Biology subjects

Lopes, C.

Publications and source records attributed to Lopes, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Janus kinase 2 regulates Nurr1 protein stability in dopaminergic neurons of the aging midbrain

The nuclear receptor Nurr1 (NR4A2) is an essential transcription factor that governs the differentiation, maturation, and long-term maintenance of midbrain dopaminergic (mDA) neurons in the substantia nigra. Reduced Nurr1 expression has been closely linked to age-related dopaminergic neuronal loss and the pathogenesis of Parkinsons disease. However, the molecular mechanisms regulating Nurr1 expression and protein stability in the aging midbrain remain poorly understood. Here, we identify Janus kinase 2 (JAK2) as a previously unrecognized regulator of Nurr1 in mDA neurons. In the substantia nigra of aged mice (12-and 18-month-old), JAK2 was robustly expressed in Nurr1-positive mDA neurons, whereas its expression was minimal in young adult mice. In SK-N-BE(2)C neuroblastoma cells, overexpression of JAK2 modestly enhanced Nurr1 transcriptional activity, while the constitutively active mutant JAK2V617F markedly increased it. Notably, this effect was not blocked by pharmacological inhibition of STAT, PI3K, or Akt signaling pathways, indicating that JAK2 regulates Nurr1 independently of canonical JAK/STAT or PI3K/Akt signaling. Mechanistically, JAK2 did not promote tyrosine phosphorylation of Nurr1 but instead physically interacted with Nurr1, leading to enhanced nuclear stability of the Nurr1 protein. Consistent with this mechanism, expression of JAK2V617F increased Nurr1 protein levels without altering its mRNA expression. Functionally, co-expression of JAK2V617F and Nurr1 attenuated oxidative stress-induced cytotoxicity and reduced reactive oxygen species accumulation. Together, these findings reveal a phosphorylation-independent mechanism by which JAK2 stabilizes Nurr1 protein and enhances its transcriptional activity. Our results further suggest that age-associated induction of JAK2 in dopaminergic neurons may promote neuronal resilience by maintaining Nurr1 protein stability during aging.

neuroscience↗

bioRxiv2025

Micronuclear collapse under oxidative stress drives amphisome-mediated export of DNA in Parkinson disease

The diversity of extracellular vesicle (EV) subpopulations and their impact on intercellular communication are increasingly recognized, but how organelle dysfunction shapes EV content in neurodegenerative diseases remains unclear. Mitochondrial and lysosomal functional defects are hallmarks of Parkinsons disease (PD). Here we uncover a novel pathway linking this dysfunctional axis to EV remodeling and immune activation. We show that mitochondrial reactive oxygen species (ROS) induce genomic instability and micronuclei formation in PD fibroblasts, with ruptured micronuclei being sequestered into amphisomes and exported through small EVs. These EVs are enriched in oxidized mitochondrial and nuclear DNA, which potently stimulate microglial inflammatory responses. Mechanistically, this work identifies micronuclei not as passive byproducts of genome instability but as active intermediates in EV cargo loading. Importantly, treatment with the mitochondria-targeted antioxidant AntiOxCIN4 elicited a mitohormetic response, enhancing ATM-mediated DNA damage repair, restoring mitochondrial dynamics, and improving lysosomal function. This reduced the incorporation of oxidized DNA into EVs and blunted their pro-inflammatory activity. Together, our findings reveal a previously unrecognized mechanism by which mitochondrial-lysosomal dysfunction drives the release of DNA-enriched EVs that fuel neuroinflammation in a neurodegenerative context. Targeting mitochondrial quality control to limit oxidized cargo in EVs emerges as a potential strategy to mitigate early inflammatory events in PD.

