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Results for “pharmacology and toxicology”

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bioRxiv2025

Alignment between Duplex Sequencing and transgenic rodent mutation assay data in the assessment of in vivo NDMA-induced mutagenesis

The nitrosamine N-nitrosodimethylamine (NDMA) is a mutagen and rodent carcinogen that has been identified as a process impurity in some commercially available medicines, leading to market withdrawals and new impurity control measures. Error-corrected DNA sequencing techniques, such as Duplex Sequencing (DS), have error rates low enough to revolutionise genetic toxicology testing by directly measuring in vivo mutagenesis within days of exposure. Here, DS was performed on liver samples from an OECD-compliant, Transgenic Rodent Gene Mutation Assay (TGR) conducted under GLP standards. MutaMouse specimens were orally dosed with NDMA using either a repeat-dose 28-day regimen (0.02-4 mg/kg(bw)/day) or single bolus doses of either 5 or 10 mg/kg(bw) administered on day one. Dose-dependent increases in mutation frequency were detected by DS in liver, enabling a No-Observed Genotoxic Effect Level (NOGEL) of 0.07 mg/kg(bw)/day to be determined, supported by mechanistic analyses of trinucleotide mutation spectra. Benchmark dose (BMD) modelling determined similar BMD50 values from either DS or TGR, demonstrating concordance across the two techniques albeit with greater precision from DS due to smaller inter-animal variation. DS offers a fundamental change in mutagenicity assessments enabling more precise point-of-departure determinations with mechanistic clarity and 3Rs advantages compared to the standard TGR approach.

pharmacology and toxicology↗

bioRxiv2020

SARS-CoV-2 inhibition in human airway epithelial cells using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of -3 to -4 at a concentration of 10 - 100 g/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 g/ mL (p < 0.05 compared to untreated controls). GCPQ is currently being developed as a pharmaceutical excipient in nasal and ocular formulations. GCPQs electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/ kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 hours after nasal dosing. With a no observed adverse effect level of 18 mg/ kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.

pharmacology and toxicology↗

bioRxiv2023

Predictive toxicology of chemical mixtures using proteome-wide thermal profiling and protein target properties

Our capability to predict the impact of exposure to chemical mixtures on environmental and human health is limited in comparison to the advances on the chemical characterization of the exposome. Current approaches, such as new approach methodologies, rely on the chemical mixture characterization and the available toxicological knowledge of individual compounds or similar mixtures. In this study, we show a new methodological approach for assessment of chemical mixtures based on a proteome-wide identification of the protein targets and revealing the relevance of new targets based on their role in the cellular crosstalk. We applied a proteome integral solubility alteration assay to identify 24 protein targets from a chemical mixture of 2,3,7,8- tetrachlorodibenzo-p-dioxin, alpha-endosulfan, and bisphenol A among the HepG2 soluble proteome, and validated the chemical mixture-target interaction orthogonally. To define the range of interactive capability of the new targets, the data from intrinsic properties of the targets were retrieved. Introducing the target properties as criteria for a multi-criteria decision-making analysis called the analytical hierarchy process, the prioritization of targets was based on their involvement in multiple pathways. This methodological approach that we present here opens a more realistic and achievable scenario to address the impact of complex and uncharacterized chemical mixtures in biological systems. SYNOPSISMethods for unbiased identification of protein targets of chemical mixtures and prediction of their impact in human and environmental health.

pharmacology and toxicology↗

bioRxiv2021

Qualifying a human Liver-Chip for predictive toxicology: Performance assessment and economic implications

Human organ-on-a-chip (Organ-Chip) technology has the potential to disrupt preclinical drug discovery and improve success in drug development pipelines as it can recapitulate organ-level pathophysiology and clinical responses. The Innovation and Quality (IQ) consortium formed by multiple pharmaceutical and biotechnology companies to confront this challenge has published guidelines that define criteria for qualifying preclinical models, however, systematic and quantitative evaluation of the predictive value of Organ-Chips has not yet been reported. Here, 870 Liver-Chips were analyzed to determine their ability to predict drug-induced liver injury (DILI) caused by small molecules identified as benchmarks by the IQ consortium. The Liver-Chip met the qualification guidelines across a blinded set of 27 known hepatotoxic and non-toxic drugs with a sensitivity of 87% and a specificity of 100%. A computational economic value analysis suggests that with this performance the Liver-Chip could generate $3 billion annually for the pharmaceutical industry due to increased R&D productivity.

