Biology and Life Sciences

Abstract: Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants with established carcinogenic properties traditionally linked to genotoxicity, oxidative stress, and DNA adduct formation. Emerging evidence, however, suggests that PAHs also function as chronotoxic agents capable of disrupting circadian homeostasis through transcriptional and epigenetic reprogramming of core clock genes. This review critically examines the molecular interplay between PAH exposure, circadian clock dysregulation, and the initiation and progression of lung and breast cancers. Central to this interaction is the activation of the aryl hydrocarbon receptor (AhR), which exhibits functional crosstalk with circadian regulators including CLOCK and BMAL1. Sustained AhR activation, coupled with oxidative stress, inflammatory signaling, and epigenetic modifications such as DNA methylation, histone remodeling, and non-coding RNA dysregulation, contributes to altered rhythmic expression of key circadian genes including PER, CRY, BMAL1, and CLOCK. These alterations impair DNA repair, cell-cycle regulation, apoptosis, and metabolic homeostasis, thereby creating a permissive environment for tumorigenesis. The review further highlights tissue-specific mechanisms underlying PAH-induced chronodisruption in lung and breast tissues and discusses the translational relevance of circadian biomarkers in cancer prognosis and therapy. Finally, emerging therapeutic strategies including chronotherapy, circadian-targeted interventions, and epigenetic modulation are explored as potential approaches for mitigating environmentally induced carcinogenesis. Collectively, this review positions environmental chronotoxicology as a critical framework for understanding the temporal dimension of cancer development associated with PAH exposure.

Abstract: DNA sequence context plays a critical role in modulating the mutational effects of DNA damage. Here, we investigated how base identity influences the replication bypass and mutagenicity of a site-specific dG-AAF (2-acetylaminofluorene) bulky adduct in the well-defined AG*N and TG*N sequence contexts. By selecting A (purine) and T (pyrimidine) as representative 5’-flanking bases and systematically varying the 3’-base, we established a controlled system to examine sequence-dependent lesion replication. We found that the 5’-flanking base strongly affects the bypass profile, with AG*N sequences exhibiting uniformly low bypass (≤ 9.7%) and TG*N sequences showing markedly elevated bypass (23.6 – 50.4%) with strong sequence dependence. These differences may arise from the structure of the dG-AAF, whose conformation heterogeneities are sensitive to the flanking sequence context. In contrast, mutagenicity remains consistently low across all sequences examined, with a low frequency of point mutations and no detectable frameshift events. These results reveal a clear decoupling between lesion bypass efficiency and replication fidelity, where sequence context strongly controls lesion tolerance but has limited impact on mutagenicity. In total, our findings demonstrate that DNA sequence affects lesion processing, providing insights into how local sequence context shapes genome stability and mutational processes.

Abstract: Cadmium (Cd) is a global toxic pollutant and a major foodborne hazard. Its widespread use in industrial processes, including its presence in fertilizers, combined with natural environmental occurrence, has led to persistent contamination of food and water supplies. Ingested Cd has been associated with visual impairments, but early predictors such as disruptions to nervous system function are elusive largely due to the reliance of in vitro and in vitro assays. Here, we examined the effects of human relevant dietary Cd concentrations (0, 30, and 600 µg/g Cd) on in vivo neuronal calcium (Ca²⁺) activity and visually-guided behavior, as assessed by the optomotor response, across multiple exposure windows. We found that human relevant dietary Cd exposure induced immediate deficits in whole brain neuronal activity that preceded impairments in the optomotor response. While Cd disrupted in vivo neuronal Ca²⁺ activity in zebrafish after a single day of exposure, these effects were transient, with differences across treatments diminishing after two weeks. In contrast, optomotor deficits emerged after two weeks of exposure and were concentration dependent. Notably, while alterations in neuronal Ca²⁺ activity occurred at Cd exposure levels comparable to those in human populations, early-life optomotor deficits were observed only at dietary Cd concentrations at the upper limit of human exposures. Overall, these findings demonstrate that ingested Cd poses significant risks to sensitive systems, including the nervous system, with downstream consequences for visually-guided behavior. This study provides insight into early neurophysiological predictors of dietary Cd–induced neurotoxicity and visual dysfunction.

