Publications

Environmental immunotoxicity is commonly framed through oxidative stress, cytotoxicity, inflammation, receptor-mediated signaling and cell- or tissue-specific mechanisms. This review proposes that proteotoxic stress resolution represents an additional layer linking environmental exposure to immune dysfunction. Specifically, the unfolded protein response (UPR) is considered as a branch-selective proteotoxic stress-resolution circuit that can shape immune outcomes when endoplasmic reticulum (ER) homeostasis is perturbed. The framework is offered as a hypothesis-generating conceptual structure rather than an established mechanistic paradigm, and the causal step linking failed resolution to immune dysfunction remains largely extrapolated from non-toxicological ER-stress models. Evidence from ER proteostasis biology, immune-cell function and toxicology indicates that environmental toxicants can disrupt protein folding, ER calcium balance, redox homeostasis, lipid composition, degradation pathways and secretory load, thereby engaging distinct combinations of IRE1α, PERK and ATF6 signaling. These branches generate immune-relevant outputs: IRE1α links ER stress to RNA processing and inflammatory signaling, PERK controls translational suppression and fate selection, and ATF6 supports restoration of folding capacity and secretory competence. Across macrophages, dendritic cells, T cells, plasma cells and barrier epithelial cells, immune outcomes depend on branch bias, signaling duration, cell-type context and resolution through ER-associated degradation, autophagy, ER-phagy, translational recovery and restoration of calcium and redox balance. This framework predicts that repeated low-dose exposures, mixed toxicant inputs and incomplete post-exposure recovery can shift immune or barrier cells into inflammatory, suppressive or barrier-disruptive states without overt cytotoxicity. It also supports time-resolved, branch-specific and cell-specific profiling for immunotoxic risk assessment.

Mechanical forces regulate cell fate, tissue homeostasis, regeneration, fibrosis and cancer through interconnected mechanotransduction networks in which Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) serve as major transcriptional effectors. This review develops a mechanochemical signal-resolution circuit framework that integrates evidence from mechanobiology, Hippo signaling, nuclear transport, chromatin regulation, extracellular matrix remodeling and mechanical memory. The framework defines YAP/TAZ regulation as a distributed process in which mechanical inputs are sensed, integrated, temporally decoded, actively terminated and followed by restoration of cellular mechanosensitivity and tissue mechanical homeostasis. Current evidence indicates that YAP/TAZ output depends not only on nuclear abundance but also on signaling duration, nucleocytoplasmic dynamics, transcriptional context, feedback control and the persistence of chromatin, cytoskeletal, metabolic and extracellular changes. Failure at different circuit components may produce abnormal sensing, controller failure, effector escape, resolution failure or memory lock, thereby converting adaptive responses into fibrosis, cancer and other chronic tissue states. This model also explains why transient YAP/TAZ activation can support regeneration, whereas sustained or poorly resolved activation promotes pathological remodeling. Testing the framework will require reversible mechanical perturbations, endogenous live-cell reporters, temporally controlled YAP/TAZ manipulation and integrated single-cell analysis of signaling, transcription, chromatin and mechanics. Therapeutically, restoring signal termination and the mechanical baseline may preserve beneficial YAP/TAZ functions while limiting pathological persistence more selectively than continuous pathway suppression.

Transcriptional regulation is often described as a spatial process in which transcription factors, cofactors, and RNA polymerase II assemble at enhancers and promoters. However, this framework does not fully explain how transcriptional systems interpret fluctuating signaling inputs. This review integrates evidence from condensate biology, signaling dynamics, chromatin regulation, and transcriptional bursting to examine transcriptional condensates as candidate kinetic intermediaries in temporal signal decoding. Established findings show that transcription-associated condensates can enrich regulatory factors, exchange components dynamically, undergo signal-dependent remodeling, and associate with transcriptional activity. We propose a kinetic-filter model in which concentration thresholds, nucleation delays, finite assembly and exchange kinetics, persistence, and regulated dissolution support duration-dependent integration, attenuation of rapid fluctuations, and short-term molecular memory. These properties are predicted to influence transcriptional burst frequency, duration, and output, while cellular metabolic and physicochemical conditions define the operating regime of condensate responsiveness. The model can be tested using live-cell imaging, fluorescence recovery after photobleaching, optogenetic pulsing, nascent RNA reporters, perturbation of multivalent interactions, orthogonal controls, and quantitative kinetic modeling. The complete causal sequence linking defined temporal inputs, condensate kinetics, and endogenous nascent transcription remains unproven. Establishing when this sequence operates will determine whether condensate-mediated temporal filtering is a general regulatory principle or a context-dependent mechanism.