pharmacology and toxicology↗

bioRxiv2019

Safety assessment of a novel C-type natriuretic peptide derivative and the mechanism of bone- and cartilage-specific toxicity

ASB20123, a C-type natriuretic peptide/ghrelin chimeric peptide, was designed as a novel peptide and demonstrated full agonistic activity for natriuretic-peptide receptor B and a significantly longer half-life in plasma compared with the native peptide. We researched the toxicological profile of ASB20123, the correlation between the morphological change of the epiphyseal plate and bone and cartilage toxicity, and biomarkers to detect the toxicity. ASB20123 was systemically administered to male and female rats at daily dose levels of 0.5, 1.5, and 5.0 mg/kg/day for 4 weeks. In this study, toxicity was observed as changes related to bone and cartilage tissues, and no other toxicological changes were observed in all animals. Next, ASB20123 was administered to 12-month-old rats with a little epiphyseal plate. The toxic changes related to bone and cartilage tissues were not observed in any animal with a closed epiphyseal plate, indicating that the toxic changes were triggered by the growth-accelerating effect on the bone and cartilage. Furthermore, we searched for the biomarker related to the bone and cartilage toxicity using rats treated with ASB20123 at doses of 0.005, 0.05, 0.5, and 5.0 mg/kg/day for 4 weeks. A close correlation between necrosis/fibrosis in the epiphysis and metaphysis and thickness of the epiphyseal plate in the femur was confirmed in this study. A decrease in the bone mineral density (BMD) of the femur also was associated with the appearance of bone toxicity. These results indicated that the toxicity of ASB20123 was limited to bone- and cartilage-specific changes, and these changes were triggered by an excessive growth accelerating effect. Furthermore, our data suggested that the thickness of the epiphyseal plate and BMD could be reliable biomarkers to predict bone toxicity.

pharmacology and toxicology↗

bioRxiv2026

The effects of estrogen exposure on survival, growth, and fecundity of Daphnia magna

High concentrations of steroidal hormone compounds are a growing source of concern for environmental pollution in aquatic ecosystems. In this study, we examine the effects of two estrogenic compounds (estriol and 17-ethinylestradiol) on fitness traits in the aquatic microcrustacean, Daphnia magna, a key bioindicator species for toxicology studies. The impacts were compared of two forms representing a natural and synthetic estrogenic compound. Growth and reproduction traits were assayed by exposing Daphnia to each estrogen type at four concentrations reflecting potential environmental exposure conditions up to acute toxicity levels (ranging from 0.1 - 50 {micro}g/L). Assaying the effects at a variety of concentrations is important given that it is known that hormone exposures can often result in non-monotonic responses. Both forms of estrogen impact a subset of the traits assessed, in some cases leading to beneficial changes and others causing harm. Estriol, the naturally-occurring estrogen, and EE2, the synthetic version, at high doses shift fitness traits in opposite directions such as adult growth rate as do at low doses for fecundity. In conclusion, our results support the need to assay a wide array of traits using multiple forms of steroidal hormones at a range of doses in order to assess non-monotonic patterns and their impact on an organismal fitness. In particular, assays that extend beyond the conventional measurements of lethality during acute exposure windows will be essential for understanding the impact of increased levels of hormone pollution on aquatic organisms and ecosystem health.

pharmacology and toxicology↗

bioRxiv2018

The AOPOntology: A Semantic Artificial Intelligence Tool for Predictive Toxicology