Abstract: Perfluorohexanesulfonic acid (PFHxS) is a per- and polyfluoroalkyl substance (PFAS) frequently detected in aquatic environments, while chlorpyrifos (CPF) is a widely used organophosphate insecticide. Although their individual toxicity is well described, their combined effects remain poorly understood. Here, we evaluated the effects of CPF (0.7 to 700 µg/L), alone or in combination with PFHxS (10 µg/L), in zebrafish embryos. Survival, hatching, malformations, locomotor activity, oxidative stress, apoptosis, and gene expression were assessed after five days of exposure. CPF reduced survival in a concentration-dependent manner, with moderate enhancement under co-exposure, while hatching success was unaffected. Deformities increased with CPF concentration, which remained consistent with PFHxS co-exposure, suggesting toxicity was mediated by CPF. Locomotor activity was largely decreased in a concentration- and phase-dependent manner. No significant changes were observed in ROS levels nor apoptosis. Gene expression analysis revealed upregulation of neurotoxicity-related markers (ache, gfap, shha, syn2a), particularly at intermediate CPF concentrations and under co-exposure. Oxidative stress–related genes showed differential responses, with sod1 upregulated and cat downregulated only in the combined treatment. These findings highlight the importance of evaluating mixture toxicity to better understand the ecological risks of co-occurring contaminants.

Abstract: 2,2′,4,4′-Tetrabromodiphenyl ether (BDE-47) is a persistent organic pollutant detected in coastal environments. The effects of BDE-47 on mangrove plants at the molecular and histological levels remain elusive. In this study, seedlings of the man-grove species Avicennia marina were exposed to BDE-47 at concentrations of 0, 1 and 10 ng L-1 for 20 days under hydroponic conditions. Leaf growth parameters, anatomical structures, and transcriptomic profiles were examined. At 1 ng L-1 BDE-47, no signif-icant changes were observed in leaf growth or vascular tissue morphology. However, transcriptome analysis showed significant enrichment of differentially expressed genes in the linoleic acid metabolism pathway, indicating that A. marina initiates early stress perception via enhanced stress perception and signal transduction, trigger adaptive defense responses to low-level BDE-47 exposure, and circumvent growth inhibition. At 10 ng L-1 BDE-47, leaf area, width, length, and fresh weight were all reduced. In addi-tion, histological examination revealed vascular bundle sheath atrophy, impaired xy-lem and phloem development, reduced parenchyma cell diameter, and a decreased proportion of intercellular space. Transcriptomic analysis at 10 ng L^-1 exposure identi-fied significant enrichment of differentially expressed genes in the circadian rhythm and spliceosome pathways, indicating that the pollutant's toxicity has progressed from local metabolic disruption to perturbation of the plant's core regulatory network. Overall, our findings reveal distinct response patterns of A. marina leaves to BDE-47 exposure at environmentally relevant concentrations, initially elucidate the adaptive defense mechanism and underlying molecular basis of toxic effects in mangrove plants under low-concentration BDE-47 exposure, and provide critical scientific support for the ecological risk assessment and conservation of coastal mangrove wetlands.

Abstract: Chronic lung disease of prematurity (CLD) is a common complication of preterm birth with a com-plex pathology. Recent epidemiologic studies have identified a link between neonatal exposure to di(2-ethylhexyl) phthalate (DEHP), frequently used in medical equipment, and the development of CLD. We hypothesize that DEHP exposure in the early neonatal period contributes to lung injury in newborn rats. Newborn rat pups were raised in one of the following environments: room air (RA), RA + DEHP, hyperoxia (60% oxygen), and hyperoxia + DEHP. Ambient DEHP was inhaled in a dose of 25mg/m3 for 6 hours daily for 14 days. Lung tissue and blood samples were collected on day 14 of life. Independent exposure to DEHP and hyperoxia resulted in thicker pulmonary septal walls, fewer alveoli, increased pulmonary polymorphonuclear leukocytes and myeloperoxidase (MPO) activity and decreased expression of CD31 on endothelial cells in lung tissue. Additionally, DEHP-exposed rats showed higher serum malondialdehyde (MDA) levels and reduced vascular endothelial growth factor (VEGF) mRNA and protein levels compared to controls. Our experiments demonstrate that inhaled DEHP, with or without hyperoxia, resulted in a similar pattern of morphological lung injury and inflammation characteristic of CLD, and a causative link to CLD of prematurity.

