to better utilize existing exposome data from digital data platforms, such as cohort data. And to facilitate working across disciplines using innovative tools of working transdisciplinary across research, policymakers and other professionals. Furthermore, we study how to enhance, harmonize and interpretation of data on child health. Furthermore, we look how child health depends not only on the quality of a healthcare system, but also on the magnitude of negative or positive influencing factors, such as social and environmental factors. Identifying such stressors and reducing their impact through adequate policies can improve child health on local, national, or even global scales. One innovative way of identifying such stressors is the exposome approach. The exposome approach is the characterization of the non-genetic drivers of health and disease. The exposome comprises aspects of the Built environment (characteristics of where we live); the Social environment (with whom we interact, social networks and income); the Physio-Chemical environment (chemical and environmental factors exposure) and the Lifestyle/Food environment (what we eat, how much we exercise) over the entire life-course. Workshop aims: - Provide a background on the urgency of adolescent mental health problems in Europe. - Compare approaches of stakeholders and researchers: stakeholders’ input from the practical field can shape the approach of the research process. The second benefit is to derive implications for creating effective interventions and policies to prevent adverse effects of environmental exposures and to foster positive health in children and later in life. - Explore existing interventions on child health for issues, experiences and possible solutions to the governance and organization of health adaptation in urban and social planning. - How to act in the process of research to intervention to public policies. The workshop consists of three short presentations followed by interactive panel discussions. We end with the audience actively engaging in the debate, as well as entering their questions. The workshop will end by identifying the current and future necessary roles, responsibilities, capacities of the public health researchers, policymakers, and professionals for child health protection in complicated exposure settings. Key messages • Child mental health issues are increasing in an unexplainable way. • Engaging stakeholders into an exposome research process can help to form a child health strategy in Europe.

Semaglutide improves contractile function in isolated human atrium

Abstract Background Recently, the results of the STEP-HFpEF trial were announced, in which high-dose treatment with the antidiabetic glucagon-like-peptide 1 agonist semaglutide resulted in a significant improvement of HFpEF-associated symptoms and reduction of NT-proBNP levels. Interestingly, treatment effects were independent of initial body weight and left-ventricular ejection fraction, sparking interest regarding the precise mechanism of action. Purpose We tested the effects of acute semaglutide treatment in isolated human right-atrial trabeculae. Methods Trabeculae were prepared from right atrial appendage biopsies from 32 patients undergoing elective coronary artery bypass grafting and/or valve surgery. Regular contractions were elicited by electrical field stimulation (1Hz, 5V/50ms, 37°C). Paired experiments were performed simultaneously per patient with a control group and one exposed to semaglutide (100 or 300nM). Developed tension was analysed at steady state after 30 min. Arrhythmias were defined as deviations from baseline not arising from electrical stimulation. L-type calcium channel blockade was achieved with nifedipine (2µM) in some experiments. Rapid cooling contraction was elicited to assess sarcoplasmic reticulum Ca2+ content (RCC1) by rapidly superfusing the trabeculae with chilled solution (2°C). After a short rewarming period of 10s to 37°C, RCC was repeated to assess the Na+/Ca2+ exchanger function (RCC2). Statistical analysis was conducted using paired t-test or Wilcoxon test as appropriate (for 2 groups) and one-way ANOVA with test for trend (for >2 groups). Results Exposure to semaglutide increased developed tension by over 3-fold in human atrial trabeculae in a dose-dependent manner: from 3.14±1.14 for control to 5.43±2.35mN/mm2 for 100nM semaglutide (p=0.03 vs. control) to 12.5±3.53 for 300nM semaglutide (p=0.004 vs. control, mean±SEM, fig. A-D, p=0.005 for linear trend). L-type calcium channel blockade with nifedipine blunted developed tension overall but did not abolish the effect of semaglutide (fig. E, p=0.02). In contrast, the developed tensions upon RCC1 and RCC2 were increased by semaglutide (300nM) compared to control, while the ratio of RCC2:RCC1 was elevated by semaglutide, indicating both increased SR Ca2+ reuptake and less external Ca2+ removal in the presence of semaglutide (fig. H-J). Relaxation time to 50% of baseline was unaltered (not shown), while relaxation time to 90% of baseline was mildly prolonged by semaglutide at 300 nM (fig. F). No increase in the rate of arrhythmias was observed by semaglutide treatment (fig. G). Conclusion Acute exposure of human atrial trabeculae to semaglutide results in a strong positive inotropic effect in a dose-dependent manner without increasing the propensity for arrhythmias. This effect is most likely due to increased SR Ca2+ reuptake. Treatment of heart failure patients with high-dose semaglutide can improve atrial function, which may ameliorate symptoms.