IntroductionToxicology needs artificial intelligence tools that can automate the prediction of toxicity. Today we are at an interesting nexus. We have thousands of chemicals in the environment that lack regulatory thresholds for determining risk. New high throughput in vitro testing methods are becoming available to test these chemicals. Causal Adverse Outcome Pathway Networks (CAOPN) are emerging that will allow us to make predictions based on perturbations of specific key events within the network. The AOPOntology was developed as infrastructure for this nexus, providing the ability to model and marry the data from the in vitro tests for the thousands of chemicals and place them within the CAOPN framework to facilitate adverse outcome predictions.\n\nMaterials and MethodsThe AOPN is a functional specialized ontology that creates classes that model biological pathways and CAOPNs. Adverse outcome predictions are based on mathematical determinations of key events that are sufficient to infer adverse outcomes will occur, or biological information. These sufficiency relationships are captured in the AOPOntology and used by the semantic reasoners to make predictions.\n\nResultsThe AOPOntology version 1.0 architecture is in place, and a CAOPN for steatosis demonstrates how causal network theory is used to make predictions. The AOPOntology is available at https://github.com/DataSciBurgoon/aop-ontology.\n\nDiscussionThe AOPOntology is a knowledge base for CAOPNs that one can use to make predictions about a chemicals potential toxicity using in vitro high throughput and other assays.\n\nConclusionsUsing CAOPNs and causal network theory one is able to predict potential toxicity for chemicals using in vitro high throughput and various high content screens.

pharmacology and toxicology↗

bioRxiv2023

Pharmaceutical agent cetylpyridinium chloride inhibits immune mast cell function by interfering with calcium mobilization

Cetylpyridinium chloride (CPC) is an antimicrobial used in numerous personal care and janitorial products and food for human consumption at millimolar concentrations. Minimal information exists on the eukaryotic toxicology of CPC. We have investigated the effects of CPC on signal transduction of the immune cell type mast cells. Here, we show that CPC inhibits the mast cell function degranulation with antigen dose-dependence and at non-cytotoxic doses [~]1000-fold lower than concentrations in consumer products. Previously we showed that CPC disrupts phosphatidylinositol 4,5-bisphosphate, a signaling lipid critical for store-operated Ca2+ entry (SOCE), which mediates degranulation. Our results indicate that CPC inhibits antigen-stimulated SOCE: CPC restricts Ca2+ efflux from endoplasmic reticulum, reduces Ca2+ uptake into mitochondria, and dampens Ca2+ flow through plasma membrane channels. While inhibition of Ca2+ channel function can be caused by alteration of plasma membrane potential (PMP) and cytosolic pH, CPC does not affect PMP or pH. Inhibition of SOCE is known to depress microtubule polymerization, and here we show that CPC indeed dose-dependently shuts down formation of microtubule tracks. In vitro data reveal that CPC inhibition of microtubules is not due to direct CPC interference with tubulin. In summary, CPC is a signaling toxicant that targets Ca2+ mobilization.

pharmacology and toxicology↗

bioRxiv2024

Human internal exposures of bisphenol A and six data-poor analogues predicted by physiologically based kinetic models with multimodal parameterization

BackgroundBisphenols (BP) AF, B, E, F, M, and S have been introduced as substitutes for bisphenol A (BPA) and are increasingly used in consumer products. Despite widespread human exposure and potential adverse health outcomes related to BPF, BPB, BPS, and BPAF, their physiological disposition in humans is poorly characterized, which hinders assessment of associated risks. ObjectivesOur goal was to simulate the kinetic behavior of prevalent bisphenol analogs in organs of toxicological interest. To enable predictions of physiologically relevant internal concentrations of a family of structurally similar compounds with limited available human data, we aim to establish a reproducible framework using multimodal parameterization methods. MethodsHerein we developed physiologically based kinetic (PBK) models, following oral exposure. Their parametrization was primarily based on structural, physiological and experimental values, as well as quantitative structure-activity relationship (QSAR) predictions. Outputs were evaluated against available biomonitoring data for BPA and BPS. Critical parameters were identified by sensitivity analysis and iteratively re-sampled in Monte Carlo (MC) simulations to quantify uncertainties. ResultsAmong human models parametrized for males and females of different ages, we predicted that bisphenols reached the highest concentrations in 5-year-old males. Environmentally relevant exposure levels resulted in maximum concentrations in the blood and testes for BPS, and in the thyroid for BPM. After 96 hours, steady-state concentrations were not yet reached in the breasts for BPA, BPAF, BPB, BPE, BPF and BPM. ConclusionsThe data from this study suggest significant variability in internal concentrations for identical exposures to different bisphenols analogs that further depend on age, sex and organ. This diversity in toxicokinetic behavior should be considered for health risk assessment of these substitutes.

