Search Results (27)

Background: Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. Methods: We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. Results: PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα^−/− mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood–brain barrier (BBB) function, pointing to broader systemic toxicity. Conclusions: Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure. Full article

The cerebellum, a key target of ethanol’s toxic effects, is associated with ataxia following alcohol consumption. However, the impact of ethanol on Purkinje cell (PC) mitochondria remains unclear. To investigate how ethanol administration affects mitochondrial dynamics in cerebellar Purkinje cells, we employed a transgenic mouse model expressing mitochondria-targeted yellow fluorescent protein in Purkinje cells (PC-mito-eYFP). Both male and female PC-mito-eYFP mice received an intraperitoneal injection of ethanol or vehicle. One hour after ethanol administration, the animals were perfusion fixed or their cerebellum tissue or isolated mitochondria were collected. Cerebellum sections were analyzed using confocal microscopy to assess changes in mitochondrial length distribution. In vivo superoxide levels were measured using dihydroethidium (DHE), and mitochondrial NAD levels were determined by high-performance liquid chromatography (HPLC). Our findings revealed a sex-dependent response to ethanol administration in mitochondrial size distribution. While male Purkinje cell mitochondria exhibited no significant changes in size, female mitochondria became more fragmented after one hour of ethanol administration. This coincided with elevated phosphorylation of the fission protein Drp1 and increased superoxide production, as measured by DHE fluorescence intensity. Similarly, mitochondrial NAD levels were significantly reduced in female mice, but no changes were observed in males. Our results demonstrate that ethanol induced mitochondrial fragmentation through increased free radical levels, due to reduced NAD and increased p-Drp1, in PC cells of the female cerebellum. Full article

Since the publication of the Adverse Childhood Experiences (ACEs) Study in 1998, there has been a dramatic increase in the number of studies exploring the immunoendocrinological sequelae of toxic stress. However, the literature exploring this in relation to paediatric atopy predominantly revolves around asthma. This review aims to (1) explore the association between ACEs and non-asthmatic, non-iatrogenic paediatric allergies (NANIPA) in the developed world and (2) further focus on the association between exposure to violence and NANIPA. Methods: PubMed and Scopus were searched for articles examining adversity and NANIPA before age 18. Non-English papers, publications before 1998, reviews, opinion pieces and case reports/series were excluded. Screening, data extraction, and risk-of-bias were independently reviewed by the first two authors. Results: Nine of the one thousand eighty-nine records identified were included. Four pertained to objective 1, four to objective 2, and one pertained to both. Regarding objective 1, all studies reported a positive dose-response relationship between ACEs and NANIPA, which was most significant among preschoolers and diminished with age. Studies relevant to objective 2 were too heterogenous to compare. However, two interesting associations emerged: (1) The types of violence significantly associated with NANIPA in adolescence differ in a sex-dependent manner, and (2) verbal abuse and bullying are the violence types most powerfully and significantly associated with NANIPA. Conclusion: Psychological stress is a probable IgE-independent driver of atopy in children exposed to adversity and/or violence. While the literature is too underdeveloped to allow for meaningful cross-comparison between studies, this review has identified many interesting areas for future research. Full article

Sex is a biological variable that can reflect clinical outcomes in terms of quality of life, therapy effectiveness, responsiveness and/or toxicity. Sphingosine-1-phosphate (S1P) is a lipidic mediator whose activity can be influenced by sex. To evaluate whether the S1P axis underlies sex ‘instructions’ in the lung during physiological and oncological lung conditions, sphingosine and S1P were quantified in the blood of healthy (H) volunteers, lung adenocarcinoma (ADK) and squamous cell carcinoma (SCC) patients of both sexes. S1P receptors and their metabolic enzymes were evaluated in the tissues. Circulating levels of S1P were similar among H female and male subjects and female SCC patients. Instead, male and female ADK patients had lower circulating S1P levels. S1P receptor 3 (S1PR3) was physiologically expressed in the lung, but it was overexpressed in male SCC, and female and male ADK, but not in female SCC patients, who showed a significantly reduced ceramide synthase 1 (CERS1) mRNA and an overexpression of the ceramidase (ASAH1) precursor in lung tumor tissues, compared to male SCC and both male and female ADK patients. These findings highlighted sex differences in S1P rheostat in pathological conditions, but not in physiological conditions, identifying S1P as a prognostic mediator depending on lung cancer histotype. Full article