Contaminant Exposure Profiles Demonstrate Similar Physiological Effects Across Environments Despite Unique Profile Composition in Formosa, Argentina, and Connecticut, USA.

Exposure to environmental contaminants is globally universal. However, communities vary in the specific combination of contaminants to which they are exposed, potentially contributing to variation in human health and creating "locally situated biologies." We investigated how environmental exposures differ across environments by comparing exposure profiles between two contexts that differ markedly across political, economic, and sociocultural factors-Namqom, Formosa, Argentina, and New Haven, Connecticut, United States. We collected infant urine, maternal urine, and human milk samples from mother-infant dyads in Formosa (n = 13) and New Haven (n = 21). We used untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS) to annotate environmental contaminants and endogenous metabolites in these samples, and we analyzed the data using exposome-wide association studies (EWAS) followed by pathway enrichment. We found statistically significant differences between the chemical exposure profiles of the Argentinian and US mothers, mostly involving pesticides; however, we observed similarities in the infant urine and human milk environmental contaminant profiles, suggesting that the maternal body may buffer infant exposure through human milk. We also found that infants and mothers were exposed to contaminants that were associated with alterations in amino acid and carbohydrate metabolism. Infants additionally showed alterations in vitamin metabolism, including vitamins B1, B3, and B6. Differences in chemical exposure profiles may be related to structural factors. Despite variation in the composition of exposure profiles between the two study sites, environmental contaminant exposure was associated with similar patterns in human physiology when we considered contaminants comprehensively rather than individually, with implications for metabolic and cardiovascular disease risk as well as infant cognitive development.

Evolution and future prospects in quantifying the chemical burden in Portugal

Abstract The quantification of the burden associated with chemicals is essential for comprehending their impact on public health and implementing effective risk management strategies. This presentation underscores the significance of conducting such assessments at both national and local levels, taking into account the exposures and vulnerabilities of those populations. Our objective is to provide an overview of past burden quantification exercises in the Portuguese context while identifying ongoing and future initiatives. Drawing from past experiences, we have initially characterized the burden of the Portuguese population’s exposure to mycotoxins through food consumption, particularly aflatoxins, and the consequent health burden. This laid the groundwork for discussing the potential consequences of climate change in this context and the associated burden. Subsequently, various exercises have been undertaken, incorporating diverse data sources, including human biomonitoring. Currently, several exercises are ongoing or planned, addressing different chemicals and contexts. These include arsenic and its association with various types of cancer, mercury and lead linked to cognitive impairment, and air pollution (e.g., PM2.5 and NO2) and its impact on health (e.g., cardiovascular diseases, lung cancer, asthma). Given the evolving challenges posed by climate change and emerging contaminants, understanding the burden of chemicals assumes increased importance, reinforcing the role of these assessments in safeguarding public health, guiding policy decisions, and highlighting the necessity of prioritizing research and surveillance efforts to protect human health and mitigate the adverse effects of chemical exposures.

The role of BaTiO3 nanoparticles as photocatalysts in the synthesis and characterization of novel fruit dyes is investigated.