pharmacology and toxicology↗

bioRxiv2024

Suspect screening-data independent analysis workflow for the identification of arsenolipids in marine standard reference materials

There has been limited research into arsenolipid toxicological risks and health-related outcomes due to challenges with their separation, identification, and quantification within complex biological matrices (e.g., fish, seaweed). Analytical approaches for arsenolipid identification such as suspect screening have not been well documented and there are no certified standard reference materials, leading to issues with reproducibility and uncertainty regarding the accuracy of results. In this study, a detailed workflow for the identification of arsenolipids utilizing suspect screening coupled with data independent analysis is presented and applied to three commercially available standard reference materials (Hijiki seaweed, dogfish liver, and tuna). Hexane and dichloromethane/methanol extraction, followed by reversed-phase high-performance liquid chromatography-inductively coupled plasma mass spectrometry and liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry. Using the workflow developed, mass fragmentation matching, mass error calculations, and retention time matching were performed to identify suspect arsenolipids. Arseno-fatty acids (AsFAs), arsenohydrocarbons (AsHCs), and arsenosugar phospholipids (AsSugPLs) were identified with high confidence; AsHC332, AsHC360, and AsSugPL720 in seaweed, AsHC332 in tuna, and AsFA474 and AsFA502 in the dogfish liver. AsHC332, AsHC360, and AsFA502 were identified as promising candidates for further work on synthesis, quantification using MS/MS, and toxicity testing.

pharmacology and toxicology↗

bioRxiv2022

Determining the toxicity and potential for environmental transport of pyridine using the brown crab Cancer pagurus (L.)

1A series of mass mortalities (wash-ups) of marine life were documented along Englands north east coastline with peaks in September and October 2021, coincident with a programme of intensified maintenance dredging of the River Tees. Decapod crustaceans were the worst affected fauna, with brown crab (Cancer pagurus), European lobster (Homarus gammarus, L.), green shore crab (Carcinus maenas, L.) and velvet swimming crab (Necora puber, L.) populations severely affected. Moribund animals presented with twitching behaviours and paralysis. A potential release of the industrial pollutant pyridine was forwarded as one explanation; however, toxicology data for pyridine in decapods is lacking. In this study, we address this knowledge gap by executing a programme of immersion exposure experiments (pyridine at 2 - 100 mg L-1) using C. pagurus, measuring toxicity effects at the individual (survival) and cellular levels (cellular, mitochondrial, and lipid peroxidation reactive oxygen species (ROS) formation in the gills, hepatopancreas and claw muscle). Highest mortality rates were seen after 72 hours of exposure, returning an LC50 value of 2.75 mg L-1. Exposed crabs presented with patterns of convulsions, limb twitching, paralysis, and death. Crabs exposed to the lowest pyridine dose (2 mg L-1) were noticeably more docile than controls. Concentration was a significant factor influencing mitochondrial ROS formation at low concentrations, with tissue type, time, and their interaction all significant at 100 mg L-1. Computer simulations were used to model the transport of any pyridine released from the dredging work, demonstrating the potential for a pyridine plume to extend from Seaham to the north of the Tees to Whitby and Robin Hoods Bay to the south. This range corresponds well with the reported wash-ups and subsequent declines in catch rates.

pharmacology and toxicology↗

bioRxiv2026

Bidirectional interactions between gut microbiota and fluorochemical biotransformation and bioactivity