Abstract: Mangrove wetlands are important coastal ecosystems and are increasingly vulnerable to heavy metal contamination. The accumulation of heavy metals in man-grove ecosystems is well studied; however, studies on the seasonal variations of heavy metals in mangrove wetlands are scarce. This study investigated heavy metal (Cd, Cr, Cu, As, Pb, and Zn) accumulation in surface sediments of six typical mangrove wet-lands (DZG, QLH, XCP, SYR, SBW, and XY) in Hainan Island, China, during wet and dry seasons. In addition, potential ecological concerns and relationships between sedimentary physicochemical parameters and metal accumulation were assessed. The findings demonstrated significant spatial differences in heavy metal accumulation, with higher concentrations in the northern localities and lower concentrations in the southern areas. There were notable seasonal fluctuations in heavy metal concentrations, with higher levels in the dry season. Risk assessment models exhibited that Cadmium (Cd) and Arsenic (As) were the principal contaminants of concern in most research sites with moderate levels of contamination and posed at least moderate ecological concerns in both wet and dry seasons. The overall ecological risk index indicated a moderate risk to the environment, especially in the dry season. The principal component analysis (PCA) and correlation analysis results indicated that the physicochemical properties of sediments, mainly total organic carbon (TOC), total phosphorus (TP), total nitrogen (TN), and salinity, had significant effects on the heavy metals accumulation in the mangrove sediments. The present study helps raise awareness of seasonal fluctuations in heavy metal pollutants and provides strategies for the prevention and monitoring of metal pollution in mangrove wetlands.

Abstract: Microplastics (MPs) are widespread pollutants in aquatic environments, but their impacts throughout the life cycle remains of organisms are still not well understood. This systematic review integrates recent experimental results on the developmental, physiological, and neurobehavioral effects of MPs exposure on zebrafish (Danio rerio), a popular model organism for ecotoxicology research. A PRISMA-guided search using Web of Science (WoS) and Scopus as databases generated 371 articles, which was screened to 60 eligible articles. The collated results showed that MP toxicity strongly related to concentration, size, and extent of weathering or aging at various life stages of zebrafish. For developmental toxicity, a concentration-dependent yielded peer-reviewed publications assessing specific MPs properties, such as polymer identity, size, concentration, shape, and aging status. At various life stages, the toxicity of MPs was most affected by concentration, size, and aging. The developmental toxicity showed a concentration-dependent decrease in the rate of hatching, growth inhibition, and cardiac dysfunction, while, an increase in malformations, especially at concentrations of ≥100 µg/L or ≥10 mg/L has been reported. Non-monotonic and threshold effects have also been observed, the complexity of particle-based versus mass-based concentrations. Weathered and photo-aged MPs were found to exhibit higher embryotoxicity and neurodevelopmental toxicity, including changes in gene expression of neurons, decreased integrity of motor neurons, and impaired retinal development, compared with virgin MPs. Furthermore, physiological endpoints showed that oxidative imbalance was a key mechanistic process, which included changes in the activity of antioxidant enzymes (SOD, CAT, GPx), lipid peroxidation, inflammation, and disruption of tight junctions. Chronic MP exposures caused changes in the gut microbiota, hepatic metabolism, endocrine disruption, reproductive damage, thyroid function disruption, and genotoxicity in zebrafish. Neurobehavioral alterations, such as changes in locomotor activity, anxiety response, neurotransmitter homeostasis, and acetylcholinesterase function, occurred in both larvae and adults, with a potentiation effect in aged MP exposure. Previous, experimental data have also shown that zebrafish are very sensitive to MPs exposure in various biological systems, with toxicity being a function of physicochemical properties and exposure conditions. Finally, this review found major limitations for inter-study comparisons because of inconsistencies and differences in methodology related to MP concentration, simulation of MP aging, and MP dose measurements.