E-cigarette devices emit ultrafine metal-containing particles from heating coils, solder joints, and other wetted components, but their reproductive toxicology remains poorly defined. This review integrates evidence from aerosol chemistry, nanoparticle toxicology, and male reproductive biology to evaluate whether these particles may contribute to male reproductive dysfunction through mitochondrial injury. E-cigarette aerosols can contain nanoscale and ultrafine particles bearing chromium, nickel, iron, copper, zinc, tin, and lead. These particles may deposit in the distal lung and, based on broader nanoparticle toxicokinetics, could enter the systemic circulation. However, direct particle-resolved evidence of their accumulation in testicular tissue is currently absent. Mechanistic evidence therefore derives mainly from engineered nanoparticle and soluble-metal models. These studies indicate that metal exposure can disrupt blood-testis barrier integrity, impair Sertoli- and Leydig-cell function, alter steroidogenesis, damage germ cells, and reduce sperm quality. Mitochondria represent a plausible point of convergence because particle- and ion-mediated mechanisms can promote mitochondrial reactive oxygen species generation, lipid peroxidation, respiratory dysfunction, mitochondrial DNA damage, altered fusion-fission balance, defective mitophagy, apoptosis, and inflammatory signaling. These pathways provide a biologically plausible framework linking inhaled metal-containing particles to impaired spermatogenesis and steroidogenesis, without establishing causality under realistic vaping conditions. Future studies should combine inhalation-relevant exposure models with particle-resolved biodistribution, dosimetry, and mechanistic reproductive endpoints to determine whether these pathways operate following e-cigarette exposure.

E-cigarette use has increased substantially, particularly among adolescents and young adults, yet its long-term respiratory effects remain incompletely understood. E-cigarette aerosol contains biologically active constituents, including nicotine, propylene glycol, vegetable glycerin, flavoring chemicals, aldehydes, metals, particles, and reactive oxygen species, which may disrupt respiratory epithelial homeostasis. This review synthesizes experimental, preclinical, and human-relevant evidence linking e-cigarette aerosol exposure to respiratory epithelial injury, with emphasis on ferroptosis-related mechanisms. Available evidence indicates that e-cigarette aerosol can impair epithelial barrier integrity, alter mucociliary defense, increase MUC5AC expression, induce oxidative stress, and promote inflammatory signaling. Emerging preclinical data suggest that electronic nicotine delivery system exposure may induce ferroptosis-associated lung injury through increased CD71/TFR1 and ACSL4 expression, reduced GPX4, altered lipid profiles, BODIPY-C11-positive lipid peroxidation, epithelial cell death, inflammation, mucus accumulation, emphysema-like pathology, and fibrosis. Mechanistically, e-cigarette aerosol may create a ferroptosis-permissive epithelial environment by promoting redox imbalance, GPX4/GSH/SLC7A11 antioxidant defense impairment, altered iron handling, ACSL4-mediated PUFA-phospholipid remodeling, NRF2/ARE stress responses, mitochondrial dysfunction, and lipid peroxide accumulation. Ferroptotic epithelial injury may further amplify airway inflammation and remodeling through DAMP release, macrophage recruitment, cytokine production, barrier disruption, mucus dysregulation, and extracellular matrix deposition. However, direct human evidence remains limited, and many mechanistic links are extrapolated from cigarette smoke, particulate matter, and broader lung injury models. Future studies should use standardized exposure systems, human-relevant airway and alveolar models, comprehensive ferroptosis markers, and ferroptosis-specific rescue experiments to determine whether ferroptosis is a driver, amplifier, or downstream marker of e-cigarette-associated respiratory injury.

