Frontiers in toxicology最新文献

Introduction: Heating tobacco products (HTPs) are advanced electronic cigarette models. Classified by the FDA as a modified-risk tobacco product and can be used as part of efforts to quit smoking. Using heat-not-burn (HnB) technology, these devices heat tobacco avoiding complete combustion. Although the levels of toxicants in the mainstream are significantly lower than those observed in tobacco smoke, some recent studies have raised concerns about potential health risks associated with their use, particularly regarding their effects on male gonadal function, which remain largely unexplored.

Methods: Adult male Sprague-Dawley rats were exposed, whole body, 5 days/week for 4 weeks to HnB mainstream.

Results: The expression of the cell cycle regulators Bax/Bcl-2 ratio is not affected, along with no changes in p-38. On the other hand, an increase in oxidative stress markers, including those associated with DNA damage, was observed in exposed animals, along with the induction of NF-kB dependent pro-inflammatory mediators: TNF-α, IL-1β, IL-6 and COX-2. Furthermore, inactivation of key androgenic enzymes, such as 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase, together with decreased testosterone synthesis suggest a potential impairment of male gonadal function.

Discussion: The results indicate that animals exposed to HnB smoke show higher levels of oxidative stress markers, including those associated with DNA damage, as well as higher levels of pro-inflammatory cytokines. The impairment of some androgenic key enzymes and those related to the activity of seminiferous epithelium, together with the decrease in testosterone levels, suggest an impairment of gonadal function through the alteration of some cellular pathways typically associated with tobacco consumption.

Background: Cocaine intoxication and abuse is a worldwide problem that can be the cause of numerous acute medical complications, including severe acute hepatitis. Although these cases are scarce, they are extremely serious and may lead to liver transplantation or death. Management of toxic hepatitis, once the causative agent has been discontinued, is essentially symptomatic, based on clinical and biological monitoring and prevention of complications related to acute hepatitis.

Case details: We present a case of a 28-year-old woman admitted to the emergency department for acute hepatitis due to cocaine intoxication. In addition to a sharp rise in her liver enzymes, the patient also presented metabolic acidosis, renal failure, and rhabdomyolysis. Treatment consisted of administering N-acetylcysteine (NAC), dialysis, and additional supportive measures. An improvement in the liver function with a decrease in transaminases occurred after the NAC administration. The toxicokinetics of major cocaine metabolites and clinical chemistry concentrations were monitored.

Conclusion: In addition to the usual management measures for acute hepatitis, the administration of N-acetylcysteine should be investigated further, although it is currently used only in cases of acetaminophen acute toxic hepatitis.

Strategies emphasizing animal-free innovation are imperative for the contemporary and future scientific research. They not only address important ethical concerns, but also should directly improve research accuracy and reliability through redirecting scientific inquiry toward more reliable and translatable methodologies. Promotion and encouragement for use of animal-free innovations among the next-generation of scientists, alongside knowledge acquisition and training in the increased capabilities of novel technologies, are fundamental for advancing science and the welfare of animals used for scientific purposes. The Dutch government has promoted initiatives such as Transitie Proefdiervrije Innovatie (TPI) to make the public aware of the current situation. However, the transition towards animal-free innovations will span over more than two generations. In this context, Young TPI emerged as the-first-of-its-kind network comprising young professionals and students dedicated to revolutionizing scientific practices by catalyzing the shift towards animal-free research. Grounded on three pillars - collaboration, awareness-raising, and networking - Young TPI has evolved into a premier youth network in the Netherlands. Boasting over 270 members spanning Dutch 49 institutions, including biotechnology startups and pharmaceutical companies and universities, Young TPI harnesses the diverse expertise of its members to propel a sustainable, future-proof transition and to promote a continuous dialogue with a wide range of stakeholders. This manuscript describes the conception, establishment, and progress of Young TPI from its start to present, detailing its strategy for communication, activities, and funding mechanisms, and ongoing endeavors to enlist new members and forge strategic alliances in pursuit of its mission.