Abstract: The microbiota-gut-brain axis (MGBA) represents a bidirectional neuroendocrine system essential for maintaining metabolic and neurological homeostasis. While dietary macronutrients are known modulators of this axis, the cumulative impact of modern industrial xenobiotics remains insufficiently characterized. This review synthesizes contemporary, multidisciplinary evidence to elucidate how four ubiquitous environmental stressors Particulate Matter (PM2.5), Microplastics (MPs), Inorganic Nanoparticles (NPs), and Non-Nutritive Sweeteners (NNS) synergistically perturb this delicate enteric ecosystem. We integrate independent lines of research to propose a unifying pathological framework: these agents induce profound dysbiosis, significantly depleting beneficial, short chain fatty acid (SCFA) producing taxa (e.g., Lachnospiraceae, Faecalibacterium) and sharply diminishing the bioavailability of critical neuroactive mediators, including butyrate, GABA, serotonin, and indole derivatives. Concurrently, NNS-driven bacteriostatic shifts, the MP “plastisphere” phenomenon, and NP-induced oxidative mucosal abrasion critically compromise the intestinal barrier. This “leaky gut” facilitates the unrestricted systemic translocation of lipopolysaccharides (LPS) and trimethylamine-N-oxide (TMAO), driving a peripheral Treg/Th17 immune imbalance that propagates via the gut-liver and gut-heart axes directly to the central nervous system (CNS). Crucially, the synthesis of this data points toward a potential “Dual-Hit” mechanism, suggesting that these xenobiotics aggravate neurological pathology through simultaneous mechanisms: acting as direct neurotoxicants via CNS translocation (e.g., NPs crossing the blood-brain barrier to trigger epigenetic reprogramming and amyloid aggregation) while concurrently driving “bottom-up” systemic neuroinflammation. By linking these disruptions to classic neurodegeneration (Alzheimer’s, Parkinson’s) as well as underexplored pathologies (migraine, epilepsy, restless leg syndrome, and substance use disorders), this review underscores the urgent need for a paradigm shift in environmental neurotoxicology and the development of targeted microbiome-based interventions.

Abstract: Lipid nanoparticles (LNPs) are central to modern mRNA therapeutics, including COVID‑19 vaccines. Far from passive carriers, their ionizable lipids actively interact with cellular membranes. Evidence from cellular, transcriptomic, and proteomic studies indicates that LNPs, with or without nucleic acid, alter gene and protein expression, thereby initiating inflammatory, detoxification, and stress responses at the membrane. Key pathways affected include lipid metabolism and detoxification, with roles for Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and cytochrome P450 enzymes. We hypothesize that the phosphatidylinositol (PI) cycle is the primary site of LNP-induced perturbations, regulating membrane restructuring and organelle trafficking during endocytosis. Disruption of this cycle triggers downstream signaling cascades, including Nuclear Factor kappa B (NF-κB), Mitogen-Activated Protein Kinases (MAPKs), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Mechanistic Target of Rapamycin (mTOR). We term this systemic effect lipid-nanoparticle-driven membrane dysfunction (L‑DMD), characterized by dysregulated cellular communication, stress responses, and energy balance. This review provides a mechanistic framework for understanding the persistent biological effects of modified modRNA-LNP exposure and emphasizes a systems-level intracellular perspective.

Abstract: The recreational use of fentanyl (FT) combined with xylazine (XZ), known as “tranq-dope,” poses a growing public health threat due to its high toxicity and mortality. This study evaluated the effectiveness of naloxone (NX), its lipophilic prodrug NX90, and their combinations with the κ-agonist/µ-antagonist nalbuphine (NB) in reversing overdose and restoring respiratory function in a rat model. At the low FT dose (0.052 mg/kg), adding XZ (1 mg/kg) shortened time to overdose by ~2,600 seconds compared with FT alone, whereas onset times were similar at medium and high FT doses. Respiratory rate at overdose was also higher with XZ, showing a 2.2-fold increase at high FT doses. Most interventions did not significantly shorten time to reversal. Only NX+NB in females and NX90+NB in both sexes reduced reversal time compared with NX alone. However, respiratory rate at reversal was significantly improved with NX+NB, ½NX90+NB, and NX90+NB (90–92 breaths/min) compared with naloxone alone (80 ± 6 breaths/min). Interventions containing nalbuphine (κagonist/µantagonist) yielded higher RR and HR at reversal than NX alone, suggesting a contribution of κagonism to physiological recovery. In this FT+XZ dose range, coadministration of xylazine (1 mg/kg) was associated with higher respiratory rates at the time of overdose onset across ascending fentanyl doses, blunting the dosedependent RR decline observed with fentanyl alone at that specific endpoint. Comparable or improved reversal outcomes could be achieved using half-doses of NX or NX90 with NB—potentially reducing total dose of naloxone and mitigating the risk of precipitated withdrawal in individuals with opioid use disorder.