Animal feed is very frequently contaminated with different types of mold, the metabolites of which are toxic to living organisms. Mold-contaminated cereal is rich in heat-resistant and harmful metabolites such as fumonisins (FBs). The amount of FBs consumed as part of animal feed, including livestock feed, is unknown. Therefore, this study aimed to evaluate the effects of maternal oral FB intoxication on basal duodenum morphology and the immunolocalization of gut hormones responsible for food intake (leptin and ghrelin), as well as their receptors, in newborn rat offspring. Pregnant Wistar rats were randomly allocated to one of three groups: a control group or one of two FB-intoxicated groups (60 or 90 mg FB/kg b.w., respectively). Basal morphological duodenal parameters changed in a dose- and sex-dependent manner. The intensity of the ghrelin immunoreaction was unchanged in females, while in males it increased after FB exposure (60 mg/kg b.w.), with a simultaneous decrease in expression of the ghrelin receptor. Leptin and its receptor immunoreaction intensity was decreased in both sexes following FB exposure. The current study highlighted the potential involvement of intestinal ghrelin and leptin in the metabolic disturbances observed later in life in offspring that were prenatally exposed to fumonisins. Full article

Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low. Full article

Plant-extracted essential oils are generally suggested as potential sources for alternatives to synthetic insecticides in insect pest control strategies. The increased interest in the use of essential oils derives from the generalized perception of their safety for the environment, human health, and non-target organisms as well as a lower risk of resistance development. However, studies on essential oils have largely focused on their activity on targeted insect pests while overlooking their potential unintended effects on insect biological and reproductive traits, especially with sublethal exposures. Here, we first determined the toxicity of Eucalyptus globulus essential oil to adults of Drosophila suzukii and assessed the effects of low concentrations (i.e., LC₅ and LC₂₀) in old (5–7 days) and mated flies. Subsequently, we assessed longevity and fecundity in newly emerged virgin flies from four couples’ combinations: unexposed couples, exposed females, exposed males, and exposed couples to the low concentration LC₂₀. Our results show that eucalyptus essential oil has good insecticidal activity against adults of D. suzukii. However, compared to untreated flies, the exposure to low concentrations enhanced the females’ fecundity only when both old and mated female and male flies were exposed, while the females’ but not males’ life span was extended only in couples where newly emerged virgin females were exposed. Our findings suggest that although the eucalyptus essential oil may be a good control alternative for adult D. suzukii, its age-, sex-, and mating status-dependent stimulatory responses mediated by exposure to low concentrations need to be considered and further investigated. Full article

Cancer development is often connected to impaired DNA repair and DNA damage signaling pathways. The presence of DNA damage in cells activates DNA damage response, which is a complex cellular signaling network that includes DNA repair, activation of the cell cycle checkpoints, cellular senescence, and apoptosis. DNA double-strand breaks (DSBs) are toxic lesions that are mainly repaired by the non-homologous end joining and homologous recombination repair (HRR) pathways. Estrogen-dependent cancers, like breast and ovarian cancers, are frequently associated with mutations in genes that play a role in HRR. The female sex hormone estrogen binds and activates the estrogen receptors (ERs), ERα, ERβ and G-protein-coupled ER 1 (GPER1). ERα drives proliferation, while ERβ inhibits cell growth. Estrogen regulates the transcription, stability and activity of numerus DDR factors and DDR factors in turn modulate ERα expression, stability and transcriptional activity. Additionally, estrogen stimulates DSB formation in cells as part of its metabolism and proliferative effect. In this review, we will present an overview on the crosstalk between estrogen and the cellular response to DSBs. We will discuss how estrogen regulates DSB signaling and repair, and how DDR factors modulate the expression, stability and activity of estrogen. We will also discuss how the regulation of HRR genes by estrogen promotes the development of estrogen-dependent cancers. Full article

Daptomycin pharmacokinetics may not depend on renal function only and it significantly differs between healthy volunteers and severely ill patients. Herein, we propose a population pharmacokinetics model based on 424 plasma daptomycin concentrations collected from 156 patients affected by severe Gram-positive infections during a routine therapeutic drug monitoring protocol. Model building and validation were performed using NONMEM 7.2 (ICON plc), Xpose4 and Perl-speaks-to-NONMEM. The final pop-PK model was a one-compartment first-order elimination model, with a 2.7% IIV for drug clearance (Cl), influence of creatinine clearance on drug clearance and of sex on distribution volume. After model validation, we simulated 10,000 patients with the Monte-Carlo method to predict the efficacy and tolerability of different daptomycin daily dosages. For the most common 6 mg/kg daily dose, the simulated probability of overcoming the toxic minimum concentration (24.3 mg/L) was 14.8% and the efficacy (expressed as a cumulative fraction of response) against methicillin-resistant S. aureus, S. pneumoniae and E. faecium was 95.77%, 99.99% and 68%, respectively. According to the model-informed precision dosing paradigm, pharmacokinetic models such as ours could help clinicians to perform patient-tailored antimicrobial dosing and maximize the odds of therapy success without neglecting toxicity risks. Full article