In the present work, the photocatalytic activity against the natural dye extracted from the novel fruits has been studied by the BaTiO3 nanoparticles (NPs) under a ultra-violet (UV) light source. The large concentrations of an essential phenolic agent present in this phytochemical extract superimposed with cloths fibers make strong stain and degrade into another form of toxic, which is excluded from the many textiles industries as the colorful waste waters without recycling and removal of that dye pigments have been investigated using both photodegradation and photoluminescence techniques. The entitled nanoparticles (NPs) were prepared using the soft chemical root-modified solvothermal synthesis combo method and exposure to heat treatment such that the annealing process has been done for different temperatures ranging from 100°C to 250°C. As for as concern the characterization, as a start, structural and morphology studies have been reported here that highly crystalline oriented peaks data using powder x-ray diffraction techniques (PXRD) as well as the surface morphology including the size, shape, and mass distribution using the field emission scanning electron microscopy (FESEM) techniques, which purely belong to rutile tetragonal structure of the crystal system and circular and noncircular flakes like rough surface morphology materials respectively. The lattice dissociation constant 'ε' value of the BaTiO3 NPs has determined to be ~2.71 × 10-3 using the Williamson-Hall (W-H plot) analysis of crystallographic data. In the UV visible spectroscopy findings, since the extreme quantum confinement of BaTiO3 nanoflakes/nanodisc, the optical energy bandgap has been estimated to be a range of 1.98 to 2.67 eV (~2.48 eV) found from the Tauc plot analysis, which contributes to the significantly owing to the enhanced photocatalytic efficiency with excellent performance along exciton formation, superoxide ions, and hydroxyl free radicals generations under UV-vis light irradiation resulting in efficient degradation of typical novel fruit organic dye. Photoluminescence spectra observed at room temperature and low temperature have been observed for the BaTiO3 nanoflakes, which exhibit the blue emission due to the crystalline defects such as the appearance of Ba vacancies leads to the conceivable beginning of p-type conductivity and the origination of free exciton emission reveals the direct bandgap transition nature of nanoflakes. RESEARCH HIGHLIGHTS: According to our findings, 89.71% of the natural syzygium cumin is degraded by photocatalysis reaction. As a plausible mechanism for the destruction of natural dyes under solar light, photocatalytic destruction has been proposed. The reaction between these reactive free radical species leads to high efficiency photodegradation with a short decay time. In addition to water treatment and environmental cleaning applications, the excellent performance of this photocatalyst makes it a promising candidate for other applications. Hence, the synthesized BaTiO3 nanoflakes showcase a highly significant advancement towards the development of a textiles dye recycling method.

MK-801-exposure induces increased translation efficiency and mRNA hyperacetylation of Grin2a in the mouse prefrontal cortex

ABSTRACT Acute exposure to MK-801, the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, induces schizophrenia-like behavioural changes in juvenile male mice. However, the effects of acute MK-801 exposure on brain gene expression at the translation level remain unclear. Here, we conducted ribosome profiling analysis on the prefrontal cortex (PFC) of acute MK-801-exposed juvenile male mice. We found 357 differentially translated genes, with the N 4-acetylcytidine (ac4C) consensus motif enriched in the transcripts with increased translation efficiency. Acetylated RNA immunoprecipitation sequencing revealed 148 differentially acetylated peaks, of which 121 were hyperacetylated, and 27 were hypoacetylated. Genes harbouring these peaks were enriched in pathways related to axon guidance, Hedgehog signalling pathway, neuron differentiation, and memory. Grin2a encodes an NMDA receptor subunit NMDAR2A, and its human orthologue is a strong susceptibility gene for schizophrenia. Grin2a mRNA was hyperacetylated and exhibited significantly increased translation efficiency. NMDAR2A protein level was increased in MK-801-exposed PFC. Pretreatment of Remodelin, an inhibitor of N-acetyltransferase 10, returned the NMDAR2A protein levels to normal and partially reversed schizophrenia-like behaviours of MK-801-exposed mice, shedding light on the possible role of mRNA acetylation in the aetiology of schizophrenia.