Fluorinated chemicals are increasingly prevalent in pharmaceuticals and agrochemicals, yet their influence on the human gut microbiome and the potential for microbial biotransformation to alter therapeutic and toxicological profiles remain poorly understood. Here, we investigated the bidirectional relationship between 15 structurally diverse fluorinated chemicals and the gut microbiota by using an ex vivo high-throughput fermentation system. Screening revealed that flutamide, fluazinam, and pretomanid were consistently biotransformed across the donor microbiomes, while other compounds showed substantial inter-individual variability in degradation. Furthermore, exposure to fluorinated chemicals induced compound-specific shifts in microbial diversity and community composition, demonstrating their capacity to alter gut microbial ecology. Using a computational workflow combining in silico biotransformation predictions with untargeted LC-MS/MS analysis, we identified nitroreduction as the primary gut microbial transformation across all three compounds. Single-strain experiments confirmed that the nitroreduction of flutamide to flu-6, previously attributed only to hepatic metabolism, is a widespread capacity among gut bacterial strains. Finally, in vitro cytotoxicity assays and in silico modelling further revealed flu-6 to be a less hepatotoxic derivative than the parent compound, suggesting a potential detoxifying role for the gut microbiota. Together, these findings establish an integrated ex vivo, in vitro, and in silico approach for assessing the bidirectional interactions between fluorinated chemicals and the gut microbiome.

pharmacology and toxicology↗

bioRxiv2023

hb or not hb - when and why accounting for background mortality in toxicological survival models matters?

Decisions in Environmental Risk Assessment (ERA) about impacts of chemical compounds on different species are based on critical effect indicators such as the 50% lethal concentration (LC50). Regulatory documents recommend concentration-response (or concentration-effect) model fitting on standard toxicity test data to get LC50 values. However, toxicokinetic-toxicodynamic (TKTD) models proved their efficiency to better exploit toxicity test data, at Tier-2 but also at Tier-1, delivering time-independent indicators. In particular, LC50 values can be obtained from the reduced General Unified Threshold model of Survival (GUTS-RED) with both variants, Stochastic Death and Individual Tolerance, that include parameter hb, the background mortality. Estimating hb during the fitting process or not depends on studies and fitting habits, while it may strongly influence the other GUTS-RED parameters, and consequently the LC50 estimate. We hypothesized that estimating hb from all data in all replicates over time should provide more precise LC50 estimates. We then explored how estimating hb impacted: (i) GUTS-RED model parameters; (ii) goodness-of-fit criteria (fitting plot, posterior predictive check, parameter correlation); (iii) LC50 accuracy and precision. We finally show that estimating hb does not impact the LC50 precision while providing more accurate and precise GUTS parameter estimates. Hence, estimating hb would lead to a more protective ERA. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/525496v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@3ee285org.highwire.dtl.DTLVardef@89931eorg.highwire.dtl.DTLVardef@19c70forg.highwire.dtl.DTLVardef@5bb72c_HPS_FORMAT_FIGEXP M_FIG C_FIG Specifications table O_TBL View this table: org.highwire.dtl.DTLVardef@156b31eorg.highwire.dtl.DTLVardef@109991borg.highwire.dtl.DTLVardef@122f597org.highwire.dtl.DTLVardef@29a3a7org.highwire.dtl.DTLVardef@1b75315_HPS_FORMAT_FIGEXP M_TBL C_TBL