Electronic cigarettes are widely used by individuals in their reproductive years, yet polymer materials in pods, wicks, seals, and casings remain underexamined as possible contributors to inhaled particulate exposure. This narrative review evaluates whether e-cigarette device components could plausibly generate microplastics or nanoplastics during use and whether such particles, if present, could have reproductive relevance. Evidence from device-material studies, polymer degradation chemistry, aerosol physics, inhalation toxicology, and reproductive microplastic models was synthesized. Current devices place polycarbonate, polydimethylsiloxane, nylon, and other polymers near heating and aerosolization zones, where thermal cycling, solvent contact, and mechanical stress could theoretically promote oxidation, chain scission, embrittlement, or fragmentation. However, no study has chemically identified or quantified device-derived microplastics or nanoplastics in e-cigarette aerosols using polymer-resolving methods. Thus, links between e-cigarette use, inhaled polymer particles, and reproductive harm remain hypothetical. Evidence from non-e-cigarette models shows that micro- and nanoplastics can induce oxidative stress, inflammation, endocrine disruption, barrier interaction, and cellular injury, but these findings cannot be extrapolated without confirming particle formation, polymer identity, dose, and biodistribution. Future research should prioritize polymer-resolved aerosol testing under realistic puffing regimens, including unused and aged devices, e-liquids, condensates, and emitted aerosols. Key endpoints should include polymer identity, particles per puff, particles per mL of e-liquid consumed, particle size distribution, polymer mass, pulmonary deposition, systemic translocation, and reproductive or placental effects. Device-derived microplastics should be treated as a plausible particle-safety concern requiring direct experimental evaluation.

Background. Obesity and erectile dysfunction (ED) are increasingly co-prevalent, yet adipose tissue is often viewed as a secondary contributor rather than a primary driver of erectile impairment.

Objective. To evaluate an adipose-centric framework in which depot-specific adipose dysfunction regulates vascular, neuroendocrine, and smooth muscle processes essential for erection.

Methods. A narrative synthesis of mechanistic, preclinical, and clinical studies was conducted, focusing on inflammation, cellular senescence, extracellular vesicle signaling, ferroptosis, mitochondrial dysfunction, and glycocalyx injury across visceral, perivascular, and periprostatic adipose depots.

Results. Dysfunctional adipose tissue remodels systemic and local microenvironments through adipokines, cytokines, extracellular vesicle cargo, and oxidized lipid mediators. These processes reduce nitric oxide bioavailability, increase vascular stiffness, disrupt neuroendocrine signaling, and promote cavernosal fibrosis. Perivascular adipose tissue exerts localized effects on penile hemodynamics. Clinical and genetic evidence supports a causal link between central adiposity and ED, while weight loss and adipose-targeted interventions improve erectile outcomes.

Conclusion. Adipose tissue functions as an upstream regulator of ED pathogenesis. Targeting adipose dysfunction through lifestyle, pharmacological, and emerging strategies such as senolytics and extracellular vesicle modulation may modify disease progression rather than provide symptomatic relief.

The rising prevalence of e-cigarette use has raised concerns regarding potential adverse effects on male reproductive and endocrine health, yet its impact on testosterone regulation remains poorly defined. This narrative review critically synthesizes evidence from preclinical in vivo and in vitro models and from human observational studies to evaluate how e-cigarette exposure may influence testosterone homeostasis and hypothalamic-pituitary-gonadal axis function. Across experimental models, e-cigarette aerosols and their constituents consistently impair Leydig cell function and testosterone biosynthesis through convergent mechanisms involving oxidative stress, inflammatory signaling, mitochondrial dysfunction, epigenetic modification, and suppression of key steroidogenic enzymes. Several of these mechanisms overlap with those described for combustible cigarette exposure, whereas others, particularly those related to aerosolized solvents, flavoring agents, and device-derived metals, appear more specific to e-cigarettes. In contrast, the available human evidence is limited to cross-sectional studies and yields inconsistent findings, with the largest population-based study reporting no significant differences in circulating testosterone concentrations between e-cigarette users and non-users. Collectively, the evidence supports biological plausibility for e-cigarette-associated disruption of testosterone steroidogenesis but remains insufficient to establish causality in humans. This review therefore identifies critical methodological gaps and highlights priorities for longitudinal, biomarker-anchored human studies required to determine the clinical relevance and reversibility of e-cigarette-associated endocrine disruption.