Elucidation of endogenous and exogenous chemicals in maternal serum using high-resolution mass spectrometry

The increasing exposure to environmental chemicals calls for comprehensive non-targeted analysis to detect unrecognized substances in human samples. We examined human serum samples to classify compounds as endogenous or exogenous using public databases and to explore the relationships between exposure markers and metabolic patterns. Serum samples from 84 pregnant women at 32 weeks gestation were analyzed using LC-QToFMS. Using the PubChemLite for Exposomics database, we annotated and classified 106 compounds (51 endogenous, 55 exogenous). The compound patterns were analyzed using three dimensional reduction methods: Principal Component Analysis (PCA), regularized Generalized Canonical Correlation Analysis (rGCCA), and Uniform Manifold Approximation and Projection (UMAP). OPTICS clustering applied to these methods revealed two distinct clusters, with 89 % of significant compounds overlapping between clusters. The detected exogenous compounds included dietary substances, phthalates, nitrogenous compounds, and parabens. Pathway enrichment analysis showed that chemical exposure was linked to changes in amino acid metabolism, protein and mineral transport, and energy metabolism. While we found associations between exposure and metabolite changes, we could not establish causality. Our approach of analyzing both exogenous and endogenous chemicals from the same dataset using PubChemLite database presents a new method for exposome research, despite limitations in sample size and peak annotation accuracy. These findings contribute to understanding multiple chemical exposures and their metabolic effects in human biomonitoring.

Application of FISH based G2-PCC assay for the cytogenetic assessment of high radiation dose exposures: Potential implications for rapid triage biodosimetry.

The main goal of this study is to test the utility of calyculin A induced G2-PCC assay as a biodosimetry triage tool for assessing a wide range of low and acute high radiation dose exposures of photons. Towards this initiative, chromosome aberrations induced by low and high doses of x-rays were evaluated and characterized in G2-prematurely condensed chromosomes (G2-PCCs) by fluorescence in situ hybridization (FISH) using human centromere and telomere specific PNA (peptide nucleic acid) probes. A dose dependent increase in the frequency of dicentric chromosomes was observed in the G2-PCCs up to 20 Gy of x-rays. The combined yields of dicentrics and rings in the G2-PCCs showed a clear dose dependency up to 20 Gy from 0.02/cell for 0.1 Gy to 14.98/cell for 20 Gy. Centric rings were observed more frequently than acentric ring chromosomes in the G2-PCCs at all the radiation doses from 1 Gy to 20 Gy. A head-to-head comparison was also performed by FISH on the yields of chromosome aberrations induced by different doses of x-rays (0 Gy -7.5 Gy) in colcemid arrested metaphase chromosomes and calyculin A induced G2-PCCs. In general, the frequencies of dicentrics, rings and acentric fragments were slightly higher in G2-PCCs than in colcemid arrested metaphase chromosomes at all the radiation doses, but the differences were not statistically significant. To reduce the turnaround time for absorbed radiation dose estimation, attempt was made to obtain G2-PCCs by reducing the culture time to 36 hrs. The absorbed doses estimated in x-rays irradiated (0,1,2 and 4 Gy) G2-PCCs after 36 hrs of culture were grossly like that of G2-PCCs and colcemid arrested metaphase chromosomes prepared after 48 hrs of culture. Our study indicates that the shortened version of calyculin A induced G2-PCC assay coupled with the FISH staining technique can serve as an effective triage biodosimetry tool for large-scale radiological/nuclear incidents.

Structure–Function Correlation in Cobalt-Induced Brain Toxicity

Cobalt toxicity is difficult to detect and therefore often underdiagnosed. The aim of this study was to explore the pathophysiology of cobalt-induced oxidative stress in the brain and its impact on structure and function. Thirty-five wild-type C57B16 mice received intraperitoneal cobalt chloride injections: a single high dose with evaluations at 24, 48, and 72 h (n = 5, each) or daily low doses for 28 (n = 5) or 56 days (n = 15). A part of the 56-day group also received minocycline (n = 5), while 10 mice served as controls. Behavioral changes were evaluated, and cobalt levels in tissues were measured with particle-induced X-ray emission. Brain sections underwent magnetic resonance imaging (MRI), electron microscopy, and histological, immunohistochemical, and molecular analyses. High-dose cobalt caused transient illness, whereas chronic daily low-dose administration led to long-term elevations in cobalt levels accompanied by brain inflammation. Significant neurodegeneration was evidenced by demyelination, increased blood–brain barrier permeability, and mitochondrial dysfunction. Treated mice exhibited extended latency periods in the Morris water maze test and heightened anxiety in the open field test. Minocycline partially mitigated brain injury. The observed signs of neurodegeneration were dose- and time-dependent. The neurotoxicity after acute exposure was reversible, but the neurological and functional changes following chronic cobalt administration were not.