pharmacology and toxicology↗

bioRxiv2025

Decoding Cellular Stress States for Toxicology Using Single-Cell Transcriptomics

We applied the TempO-LINC(R) platform to generate single-cell transcriptomic (SCTr) profiles of [~]40,000 HepaRG cells exposed to etoposide, brefeldin A, cycloheximide, rotenone, tBHQ, troglitazone, and tunicamycin at three concentrations for 24 hours. SCTr enabled a detailed analysis of adaptive stress response pathways (SRPs), including the unfolded protein response (UPR), oxidative stress response (OSR), heat shock response (HSR), and DNA damage response (DDR). Troglitazone upregulated lipid metabolism genes (PLIN2, ACOX1) along with HSR and UPR activation, with co-expression of DNAJA1, HSP90AA1, and DDIT3 in subsets of cells. Brefeldin A and tunicamycin strongly induced UPR markers (HSPA5, SYVN1, LMF2, PDIA4) in subsets of cells, with some also expressing apoptotic (DDIT3, CASP8) and autophagic (SQSTM1) genes, indicating diverse stress responses. Rotenone activated GDF15, TRIB3, and DDIT3 in a fraction of cells, accompanied by PLIN2 and mild UPR induction, reflecting heterogeneous mitochondrial stress responses. We scored individual cells using literature-derived SRP gene signatures to characterize overall stress phenotypes and clustered them using a generalized Jaccard metric. The clustering revealed five phenotypic groups spanning cell states associated with homeostasis, adaptive responses, terminal outcomes, autophagy, and apoptosis. By systematically analyzing the distributions of cells in different states across treatments, we visualized dynamic shifts in cellular subpopulations responding to chemicals, revealing early stress responses and potential transitions to cell death. Our findings suggest the utility of SCTr in decoding stress states that could provide possible insights into transitions between cellular adaptive and terminal transitions involved in toxicity.

pharmacology and toxicology↗

bioRxiv2021

The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine hearts

Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is largely applied in agriculture and its use has increased in the last decade. Since TEB is stable in water and soil, long-term exposure of humans to this pesticide is a real threat. Acute toxicological studies to uncover the toxicity of TEB are limited, and there is evidence of an association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity. In this paper, the effects of acute exposure of cardiomyocytes and murine hearts to TEB were addressed to elucidate its impact on electromechanical properties of the cardiac tissue. In whole-cell patch-clamp records, TEB inhibited both the total outward potassium current (IC50=5.7{+/-}1.5 mol.l-1) and the L-type calcium current (IC50=33.2{+/-}7.4 mol.l-1). Acute exposure to TEB at 30 mol.l-1 prolonged the action potential duration as well as an induced out-of-pace action potential, and increased the sodium/calcium exchanger current in its forward and reverse modes. Moreover, sarcomere shortening and calcium transient in isolated cardiomyocytes was enhanced when cells were exposed to TEB at 30 mol.l-1. In ex vivo experiments, TEB 30 mol.l-1 caused significant electrocardiogram remodeling with prolonged PR, QRS, and QT interval duration. Accordingly, TEB exposure was prone to the appearance of arrhythmias. Combined, our results demonstrate that acute TEB exposure affects the cardiomyocytes electro-contractile properties and triggers the appearance of ECG abnormalities, including conduction defects and arrhythmias.

pharmacology and toxicology↗

bioRxiv2026

Integrated evaluation of immune system perturbation using structural, functional and cellular immunotoxicity endpoints in rats

Evaluation of unintended immunotoxicity represents an important component of nonclinical safety assessment, as perturbation of immune function may increase susceptibility to infection, impair vaccine responses, and disrupt immune homeostasis. Regulatory guidance, including the ICH S8 Immunotoxicity Guideline, recommends a weight-of-evidence approach in which observations from conventional toxicological endpoints are integrated with functional immune assays to support interpretation of immune system effects. The present study applied an integrated immunotoxicity evaluation framework to examine concordance among structural, functional, and cellular immune endpoints in male Sprague-Dawley rats using a well-characterized immunosuppressive reference compound. Hematological evaluation revealed leukopenia characterized primarily by lymphocyte depletion. Reductions in spleen and thymus weights were accompanied by histopathological evidence of lymphoid depletion in multiple immune tissues, including spleen, thymus, lymph nodes, Peyers patches, and bone marrow. Functional immune competence was assessed through hemagglutination antibody response to sheep red blood cells and delayed-type hypersensitivity assays, both of which demonstrated marked suppression of adaptive immune responses. Flow cytometric immunophenotyping further demonstrated substantial reductions in B-cell populations and decreases in CD4 and CD8 T-cell counts, whereas NK cell populations were comparatively less affected. The concordance of hematological alterations, lymphoid tissue changes, impaired functional immune responses, and lymphocyte subset depletion provides integrated evidence of immune system perturbation. These findings demonstrate that complementary immunotoxicity endpoints collectively support hazard characterization of immune system effects under GLP conditions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/713556v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@10154aaorg.highwire.dtl.DTLVardef@5d78e7org.highwire.dtl.DTLVardef@acaaceorg.highwire.dtl.DTLVardef@1f42c_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Kidney toxicology of a novel compound Lithium Bis(trifluoromethanesulfonyl)imide (LiTFSI, ie. HQ-115) used in energy applications: an Epigenetic evaluation