Abstract: Background/Objectives: Excessive dietary inorganic phosphate (Pi) as a food additive poses potential health risks. Methods: This study investigates its impact on intestinal and immune homeostasis in mice using gradient Pi exposure combined with an inflammatory model. Results: Pi overload induced atrophy in the thymus, spleen, and kidney, damaged the intestinal barrier, reduced villus height‑to‑crypt depth ratio, and decreased goblet cell numbers. Altered levels of serum sIgA and IgE, as well as intestinal IgA, IgG, IgE, and IgM, together with decreased IFNα, indicated disrupted immune balance caused by Pi treatment. Proteomic analysis revealed differential expression of key proteins, including CNTFR and Bcl2l1 in the JAK‑STAT pathway, and metabolic regulators CPT1α and IDH1, compared Pi treated mice with the control group. Conclusions: These findings suggest Pi may affect immune and neuronal functions through tumor‑related signaling and mitochondrial pathways, providing insight into the health implications of Pi overconsumption.

Abstract:

Benthic foraminifera, worldwide single-cell marine organisms, represent an important component of seabed ecosystems. Due to their sensitivity to environmental changes, they are often used as bioindicators, providing an efficient tool in toxicity studies. Among the pollutants affecting marine coastal and estuarine environments, persistent flame retardants such as polybrominated diphenyl ethers (PBDEs) are frequently found. Low-level exposure to BDE-47, a PBDE congener, is known to affect organisms development. In this framework, this study aims to assess the effects of BDE-47 exposure on benthic foraminifera from coastal marine environments. Foraminifera specimens belonging to the symbiont-bearing Peneroplidae family were sampled and exposed to two different BDE-47 concentrations from T0 up to 48 h (T48). Vitality indicators such as changes in pseudopodial activity, movement, reproduction, loss of symbiont algae, and eventual death were monitored during the experiment. Exposure to BDE-47 induced alterations in pseudopodial activity, movement, reproduction, and symbiont retention, with progressive loss of vitality and eventual mortality at increasing exposure levels, highlighting the sensitivity of this species to BDE-47 exposure. These findings suggest the harmful repercussions of PBDE pollution on marine coastal ecosystems, affecting benthic organisms and potentially contributing to biomagnification processes within the food web, with possible implications for human health.

Abstract: Parkinson’s disease (PD) is a neurodegenerative disorder with limited disease-modifying therapies. Computational models can provide predictive insights into drug properties, although critically limited datasets pose challenges. Fifteen FDA-approved Parkinson’s disease drugs were represented as hydrogen-suppressed molecular graphs. Twelve degree-based topological indices were computed and used as descriptors for predicting seven physicochemical properties (MR, P, MV, MW, nHA, nRotB, Complexity). Multi-layer perceptron artificial neural network (ANN) and Random Forest (RF) models were trained. Model performance was evaluated using Leave-One-Out Cross-Validation (LOOCV). The statistical robustness of the models was verified using a Y-randomization test. Shapley Additive Explanations (SHAP) were applied for interpretability. The ANN demonstrated high predictive correlation on the small dataset for MR (R² = 0.876), P (R² = 0.875), MW (R² = 0.837), and nHA (R² = 0.901). Lower predictive performance was observed for MV (R² = 0.729), molecular Complexity (R² = 0.706), and nRotB (R² = 0.308). RF provided comparable results but was generally outperformed by ANN. The Y-randomization test yielded consistently negative average R²rand values (lowest R²rand = -1.708), confirming the absence of chance correlation. SHAP analysis identified the most influential topological indices for each property in ANN. ANN-based QSPR modeling with degree-based descriptors can accurately predict physicochemical properties of PD drugs for certain endpoints. These models were proven statistically robust through Y-randomization validation. Limitations include the small dataset size and high-dimensional descriptor space, highlighting the need for external validation, larger datasets, and inclusion of additional 3D/quantum descriptors for more complex pharmacokinetic endpoints.