Primary cell cultures from rodent brain are widely used to investigate molecular and cellular mechanisms of neurotoxicity. To date, however, it has been challenging to reliably culture endogenous microglia in dissociated mixed cultures. This is a significant limitation of most in vitro neural cell models given the growing awareness of the importance of interactions between neurons, astrocytes and microglia in defining responses to neurotoxic exposures. We recently developed a tri-culture model consisting of neurons, astrocytes and microglia dissociated from the developing rat neocortex and demonstrated that this tri-culture model more faithfully mimics in vivo neuroinflammatory responses then standard neuron-only or neuron-astrocyte co-cultures. Here, we describe our protocol for generating tri-cultures of rat cortical neurons, astrocytes and microglia in which all 3 cell types can be maintained for up to 1 month in culture at the same relative ratio observed in the developing rat neocortex. We also discuss applications of this model for neurotoxicity testing, as well as the potential of this model to fill a current gap for assessing neuroinflammation in the in vitro testing battery for developmental neurotoxicity.

The adoption of in vivo digital measures in pharmaceutical research and development (R&D) presents an opportunity to enhance the efficiency and effectiveness of discovering and developing new therapeutics. For clinical measures, the Digital Medicine Society's (DiMe) V3 Framework is a comprehensive validation framework that encompasses verification, analytical validation, and clinical validation. This manuscript describes collaborative efforts to adapt this framework to ensure the reliability and relevance of digital measures for a preclinical context. Verification ensures that digital technologies accurately capture and store raw data. Analytical validation assesses the precision and accuracy of algorithms that transform raw data into meaningful biological metrics. Clinical validation confirms that these digital measures accurately reflect the biological or functional states in animal models relevant to their context of use. By widely adopting this structured approach, stakeholders-including researchers, technology developers, and regulators-can enhance the reliability and applicability of digital measures in preclinical research, ultimately supporting more robust and translatable drug discovery and development processes.

Solid lipid nanoparticles (SLNs) have gained interest as drug delivery carriers due to their efficient cellular internalization and increased therapeutic effect of the loaded drug, with minimal side effects. Although recently several studies have shown the possibility to administer SLNs during pregnancy to vehicle mRNA to the placenta, data about the effect of premating exposure to SLNs on pregnancy outcome are scant. Considering that assumption of drug-delivering nanocarriers in reproductive age may potentially affect women's reproductive health, the aim of the present study was to evaluate whether repeated oral administration of SLNs to female mice prior to mating would influence key pregnancy outcomes. For this purpose, SLNs melatonin loaded (SLN + mlt) or unloaded were orally administered to CD1 female mice at two different dosages-low (7.5 mg/kg) and high (750 mg/kg) -three times a week for 6 weeks. Females mice were mated and pregnancy was monitored from conception to delivery. All the assessed pregnancy parameters, including time to pregnancy, pregnancy duration, litter size, and the presence of any gross anomalies in the pups, and maternal key biochemical parameters were not significantly affected by SLN administration. Embryonic development was also evaluated and no effects on the number of implantation sites, fetus numbers, incidence of fetal resorptions, and measurements of crown-rump length, as well as fetal and placental weights, were observed in the treated mothers. The impact of SLNs on maternal intestinal barrier integrity and inflammation was assessed both in vivo in mice and in vitro using an intestinal epithelial barrier model by qRT-PCR. Results showed that unloaded SLNs, but not the SLN + mlt, affected intestinal barrier integrity. Although variation in the expression of inflammatory cytokines was recorded, this did not reflect in significant histological alterations and the integrity of the intestinal barrier was maintained. The in vitro model further confirmed the biocompatibility of SLNs, showing that both loaded and unloaded SLNs did not affect the integrity of the simulated intestinal epithelial barrier. In conclusion, these data suggest that administering SLNs, as a drug delivery vehicle, prior to conception does not affect either maternal health or fetal development, posing no risk to future pregnancy.