neuroscience↗

bioRxiv2025

TRIB2 supports a high glycolytic phenotype in melanoma cells

Metabolic adaptation plays a crucial role in driving the progression of human melanoma contributing to therapy resistance and disease relapse. The pseudo serine/threonine kinase Tribbles homolog 2 (TRIB2) is prominently expressed in melanoma tissue, promoting resistance to anti-cancer treatments and correlating with unfavorable clinical outcomes. Despite this understanding, the impact of TRIB2 expression on melanomas metabolic profile remains unexplored. Here we use UACC-62 melanoma cells which exhibit substantial endogenous expression of TRIB2 as well as engineered isogenic TRIB2 knock out (KO) cells to assess the effect of the loss of TRIB2 on metabolism. Our findings reveal that TRIB2-KO cells display reduced glycolytic activity and heightened vulnerability to pharmacological inhibition of oxidative metabolism, contrasting with the parental cell line. These metabolic and phenotypic changes are driven by TRIB2s coordinated regulation of multiple glycolytic genes, whose combined effect might produce the glycolytic phenotype observed in parental cells. Collectively, our results underscore important role of TRIB2 as a modulator of the metabolic shift implicated in therapy resistance. These insights highlight TRIB2 as a potential target for therapeutic intervention, aiming to counteract the metabolic adaptations driving melanomas resistance mechanisms. HighlightsO_LIMain problem in melanoma is the limited therapy efficacy due to resistance; C_LIO_LITRIB2 is a novel unexplored and druggable target; C_LIO_LITRIB2 expression contributes to increased glycolysis in melanoma cells; C_LIO_LITRIB2 is a driver of a metabolic switch that fuels therapy resistance. C_LI

cancer biology↗

bioRxiv2025

The cytoplasmic scaffolding protein PCNA as a new regulator of activation of the classical NRLP3 inflammasome

Key components of innate immune responses, the NLRP3 sensor, ASC adaptor and Caspase-1 effector form the NLRP3 inflammasome, whose assembly leads to both inflammatory cytokines secretion and cell death. Its priming and activation are regulated by numerous proteins including the serine/threonine kinase NEK7. PCNA is a nuclear scaffolding protein essential for DNA replication. In neutrophils, which are differentiated cells deprived of proliferative capacity, PCNA is exclusively cytoplasmic and regulates neutrophil functions through interactions with different protein partners. Among them, pro-Caspases-3/8/9/10 interact with PCNA to regulate apoptosis. We therefore hypothesize that cytoplasmic PCNA could serve as a regulatory platform for the NLRP3 inflammasome via its interaction with its components. In PMA-differentiated THP-1 macrophages, PCNA relocalized mainly in the cytoplasm. Furthermore, PCNA scaffold inhibitors inhibited IL-1{beta} secretion, pro-Caspase-1 cleavage and pyroptosis-activating gasdermin D cleavage, induced by either nigericin, monosodium urate crystals or Escherichia coli bacteria. Nigericin-stimulation resulted in cytoplasmic PCNA binding to NEK7 and potentially NLRP3, and the p21 peptide, the highest competitive inhibitor of PCNA partner binding, disrupted PCNA-NEK7 interaction. Finally, use of bone marrow-derived macrophages from p21 knockout mice suggested that the cyclin-dependent kinase inhibitor p21 might be a natural repressor of the NLRP3 inflammasome. This work provides a proof-of-principle for the potential of disrupting PCNA interactions to regulate both canonical and non-canonical NLRP3 inflammasomes.

immunology↗

bioRxiv2024

The Dystrophin-Dystroglycan complex ensures cytokinesis efficiency in Drosophila epithelia

Cytokinesis physically separates daughter cells at the end of cell division. This step is particularly challenging for epithelial cells, which are connected to their neighbors and to the extracellular matrix by transmembrane protein complexes. To systematically evaluate the impact of the cell adhesion machinery on epithelial cytokinesis efficiency, we performed an RNAi-based modifier screen in the Drosophila follicular epithelium. Strikingly, this unveiled adhesion molecules and transmembrane receptors that facilitate cytokinesis completion. Among these is Dystroglycan, which connects the extracellular matrix to the cytoskeleton via Dystrophin. Live imaging revealed that Dystrophin and Dystroglycan become enriched in the ingressing membrane, below the cytokinetic ring, during and after ring constriction. Using multiple alleles, including Dystrophin isoform-specific mutants, we show that Dystrophin/Dystroglycan localization is linked with unanticipated roles in regulating cytokinetic ring contraction and in preventing membrane regression during the abscission period. Altogether, we provide evidence that, rather than opposing cytokinesis completion, the machinery involved in cell-cell and cell-matrix interactions has also evolved functions to ensure cytokinesis efficiency in epithelial tissues.

cell biology↗

bioRxiv2023

Assimilation efficiencies and elimination rates of trace metals accumulated by trophic pathway in Gammarus fossarum