Electronic cigarette (e-cigarette) use is increasing worldwide, yet its effects on male endocrine and reproductive health remain poorly defined. Beyond nicotine, e-cigarette aerosols contain aldehydes, metals, and particulate matter capable of perturbing pathways essential for steroidogenesis. MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of hypothalamic-pituitary-gonadal axis signaling and Leydig cell function, and multiple miRNAs involved in GnRH release, gonadotropin synthesis, and testosterone biosynthesis are responsive to oxidative and metabolic stressors present in e-cigarette aerosols. Although direct evidence in e-cigarette users is limited, findings from studies of nicotine, flavoring agents, and metal exposures support the plausibility that e-cigarettes may alter miRNA expression and impair steroidogenic processes. This hypothesis-generating review synthesizes current evidence linking miRNA dysregulation to testosterone biosynthesis, proposes candidate e-cigarette constituents capable of modulating these miRNAs, and highlights critical gaps requiring experimental validation. Overall, miRNAs may represent integrative mediators and potential biomarkers of e-cigarette-associated testicular toxicity.

The NRF2-KEAP1 pathway is classically described as an inducible antioxidant switch, yet this binary framework fails to explain why transient NRF2 activation is broadly cytoprotective whereas sustained activation drives pathology across cancer, fibrosis, and metabolic disease. In this conceptual synthesis, we integrate evidence from redox biology, proteostasis, autophagy, metabolism, and systems biology to reinterpret NRF2-KEAP1 signaling using concepts from control theory. We propose that the pathway functions as a redoxostat, a signal-resolution control circuit that detects oxidative and electrophilic stress, encodes signal magnitude and duration, executes graded transcriptional responses, and actively promotes its own termination through genetically encoded feedback mechanisms. Central to this architecture is a resolution module involving KEAP1 resynthesis, ubiquitin-proteasome and autophagic turnover, and metabolic restoration of redox-sensitive cysteines. Within this framework, pathological outcomes arise primarily from failure of signal resolution rather than excessive activation, and distinct disease phenotypes can be mapped to specific circuit failure modes including sensor dysfunction, controller impairment, amplifier escape, and feedback disruption. This model reconciles the protective and pathogenic roles of NRF2 under a unified explanatory logic, clarifies why chronic activation is deleterious while transient activation is adaptive, and shifts experimental and therapeutic emphasis from endpoint activation toward restoration of signaling dynamics and resolution.

Electronic cigarettes are widely promoted as harm-reduction alternatives to conventional tobacco smoking, yet their potential effects on male sexual health remain incompletely characterised. Erectile dysfunction is a predominantly vascular condition with important neuroendocrine regulation and is highly sensitive to endothelial injury, oxidative stress, hormonal imbalance, and autonomic dysregulation, all of which may plausibly be influenced by electronic cigarette use. Despite increasing global prevalence, direct evidence linking electronic cigarette use to erectile dysfunction remains limited. This narrative review synthesises current experimental, clinical, and epidemiological evidence examining the association between electronic cigarette use and erectile dysfunction, with emphasis on underlying biological mechanisms and key research gaps. Emerging evidence implicates endothelial dysfunction, impaired nitric oxide bioavailability, oxidative stress, inflammation, hormonal disturbance, autonomic imbalance, sleep disturbance, and exposure to aerosolised substances and metals as interconnected pathways that may contribute to erectile dysfunction. Overall, the existing literature remains preliminary and largely hypothesis-generating, with no longitudinal studies capable of establishing causality or dose-response relationships. Well-designed prospective studies are required to clarify the long-term sexual health outcomes associated with electronic cigarette use.

E-cigarettes are promoted as reduced-harm alternatives to combustible tobacco, yet their aerosols contain metals, aldehydes, solvents, and other bioactive chemicals capable of disrupting metabolic regulation. This review synthesizes evidence from cellular, animal, and early human studies on how e-cigarette aerosol exposure affects metabolic homeostasis across mitochondrial, redox, circadian, and neurobehavioral systems. A systems-level model is proposed in which mitochondrial dysfunction, oxidative stress, circadian misalignment, and neurobehavioral alterations form a feed-forward network that drives metabolic inflexibility. Across experimental systems, e-cigarette exposure is associated with mitochondrial impairment, oxidative stress, AMPK suppression, disrupted lipid oxidation, adipose inflammation, and reduced thermogenic capacity, changes consistent with insulin resistance. Evidence also indicates disruption of circadian clock signaling and modulation of reward and appetite circuits, further biasing energy balance. These findings support a model in which e-cigarette aerosols act as multi-system metabolic disruptors affecting both peripheral organs and central regulatory pathways. However, important uncertainties remain regarding dose-response relationships, exposure patterns, device variability, and long-term human risk. This review provides an integrated framework to clarify potential links between e-cigarette aerosol exposure and metabolic dysfunction and highlights priorities for future translational and human research.