The ENDOMIX perspective: how everyday chemical mixtures impact human health and reproduction by targeting the immune system†.

Endocrine disruptor chemicals (EDCs) are natural and synthetic compounds found ubiquitously in the environment that interfere with the hormonal-immune axis, potentially impacting human health and reproduction. Exposure to EDCs has been associated with numerous health risks, such as neurodevelopmental disorders, metabolic syndrome, thyroid dysfunction, infertility, and cancers. Nevertheless, the current approach to establishing causality between EDCs and disease outcomes has limitations. Epidemiological and experimental research on EDCs faces challenges in accurately assessing chemical exposure and interpreting non-monotonic dose response curves. In addition, most studies have focused on single chemicals or simple mixtures, overlooking complex real-life exposures and EDC mechanistic insights, in particular regarding their impact on the immune system. The ENDOMIX project, funded by the EU's Horizon Health Program, addresses these challenges by integrating epidemiological, risk assessment, and immunotoxicology methodologies. This systemic approach comprises the triangulation of human cohort, in vitro, and in vivo data to determine the combined effects of EDC mixtures. The present review presents and discusses current literature regarding human reproduction in the context of immunotolerance and EDC mode of action. It further underscores the ENDOMIX perspective to elucidate the impact of EDCs on immune-reproductive health.

The environmental impact on aging: Insights from buccal mucosa and molecular biomarkers

Buccal epithelial cells serve as a primary barrier against the inhalation and ingestion of harmful substances, working alongside immune system cells such as natural killer cells to protect the body from health-damaging factors. These epithelial cells can also be used as an alternative tissue source for monitoring the genotoxic effects of external factors such as chemical exposure. This assessment can be performed using molecular biomarkers of aging, which reflect biological age and indicate cellular aging acceleration due to internal and external damage factors, such as environmental hazards. In contrast to chronological age, which merely reflects the passage of time, biological age accounts for individual variation in aging processes. Molecular biomarkers are crucial for distinguishing between normal and pathological processes in the body and for identifying the effects of external factors such as chemical exposures. The identification of specific biomarkers enhances the ability to detect and monitor adverse biological responses and accelerated aging. This review aims to highlight the routes through which environmental hazards enter the body, the application of buccal epithelial cells in assessing genetic modifications, and the introduction of potential molecular biomarkers. However, further research is necessary to elucidate the roles of these biomarkers in determining aging rates and individual variability. Understanding their implications may also help identify new therapeutic targets for preventing premature aging, treating age-related diseases, and developing potential treatments.

Evaluating the performance of multi-omics integration: a thyroid toxicity case study.

Multi-omics data integration has been repeatedly discussed as the way forward to more comprehensively cover the molecular responses of cells or organisms to chemical exposure in systems toxicology and regulatory risk assessment. In Canzler etal. (Arch Toxicol 94(2):371-388. https://doi.org/10.1007/s00204-020-02656-y ), we reviewed the state of the art in applying multi-omics approaches in toxicological research and chemical risk assessment. We developed best practices for the experimental design of multi-omics studies, omics data acquisition, and subsequent omics data integration. We found that multi-omics data sets for toxicological research questions were generally rare, with no datasets comprising more than two omics layers adhering to these best practices. Due to these limitations, we could not fully assess the benefits of different data integration approaches or quantitatively evaluate the contribution of various omics layers for toxicological research questions. Here, we report on a multi-omics study on thyroid toxicity that we conducted in compliance with these best practices. We induced direct and indirect thyroid toxicity through Propylthiouracil (PTU) and Phenytoin, respectively, in a 28-day plus 14-day recovery oral rat toxicity study. We collected clinical and histopathological data and six omics layers, including the long and short transcriptome, proteome, phosphoproteome, and metabolome from plasma, thyroid, and liver. We demonstrate that the multi-omics approach is superior to single-omics in detecting responses at the regulatory pathway level. We also show how combining omics data with clinical and histopathological parameters facilitates the interpretation of the data. Furthermore, we illustrate how multi-omics integration can hint at the involvement of non-coding RNAs in post-transcriptional regulation. Also, we show that multi-omics facilitates grouping, and we assess how much information individual and combinations of omics layers contribute to this approach.