To improve the assessment of metal toxicity in aquatic organisms, it is important to consider the different uptake pathways (i.e. trophic or aqueous). The bioaccumulation of dissolved metals such as Cd and Zn in gammarids is beginning to be well described. However, there are very few data on the contribution of the dietary pathway, and its associated toxicokinetic parameters. Among these, the assimilation efficiency (AE) is an essential parameter for the implementation of models that take the trophic pathway into account. This study aims to estimate the assimilation efficiencies and elimination rates of two types of food, i.e. alder leaves and chironomid larvae, contaminated with three metals (Ag, Cd and Zn) of major concern for the Water Framework Directive (WFD). The pulse-chase-feeding method was used. Gammarids were fed with alder leaves or chironomid larvae previously contaminated with 110mAg, 109Cd or 65Zn, for a short period of time (1 to 5 hours), followed by an elimination phase of 14 days. At different time points, the gammarids were placed alive on the gamma detector to individually quantify whole body concentrations of 110mAg, 109Cd or 65Zn. Our results indicate that: i) Cd has the highest assimilation efficiency (39% for leaves and 19% for larvae), followed by Zn (15% for leaves and 9% for larvae) and Ag (5% for leaves); ii) for Cd and Zn, the AE were higher when gammarids were fed with leaves than with larvae; iii) the elimination rates of metals seem to depend more on the food matrix than on the metal assimilated; and thus iv) the biological half-life calculated from the kes is 5.1 days for Ag, between 4.9 and 13 days for Cd and between 3.8 and 13 days for Zn.

physiology↗

bioRxiv2023

A conformational-dependent interdomain redox relay at the core of Protein Disulfide Isomerase activity

Protein disulfide isomerases (PDIs) are a family of molecular chaperones resident in the endoplasmic reticulum (ER) emerging as important factors in disease. In addition to an holdase function, some members catalyse disulfide bond formation and isomerization, a crucial step for native folding and prevention of aggregation of misfolded proteins. PDIs are characterized by a modular arrangement of thioredoxin-like domains, with the canonical, first identified PDIA1, organized as four thioredoxin-like domains forming a horseshoe with two active sites at the extremities. Using two fluorescent redox sensors, roGFP2 and HyPer, as client substrates either unfolded or native, and the in vitro reconstitution of the full pathways of oxidative protein in the ER, we clarified important aspects underlying the catalytic cycle of PDIA1. The N-terminal a active site is the main oxidant of thiols and can transfer electrons to the C-terminal a active site relying on the redox-dependent conformational flexibility of PDIA1 that allows the formation of an interdomain disulfide bond. The a active site act then as a crossing point to redirect electrons to the ER downstream oxidases or back to client proteins. The two active sites of PDIA1 work cooperatively as an interdomain redox relay that explains PDIA1 oxidative activity to form native disulfides and PDIA1 reductase activity to resolve scrambled disulfides. Moreover, this mechanism reveals a new rational for shutting down oxidative protein folding under ER redox imbalance or when the levels of unfolded proteins and folding intermediates exceed the folding capacity of the system.

biochemistry↗

bioRxiv2022

Extracellular vesicles improve GABAergic transmission in Huntington's disease iPSC-derived neurons

Extracellular vesicles (EVs) carry bioactive molecules associated with various biological processes, including miRNAs. In both Huntingtons disease (HD) models and human samples, altered expression of miRNAs involved in synapse regulation were reported. Recently, the use of EV cargo to reverse phenotypic alterations in disease models with synaptopathy as the end-result of the pathophysiological cascade has become an interesting possibility. Here, we assessed the contribution of EVs to GABAergic synaptic alterations using a human HD model and studied the miRNA content of isolated EVs. After differentiating HD human induced-pluripotent stem cells into electrophysiologically active striatal-like GABAergic neurons, we found that HD-derived neurons displayed reduced density of inhibitory synapse markers and of GABA receptor-mediated ionotropic signaling. Treatment with EVs secreted by control (CTR) fibroblasts reversed the deficits in GABAergic synaptic transmission and increased the density of inhibitory synapses on HD-neuron cultures, while EVs from HD-derived fibroblasts had the opposite effects on CTR-neurons. Moreover, analysis of miRNAs from purified EVs identified a set of differentially expressed miRNAs between manifest HD, premanifest and CTR lines with predicted synaptic targets. The EVs-mediated reversal of the abnormal GABAergic phenotype in HD-derived neurons reinforces the potential role of EVs-miRNAs on synapse regulation.