Cytochrome P450 1A1 (CYP1A1) is traditionally described as a xenobiotic detoxification enzyme induced by the aryl hydrocarbon receptor (AhR). However, its tight inducible regulation, evolutionary conservation, and prominent expression in immune and barrier tissues where xenobiotic metabolism operates alongside environmental sensing and immune regulation suggest a broader regulatory role. This review proposes that CYP1A1 functions as a metabolic feedback regulator that controls the duration and intensity of AhR signaling. AhR rapidly senses diverse environmental, dietary, microbial, and endogenous ligands, while delayed induction of CYP1A1 limits signaling by metabolizing susceptible ligands and reducing their availability. Through this feedback architecture, ligand metabolism determines signal persistence and shapes downstream transcriptional and immune outcomes. Evidence from evolutionary analyses, signaling kinetics, tissue biology, and immunology indicates that CYP1A1-mediated metabolic feedback calibrates immune differentiation and barrier homeostasis across tissues. Disruption of this feedback, through persistent ligands or impaired CYP1A1 activity, uncouples environmental sensing from signal resolution and promotes sustained AhR activation. This framework reframes the AhR-CYP1A1 axis as a regulatory control circuit rather than a linear detoxification pathway and highlights signal duration and feedback integrity as key determinants of environmental immunotoxicity.

Objective. This review assesses the respiratory effects of passive exposure to e-cigarette aerosols in adolescents, healthy adults, and individuals with pre-existing respiratory conditions.

Methods. We systematically searched for observational and experimental studies on secondhand e-cigarette aerosol (SHA) exposure. Outcomes included respiratory symptoms, pulmonary function, airway resistance or reactivity, inflammatory biomarkers, and environmental exposure metrics. Five studies met criteria: longitudinal cohorts, cross-sectional surveys, and controlled chamber experiments.

Results. Evidence suggests that SHA exposure is associated with adverse respiratory outcomes. In adolescents and young adults, household SHA increased bronchitic symptoms, wheeze, shortness of breath, and asthma outcomes. Risk rose with more frequent exposure. Controlled chamber studies in healthy non-smokers have found that 30 min of passive exposure causes immediate sensory irritation (in the eyes, nose, and throat), increased airway resistance, and a decrease in exhaled nitric oxide. In COPD patients, short-term exposure affected surfactant protein-A, increased plasma inflammatory biomarkers, and caused throat irritation, with borderline lung function decline. Environmental monitoring confirmed the presence of ultrafine particles and volatile organic compounds during exposure.

Conclusion. SHA exposure is not benign. It can cause respiratory irritation, functional impairment, and inflammation in various populations. Effects are generally less pronounced than those of combustible cigarette smoke. Nonetheless, these findings support public health measures such as regulations restricting SHA exposure in public settings, especially to protect adolescents and vulnerable individuals. Long-term studies are still needed to determine chronic health consequences and guide evidence-based policy decisions.

E-cigarette use has been linked to mitochondrial dysfunction through exposure to reactive oxygen species (ROS), toxic aldehydes, metals, and flavoring agents. These constituents can damage mitochondrial DNA, impair oxidative phosphorylation, and disrupt calcium homeostasis, resulting in oxidative stress, inflammation, and programmed cell death. Mitochondrial impairment contributes to many systemic disorders, including respiratory, cardiovascular, and metabolic conditions. Praeclinical findings suggest altered mitochondrial morphology, reduced adenosine triphosphate (ATP) production, and increased ROS, all of which can contribute to mitochondrial dysfunction following e-cigarette exposure. Certain flavorings and metals intensify these effects. While early human data suggest systemic mitochondrial stress, most research remains in vitro or animal-based. This review identifies mitochondrial dysfunction as a key mechanism in e-cigarette toxicity and calls for longitudinal research to elucidate its long-term health consequences.