Exposure to emerging energy-based environmental contaminants such as lithium bis(trifluoromethanesulfonyl)imide (LiTFSI), more commonly known as HQ-115, poses a significant threat to human health, yet its impact on kidney function and epigenetic regulation remains poorly understood. Here, we investigated the effects of LiTFSI exposure on kidney-related biochemical parameters, renal injuries, and epigenetic alterations in male CD-1 mice under both 14-day and 30-day exposure durations. Our study revealed that LiTFSI exposure led to changes in kidney-related biochemical indicators, notably affecting serum bicarbonate levels, while relative kidney weight remained unaffected. Histological analysis unveiled tubule dilation, inflammation, and loss of kidney structure in LiTFSI-exposed mice, alongside dysregulated expression of genes associated with inflammation, renal function, and uric acid metabolism. Epigenetic analysis further identified widespread DNA methylation changes in the two exposure regimes. Functional analysis revealed that differentially methylated regions are implicated in cell apoptosis and cancer-related pathways and are enriched with development-related transcription factor binding motifs, suggesting a potential mechanism of action that can lead to kidney injury. These findings underscore the intricate interplay between environmental exposures, epigenetic modulation, and kidney health, emphasizing the need for additional research to unravel precise mechanisms that can help in the development of targeted interventions to mitigate the adverse effects of LiTFSI exposure on human health. SYNOPSISLiTFSI (HQ-115), an emerging environmental contaminant, impacts kidney health in male CD-1 mice by altering biochemical indicators, to result in renal injuries, and inducing epigenetic changes, highlighting environmental health concerns.

pharmacology and toxicology↗

bioRxiv2025

AI-Driven Science Communication: Leveraging LLMs and Knowledge Graphs for Seamless Knowledge Exchange

PurposeScientific knowledge is increasingly captured in structured formats, such as knowledge graphs, yet it remains largely inaccessible to non-technical users. We present EcoToxFred, a prototype conversational AI agent that enables intuitive, natural language access to curated environmental toxicology data. Designed to support users without programming expertise, EcoToxFred facilitates the exploration of complex datasets, such as chemical exposures and species-specific hazard information in European surface waters. MethodsEcoToxFred integrates a large language model (LLM) with a Neo4j graph database via a retrieval-augmented generation (RAG) architecture. The system employs a decision-making agent to interpret user queries, invoke appropriate tools, and translate natural language input into formal graph queries. Outputs are validated and returned in multiple formats, like text, tables, and interactive maps, and are grounded in structured, curated monitoring and hazard data. ResultsThe agent bridges the gap between human intent and formal data retrieval, enabling researchers, policy advisors, and stakeholders to pose complex, multi-step queries without prior training in query languages. By grounding LLM outputs in structured data, we demonstrate the systems ability to respond to diverse question types and deliver transparent, accurate, and context-aware results. EcoToxFred successfully answers broad and highly specific queries, bridging natural language input with formal data retrieval. ConclusionEcoToxFred represents a scalable and transferable framework for human-AI interaction in domain-specific contexts, combining natural language interfaces with structured data. By lowering access barriers to scientific knowledge, the system supports evidence-based decision-making and fosters responsible, human-centered AI use in environmental science and beyond.

pharmacology and toxicology↗