neuroscience↗

bioRxiv2022

Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma

BackgroundCanine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells associated with short survival times. Understanding the genomic landscape of HSA is critical to developing more effective therapeutic strategies. ObjectivesTo determine the relationships between genomic and clinical features including treatment and outcome in canine splenic HSA. Animals109 dogs with primary splenic HSA treated by splenectomy that had tumor sequencing via the FidoCure(R) Precision Medicine Platform targeted sequencing panel. MethodsPatient signalment, weight, metastasis at diagnosis, treatment, and survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables and outcome were assessed. ResultsSomatic mutations in TP53 (n = 45), NRAS (n = 20), and PIK3CA (n = 19) were most common. Survival was associated with metastases at diagnosis, germline variants in SETD2 and NOTCH1, and nominally with breed. Age at diagnosis was associated with NRAS mutations and breed. TP53 and PIK3CA mutations were found in larger dogs, germline SETD2 variants in smaller dogs. Doxorubicin (DOX) treatment did not significantly improve survival time, while targeted therapies had a significant early survival benefit. Conclusions and clinical importanceDOX treatment may provide limited clinical benefit for dogs with splenic HSA, while targeted therapy may provide early survival benefit. Genetic signatures associated with splenic HSA may be useful in guiding targeted therapy to improve outcomes. Germline variants, age, size, and breed may be useful prognostic factors and provide insight into the genomic landscape of the tumor.

genomics↗

bioRxiv2022

Chemical effects on ecological interactions within a model-experiment loop

We propose in this paper a method to assess the effects of a contaminant on a micro-ecosystem, integrating the population dynamics and the interactions between species. For that, we developed a dynamic model to describe the functioning of a microcosm exposed to a contaminant and to discriminate direct and indirect effects. Then, we get back from modelling to experimentation in order to identify which of the collected data have really been necessary and sufficient to estimate model parameters in order to propose a more efficient experimental design for further investigations. We illustrated our approach using a 2-L laboratory microcosm involving three species (the duckweed Lemna minor, the microalgae Pseudokirchneriella subcapitata and the daphnids Daphnia magna) exposed to cadmium contamination. We modelled the dynamics of the three species and their interactions using a mechanistic model based on coupled ordinary differential equations. The main processes occurring in this three-species microcosm were thus formalized, including growth and settling of algae, growth of duckweeds, interspecific competition between algae and duckweeds, growth, survival and grazing of daphnids, as well as cadmium effects. We estimated model parameters by Bayesian inference, using simultaneously all the data issued from multiple laboratory experiments specifically conducted for this study. Cadmium concentrations ranged between 0 and 50 g.L-1 . For all parameters of our model, we obtained biologically realistic values and reasonable uncertainties. The cascade of cadmium effects, both direct and indirect, was identified. Critical effect concentrations were provided for the life history traits of each species. An example of experimental design adapted to this kind a microcosm was also proposed. This approach appears promising when studying contaminant effects on ecosystem functioning.

ecology↗

bioRxiv2022

Generic solving of physiologically-based kinetic models in support of next generation risk assessment due to chemicals

Increasing the confidence in using in vitro and in silico model-based data to aid the chemical risk assessment process is one, if not the most, important challenge currently facing regulatory authorities. A particularly crucial concern is to fully take advantage of scientifically valid Physiologically-Based Kinetic (PBK) models. Nevertheless, risk assessors remain still unwilling in employing PBK models within their daily work. Indeed, PBK models are not often included in current official guidance documents. In addition, most users have limited experience in using modelling in general. So, the complexity of PBK models, together with a lack to evaluation methods of their performances, certainly contributes to their under-use in practical risk assessment. This paper proposes an innovative and unified modelling framework, in both the writing of PBK equations as matrix ordinary differential equations (ODE), and in its exact solving simply expressed with matrix products. This generic PBK solution allows to consider as many as state-variables as needed to quantify chemical absorption, distribution, metabolism and excretion processes within living organisms when exposed to chemical substances. This generic PBK model makes possible any compartmentalisation to be considered, as well as all appropriate inter-connections between compartments and with the external medium. We first introduce our PBK modelling framework, with all intermediate steps from the matrix ODE to the exact solution. Then we apply this framework to bioaccumulation testing, before illustrating its concrete use through complementary case studies in terms of species, compounds and model complexity. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

pharmacology and toxicology↗

bioRxiv2022

Defective mitochondrial-lysosomal axis promotes extracellular vesicles release of mitochondrial components in Huntington's Disease