Hepatocyte apoptosis is triggered by hepatic inflammation in common carp acutely exposed to microcystin-LR or chronically exposed to Microcystis

Cyanobacterial blooms pose a serious threat to the survival of fish because of the hepatotoxicity of microcystins produced by toxic cyanobacteria such as Microcystis. Many studies have investigated the hepatotoxicity of microcystins in common carp, a freshwater fish distributed worldwide, but the hepatotoxicity mechanism has not been fully clarified. The present study aimed to investigate the mechanism underlying the hepatic inflammatory response and hepatocyte apoptosis induced by acute microcystin-LR exposure via intraperitoneal injection (71 μg/kg and 119 μg/kg) or gavage (357.08 μg/kg) and chronic exposure to toxic Microcystis blooms. The results of acute exposure revealed that microcystin-LR caused an increase in serum transaminase activity and increased the levels of inflammatory factors and inflammatory mediators, inducing a significant inflammatory response in the liver of common carp. Moreover, biochemical detection revealed that hepatocyte apoptosis occurred in the fish. Moreover, chronic toxic Microcystis exposure also caused hepatic inflammation and subsequent apoptosis mediated by the tumour necrosis factor-α (TNF-α) pathway and the mitochondrial pathway similar to acute exposure. Therefore, our study suggests that the inflammatory response induced by microcystin-LR exacerbates apoptosis, likely mediated by TNF-α. In summary, both acute microcystin-LR exposure and chronic toxic Microcystis exposure can cause inflammation in the liver of common carp, which subsequently triggers hepatocyte apoptosis mediated by the TNF-α pathway and the mitochondrial pathway. This study helps elucidate the mechanism of liver damage induced by cyanobacterial blooms in natural water.

Biological effects in normal human fibroblasts following chronic and acute irradiation with both low- and high-LET radiation

IntroductionRadiobiological studies at low dose rates allow us to improve our knowledge of the mechanisms by which radiation exerts its effects on biological systems following chronic exposures. Moreover, these studies can complement available epidemiological data on the biological effects of low doses and dose rates of ionizing radiation. Very few studies have simultaneously compared the biological effects of low- and high-LET radiations at the same dose rate for chronic irradiation.MethodsWe compared, for the first time in the same experiment, the effects of chronic (dose rates as low as ~18 and 5 mGy/h) and acute irradiations on clonogenicity and micronucleus formation in AG1522 normal human skin fibroblasts in the confluent state exposed to doses of low- and high-LET radiation (gamma rays and alpha particles) to investigate any differences due to the different radiation quality and different dose rate (in the dose range 0.006–0.9 Gy for alpha particles and 0.4–2.3 Gy for gamma rays).ResultsAs expected, alpha particles were more effective than gamma rays at inducing cytogenetic damage and reduced clonogenic cell survival. For gamma rays, the cytogenetic damage and the reduction of clonogenic cell survival were greater when the dose was delivered acutely instead of chronically. Instead, for the alpha particles, at the same dose, we found equal cytogenetic damage and reduction of clonogenic cell survival for both chronic and acute exposure (except for the highest doses of 0.4 and 0.9 Gy, where cytogenetic damage is greater at a low dose rate).ConclusionThe results of this study may have an impact on space and terrestrial radioprotection of humans at low doses and low dose rates, on biodosimetry, and on the use of ionizing radiation in medicine. These results also provide insights into understanding damage induction and cell reaction mechanisms following chronic exposure (at dose rates as low as 18 and 5 mGy/h) to low- and high-LET radiation.