Abstract: Biochar, a carbon-rich material traditionally used to improve soil health and as a feed additive, has recently attracted attention for its potential biological activity. This study investigated the effects of an aqueous biochar extract (BC-AE) on human intestinal epithelial cells (Caco-2), specifically examining its impact on cell viability and apoptosis. The metabolic activity of Caco-2 cells exposed to BC-AE was first evaluated using an MTS assay. A concentration of 3 mg/mL, which promoted Caco-2 metabolic activity, was selected for further testing at 24 and 72 hours. The effect of BC-AE on cell viability was assessed by epifluorescence microscopy (morphology) and flow cytometry (apoptosis profiling). The transcriptional response of cell viability-related genes (BAX, BAD, BCL-2, BCL-xL, MCL-1, P21, and P53) and microRNAs (miR-15b, miR-19, miR-21, miR-33a, miR-155, and miR-486) was analyzed by RT-qPCR. In parallel, selected proteins (BAD, BAX, BCL-2, and MCL-1) were examined by Western blotting. BC-AE decreased cell viability after 24 hours via late apoptosis, while 72-hour exposure increased necrosis without further viability loss. Both BAX and MCL-1 protein levels increased in Caco-2 cells after 72 hours of BC-AE treatment, and miR-15b and miR-21 were upregulated, suggesting the involvement of a regulatory mechanism controlling cell survival. The obtained findings highlight the importance of considering both concentration and exposure duration when assessing biochar bioactivity.

Abstract: Environmental contaminants pose threats to various organisms and negatively impact the nervous, cardiovascular, immune, and reproductive systems. Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that are ubiquitous in the environment. Given that mixtures of environmental contaminants have the potential to exacerbate toxicity, we reviewed current literature on pesticides, microplastics, or metal exposure in combination with PFAS on vertebrates and invertebrates. The objectives were to evaluate the toxicological effects of mixtures of different pollutants (microplastics, pesticides and metal ions) with PFAS on aquatic organisms to better understand biological responses in animals. Based on our review, an increase in toxicity is observed in mixtures of pollutants, including enhanced oxidative stress, developmental abnormalities, impaired reproduction, metabolic disruption, altered gene expression, and changes in enzymatic activity; however, some antagonistic interactions were also reported, underscoring the complexity of mixture effects in real environments. A computational assessment demonstrates that PFOS can engage in intermolecular interactions with pesticides, microplastic monomers, and metals, suggesting chemical-level mechanisms that could modify toxicity or bioavailability. Future studies should focus on elucidating the mechanisms underlying these complex interactions, investigating effects at different trophic levels and in a broader range of species, including mammalian models, and considering chronic exposures and environmentally relevant mixtures.

Abstract: The rapid emergence of New Psychoactive Substances (NPS), particularly pyrrolidinophenone derivatives, poses a significant challenge for public health and forensic toxicology. While their neuropharmacological profiles as dopamine transporter inhibitors are well-documented, their cardiac toxicity remains poorly understood. This study employs a high-resolution New Approach Methodology (NAM) using zebrafish embryos to integrate neurobehavioral and cardiotoxic endpoints for comparative hazard prioritization. We evaluated nine pyrrolidine-containing cathinones, including α-PVP, MDPV, α-PiHP, MDPiHP, α-D2PV, 3-Cl-, 4-Cl-, and 3,4-Cl-α-PVP, as well as 4-F-3-Me-α-PVP, on locomotor activity and cardiac rhythmicity in zebrafish embryos using high-speed video microscopy and dynamic pixel analysis.. Across the series, compounds induced concentration-dependent negative chronotropy and, in most cases, locomotor suppression. Crucially, we identified a functional dissociation between atrial rate control and atrioventricular (AV) conduction. The 3,4-dichloro substitution (3,4-Cl-α-PVP) was the most potent inducer of negative chronotropy (EC₅₀ = 52.6 μM), whereas 4-Cl-α-PVP exhibited a distinct pro-arrhythmic liability, increasing the incidence of 2:1 AV block. Time-course locomotor profiling indicated that α-PVP and chlorinated analogs were among the most potent behavioral modifiers. Using a Functional Safety Index (AV block EC₅₀ / locomotor EC₅₀-like), we show that most compounds exhibit wide separations between neurobehavioral inhibition and severe conduction impairment, while specific substitutions—particularly para-chlorination—are associated with comparatively reduced safety margins. Overall, these data demonstrate that subtle structural changes within the pyrrolidinophenone scaffold can shape distinct arrhythmic phenotypes and functional safety profiles, supporting zebrafish-based integrated screening as a rapid platform for prioritizing emerging synthetic cathinones with disproportionate cardiac risk.