Mitochondrial and autophagy dysfunction are mechanisms proposed to be involved in the pathogenesis of several neurodegenerative diseases. Huntingtons disease (HD) is a progressive neurodegenerative disorder associated with mutant Huntingtin-induced abnormalities in neuronal mitochondrial dynamics and quality control. Former studies suggest that the removal of defective mitochondria may be compromised in HD. The mitochondrial quality control is a complex, well-orchestrated pathway that can be compromised through mitophagy dysregulation or impairment in the mitochondrial-lysosomal axis. Another mitochondrial stress response is the generation of mitochondrial-derived vesicles that fuse with the endolysosomal system and form multivesicular bodies that are extruded from cells as extracellular vesicles (EVs). In this study, we comprehensively characterized the mitochondrial and autophagy alterations in premanifest and manifest HD patients and performed a proteomic and genomic EVs profile. We observed that manifest HD patients exhibit mitochondrial and autophagy impairment associated with enhanced EVs release. Further, we detected mitochondrial components in EVs released by HD cells and in neuron-derived EVs. The EV-associated mtDNA copies were elevated in manifest HD patients suggesting to be an alternative pathway for secretion of reactive mitochondrial components. This study provides a novel framework connecting EVs enhanced release of mitochondrial components to mitochondrial and lysosomal dysfunction in HD.

neuroscience↗

bioRxiv2022

Improvements in estimating bioaccumulation metrics in the light of toxicokinetics models and Bayesian inference

The surveillance of chemical substances in the scope of Environmental Risk Assessment (ERA) is classically performed through bio-assays from which data are collected and then analysed and/or modelled. Some analysis are based on the fitting of toxicokinetic (TK) models to assess the bioaccumulation capacity of chemical substances via the estimation of bioaccumulation metrics as required by regulatory documents. Given that bio-assays are particularly expensive and time consuming, it is of crucial importance to deeply benefit from all information contained in the data. By revisiting the calculation of bioaccumulation metrics under a Bayesian framework, this paper suggests changes in the way of characterising the bioaccumulation capacity of chemical substances. For this purpose, a meta-analysis of a data-rich TK database was performed, considering uncertainties around bioaccumulation metrics. Our results were statistically robust enough to suggest an additional criterion to the single median estimate of bioaccumulation metrics to assign a chemical substance to a given bioaccumulation capacity. Our proposal is to use the 75th percentile of the uncertainty interval of the bioaccumulation metrics, which revealed an appropriate complement for the classification of chemical substances (e.g., PBT (persistent, bioaccumulative and toxic) and vPvB (very persistent and very bioaccumulative) under the EU chemicals legislation). The 75% quantile proved its efficiency, similarly classifying 90% of the chemical substances as the conventional method.

pharmacology and toxicology↗

bioRxiv2022

Mitochondrial and redox modifications in early stages of Huntington disease

Defects in mitochondrial function and mitochondrial-related redox deregulation have been attributed to Huntingtons disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. Thus, in the present study, we analyzed changes in mitochondrial function and overreduced states associated with production of reactive oxygen species (ROS) at early stages and along disease progression. Studies were performed in vivo in human brain using positron emission tomography (PET) using [64Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD patients; in vivo brain [64Cu]-ATSM PET and isolated mitochondria derived from striatum and cortex were also analyzed in YAC128 transgenic mouse at pre-symptomatic (3 month-old, mo) and symptomatic (6 to 12 mo) stages. Oxygen consumption rates were assessed by Seahorse analysis, hydrogen peroxide levels were determined using fluorescent probes and mitochondrial morphology by transmission electron microscopy in human skin fibroblasts and mouse striatal and cortical isolated mitochondria. Pre-M HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number. Fibroblasts from Pre-M showed enhanced basal and maximal respiration, proton (H+) leak and increased hydrogen peroxide levels, the later progressing to manifest HD; mitochondria from fibroblasts of Pre-M HD carriers also showed reduced roundness, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. Pre-symptomatic YAC128 mouse striatal isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production, along with increased complex II and III activities; mouse HD mitochondria also showed enhanced mitochondrial hydrogen peroxide levels and roundness, as revealed by brain ultrastructure analysis, and defects in Ca2+ handling, supporting increased striatal susceptibility in YAC128 mouse brain. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter extending over manifest disease stages.

neuroscience↗

bioRxiv2021

Shared hotspot mutations in spontaneously arising cancers position dog as an unparalleled comparative model for precision therapeutics