Physiological Responses of the Green Shore Crab, Carcinus maenas, During Acute and Chronic Low Temperature Exposure

The green shore crab (Carcinus maenas) is native to Western Europe but has spread around the globe and is described as one of the top 100 worst invasive species. On the east coast of North America, their northern-most limit is the island of Newfoundland, Canada, where they can experience water temperatures as low as −1 °C. We investigated the physiological responses of C. maenas to a temperature reduction regime as well as to long-term acclimation to temperatures representative of winter (2 °C) and summer (12 °C) in Newfoundland. Heart rate, oxygen consumption and estimated energy expenditure declined steadily with decreasing temperature, but a marked change was observed between 6 and 4 °C, with lowest levels recorded in 2 °C. After long-term acclimation to 2 °C there was a sustained reduction in physiological parameters. Even though these physiological parameters were very low in 2 °C, the crabs still exhibited intermittent activity. This supports the presence of a dormancy, rather than true torpor/hibernation below 5 °C, in which crabs will continue to actively move and feed, albeit much more slowly. The population in Newfoundland contains haplotypes from both the invasive northern and southern lineages, and they appear to retain a similar low temperature response compared with most other populations of green crab from both their native and expanded range.

Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma.

There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.

A review of environmental and health effects of synthetic cosmetics

The use of cosmetic products is expanding globally, and with it, so is the range of chemical substances employed in their production. As a result, there is also a higher risk of intoxication, allergic reactions, prolonged chemical exposure, adverse effects, and indiscriminate use. Cosmetic products can contain more than 10,000 ingredients. Most users of synthetic cosmetics are unaware of the harmful effects if they even are. However, it is linked to many diseases like cancer, congenital disabilities, reproductive impairments, developmental systems, contact dermatitis, hair loss, lung damage, old age, skin diseases and reactions, allergies, and harm to human nails. Many beauty products also create a high demand for natural oils, leading to extensive and intensive cultivation, harming natural habitats through deforestation, and contaminating soil and water through pesticides and fertilizers. The adverse effects of hazardous substances in synthetic cosmetics extend beyond human health and influence ecosystems, air quality, and oceans. Thus, this review aims to assess the environmental and health impacts of cosmetics using published scientific articles. The study used a systematic review based on Scopus, Science Direct, Web databases, Scholar Google, and PubMed. The results of this review showed that the formulation of cosmetics until the disposal of their containers could adversely affect environmental and human health.

The Application of Ficus Species in the Treatment of Neurological Disorders

Background Neurological diseases represent a pressing global health concern; the World Health Organization reports that neurological conditions rank as the second leading cause of death worldwide. In the last quarter century, we have witnessed a remarkable 36% surge in global neurological mortality rates. Several factors, including oxidative stress, genetic variability, natural aging process, inflammation, hypertension, diabetes, infections, vitamin deficiencies, metabolic imbalances, chemical exposures, endocrine disorders, and dietary supplements, are implicated in the initiation and progression of various neurological diseases. Purpose This comprehensive review aims to shed light on the neuroprotective attributes of distinct Ficus and their phytoconstituents that have been harnessed for treating neurological diseases and demonstrating neuroprotective effects. Methods A literature search was conducted to obtain information about the study of neurological disease and their treatment using database and search engine like Google Scholar, Research gate, monograph, reference book, SciFinder, PubMed/Medline, Scopus, and Science Direct. Results Ficus species have exhibited remarkable neuroprotective qualities through various mechanisms of action. Moreover, these plants contain a diversity of bioactive such as flavonoids, polyphenols, terpenoids, tannins, alkaloids, glycosides, sterols, and vitamins that proven effective in enhancing memory, reducing anxiety, increasing neurotransmitter levels, mitigating neurodegeneration, and playing pivotal roles in neuroprotection. Conclusion This review consolidates the promising potential of Ficus species in the treatment of neurological diseases, paving the way for future scientific research in the development of novel herbal neuroprotective medications.