Abstract: The evolution of resistance in mosquitoes to conventional pesticides such as pyrethroids presents a challenge to vector control. Thus, alternative active ingredients for pesticides to manage pyrethroid resistant populations of mosquitoes are needed. The goal of this study was to evaluate the toxic and repellent efficacies of geraniol, a plant secondary metabolite, as a potential alternative for controlling pyrethroid-resistant Aedes aegypti. We found that addition of geraniol to rearing water of 1st instar larvae caused concentration-dependent mortality within 24 h in both strains. The resistance ratio of geraniol (2.8) was modest compared to that of cypermethrin (435.3). Topical application of geraniol to adult female mosquitoes caused dose-dependent mortality in both strains within 24 h. The resistance ratio of geraniol (1.1) was minimal compared to that for cypermethrin (457). In spatial repellency assays, geraniol repelled adult females from both strains in a dose-dependent manner. The repellency resistance ratio of geraniol (2.6) was modest compared to that for pyrethrum extract (>132). Our findings suggest that geraniol has potential use as a versatile chemical tool for controlling pyrethroid-resistant populations of Ae. aegypti.

Abstract: Intravenous lipid therapy (ILE) is used to treat neurotoxicosis in companion animals, but clinical evidence for in vivo xenobiotic partitioning and benefit remains limited. This study evaluated associations between the log n-octanol/water partition coefficient (log P), in vivo plasma partitioning, and early neurological outcome. In a case series from eight veterinary hospitals, dogs and cats with suspected neurotoxicosis received ILE; blood collected before and at the end of infusion was separated into lipid and aqueous fractions and analyzed by gas chromatography-mass spectrometry. Log P values were retrieved from PubChem. Outcome (improved vs not improved) was the change from baseline to 4- 6 h after ILE start. Thirty-four cases were analyzed (27 dogs, 7 cats; 17 xenobiotics). At end of infusion, lipid-phase concentrations exceeded aqueous concentrations in 28/34 cases, and log P did not correlate with the lipid-to-aqueous ratio. Improvement occurred in 14/34 animals and was associated with higher lipid-to-aqueous xenobiotic ratios (geometric mean ratio 5.7; 95% CI 1.73–19.05; P = 0.007). Overall, in vivo lipid sequestration was frequent and related to early improvement, whereas log P alone did not predict partitioning or outcome.

Abstract: Background Lipophilic environmental contaminants—including persistent organic pollutants (POPs), PFAS, PCBs, and PAHs - exert a long-term biological influence that cannot be explained by acute toxicity alone. Their extreme hydrophobicity drives high-affinity sequestration within lipid-rich tissues, such as adipose depots, myelin sheaths, and endocrine glands, creating "internal reservoirs" with biological half-lives measured in decades. These reservoirs fuel continuous, low-grade endogenous exposure and sequential absorption of hydrophilic species, persisting regardless of ongoing environmental contact. Scope of Review This article integrates toxicokinetic modeling with modern multi-omics evidence to update Zeliger’s model of lipophilicity-driven chronic disease. We examine how these diverse compounds activate a conserved set of biological injury pathways, regardless of their specific chemical structure. Specifically, we analyze the convergence of nuclear receptor disruption, mitochondrial dysfunction (amplified ROS production), calcium dysregulation, neuroimmune activation, and persistent epigenetic remodeling. Major Conclusions Lipophilic pollutants function as a unified category of systemic toxicants that reorganize cellular and metabolic systems. The identified mechanistic signatures provide a systems-level explanation for the epidemiological links between pollutant burdens and metabolic syndrome, cardiovascular morbidity, neurodegeneration, and cross-generational epigenetic effects. These findings validate the use of "total oxidative stress" as a predictor for non-communicable disease onset and support a paradigm shift toward mixture-based regulation and exposomic biomarkers for early detection.