Naturally occurring canine cancers have remarkable similarities to their human counterparts. In order to determine whether these similarities occur at the molecular level, we investigated hotspot mutations in a variety of spontaneously arising canine cancers and found high concordance in oncogenic drivers between cancers in both species. These findings suggest that canines may present a powerful and complementary model for preclinical investigations for targeted cancer therapeutics. Through analysis of 708 client-owned dogs from 96 breeds (plus mixed breeds) with 23 common tumor types, we discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. TP53 is the most commonly mutated gene, detected in 30.81% of canine tumors overall and >40% in hemangiosarcoma and osteosarcoma. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant (P<0.0001) association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E in urothelial carcinoma. This work positions canines as excellent spontaneous models of human cancers that can help to investigate a wide spectrum of targeted therapies.

cancer biology↗

bioRxiv2021

rbioacc: an R-package to analyse toxicokinetic data

O_LI rbioacc is an R-package dedicated to the analysis of experimental data collected from bioaccumulation tests during which organisms are exposed to a chemical (exposure phase) and then put into a clean media (depuration phase). Internal concentrations are regularly measured over time all along the experiment. C_LIO_LI rbioacc provides ready-to-use functions to visualize and fully analyze such data. Under a Bayesian framework, this package fits a generic one-compartment toxicokinetic (TK) model automatically built from the data. It provides TK parameter estimates (appropriate uptake and elimination rates) and bioaccumulation metrics (e.g., BCF, BSAF, BMF). All parameter estimates, bioaccumulation metrics as well as predictions of internal concentrations into organisms are delivered with their uncertainty. C_LIO_LIBioaccumulation metrics are primarily provided in support of environmental risk assessment, in full compliance with regulatory requirements required to approve marketing applications of chemical substances. C_LIO_LIThis paper gives brief worked examples of the use of rbioacc from data collected through standard bioaccumulation tests, and publicly available within the scientific literature. These examples constitute step-by-step user-guides to analyze any new data set, uploaded in the right format. C_LI

ecology↗

bioRxiv2021

Generic solving of one-compartment toxicokinetic models

This paper gives the full analytical solution of the generic set of ordinary differential equations that define one-compartment toxicokinetic models. These models describe uptake and elimination processes taking place within living organisms when exposed to chemical substances. The models solved in this paper consider living organisms as a unique compartment, into which a parent compound enters via several possible exposure routes and from which it is eliminated as well as its potential metabolites. Benefiting from generic solutions of one-compartment toxicokinetic models is particularly useful when fitting them to experimental data, facilitating the writing of the inference algorithms leading to parameter estimates. Additionally, these models are of crucial interest in environmental risk assessment for the calculation of bioaccumulation metrics as required by regulators in support of decision making when they evaluate dossiers for marketing authorisation of active substances. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/442956v2_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1e8381org.highwire.dtl.DTLVardef@14b957forg.highwire.dtl.DTLVardef@143dc14org.highwire.dtl.DTLVardef@25c478_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

pharmacology and toxicology↗

bioRxiv2021

Taking full advantage of modelling to better assess environmental risk due to xenobiotics

In the European Union, more than 100,000 man-made chemical substances are awaiting an environmental risk assessment (ERA). Simultaneously, ERA of chemicals has now entered a new era. Indeed, recent recommendations from regulatory bodies underline a crucial need for the use of mechanistic effect models, allowing assessments that are not only ecologically relevant, but also more integrative, consistent and efficient. At the individual level, toxicokinetic-toxicodynamic (TKTD) models are particularly encouraged for the regulatory assessment of pesticide-related risks on aquatic organisms. In this paper, we first propose a brief review of classical dose-response models to put into light the on-line MOSAIC tool offering all necessary services in a turnkey web platform whatever the type of data to analyze. Then, we focus on the necessity to account for the time-dimension of the exposure by illustrating how MOSAIC can support a robust calculation of bioaccumulation factors. At last, we show how MOSAIC can be of valuable help to fully complete the EFSA workflow regarding the use of TKTD models, especially with GUTS models, providing a user-friendly interface for calibrating, validating and predicting survival over time under any time-variable exposure scenario of interest. Our conclusion proposes a few lines of thought for an even easier use of modelling in ERA. Graphical art O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/436474v3_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@d98a72org.highwire.dtl.DTLVardef@1066b4org.highwire.dtl.DTLVardef@c6eef3org.highwire.dtl.DTLVardef@71c528_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