Gender medicine in the field of oncology is an under-researched area, despite the existing evidence towards gender-dependent response to therapy and treatment-induced adverse effects. Oncological treatment aims to fulfil its main goal of achieving high tumour control by also protecting normal tissue from acute or chronic damage. Chemotherapy is an important component of cancer treatment, with a large number of drugs being currently in clinical use. Cisplatin is one of the most commonly employed chemotherapeutic agents, used either as a sole drug or in combination with other agents. Cisplatin-induced toxicities are well documented, and they include nephrotoxicity, neurotoxicity, gastrointestinal toxicity, ototoxicity, just to name the most frequent ones. Some of these toxicities have short-term sequelae, while others are irreversible. Furthermore, research showed that there is a strong gender-dependent aspect of side effects caused by the administration of cisplatin. While evidence towards sex differences in animal models is substantial, clinical studies considering sex/gender as a variable factor are limited. This work summarises the current knowledge on sex/gender-related side effects induced by platinum compounds and highlights the gaps in research that require more attention to open new therapeutic possibilities and preventative measures to alleviate normal tissue toxicity and increase patients’ quality of life in both males and females. Full article

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper levels of RLS patients were similar to controls, suggesting a specific impairment of zinc-dependent metabolism in RLS. The aim of this study is to assess the serum concentrations of trace elements involved in oxidative stress or causing peripheral nerve toxicity in a large series of patients with iRLS and controls. We determined serum levels of iron, copper, manganese, zinc, magnesium, selenium, calcium, aluminium, lead, cadmium, arsenic and mercury in 100 patients diagnosed with iRLS and in 110 age- and sex-matched controls using Inductively Coupled Plasma Mass Spectrometry. Serum copper, magnesium, selenium, and calcium concentrations were significantly higher in RLS patients than in controls. These differences were observed both in men and women. There were no major correlations between serum trace metal concentrations and age at onset of RLS or RLS severity, nor was there any association with a family history of RLS or drug response. This study shows an association between increased serum concentrations of copper, magnesium, selenium, and calcium with RLS in a Spanish Caucasian population and does not confirm the previously reported increase in serum zinc concentrations in patients suffering from this disease, suggesting that the different accuracy of the analytical methods used could have influenced the inconsistent results found in the literature. Full article

The biological effects of environmental metal contamination are important issues in an industrialized, resource-dependent world. Different metals have different roles in biology and can be classified as essential if they are required by a living organism (e.g., as cofactors), or as non-essential metals if they are not. While essential metal ions have been well studied in many eukaryotic species, less is known about the effects of non-essential metals, even though essential and non-essential metals are often chemically similar and can bind to the same biological ligands. Insects are often exposed to a variety of contaminated environments and associated essential and non-essential metal toxicity, but many questions regarding their response to toxicity remain unanswered. Drosophila melanogaster is an excellent insect model species in which to study the effects of toxic metal due to the extensive experimental and genetic resources available for this species. Here, we review the current understanding of the impact of a suite of essential and non-essential metals (Cu, Fe, Zn, Hg, Pb, Cd, and Ni) on the D. melanogaster metal response system, highlighting the knowledge gaps between essential and non-essential metals in D. melanogaster. This review emphasizes the need to use multiple metals, multiple genetic backgrounds, and both sexes in future studies to help guide future research towards better understanding the effects of metal contamination in general. Full article

This study investigates the disruptive activity of environmental toxicants on sex hormone receptors mediating type 2 diabetes mellitus (T2DM). Toxicokinetics, gene target prediction, molecular docking, molecular dynamics, and gene network analysis were applied in silico techniques. From the results, permethrin, perfluorooctanoic acid, dichlorodiphenyltrichloroethane, O-phenylphenol, bisphenol A, and diethylstilbestrol were the active toxic compounds that could modulate androgen (AR) and estrogen-α and –β receptors (ER) to induce T2DM. Early growth response 1 (EGR1), estrogen receptor 1 (ESR1), and tumour protein 63 (TP63) were the major transcription factors, while mitogen-activated protein kinases (MAPK) and cyclin-dependent kinases (CDK) were the major kinases upregulated by these toxicants via interactions with intermediary proteins such as PTEN, AKT1, NfKβ1, SMAD3 and others in the gene network analysis to mediate T2DM. These toxicants pose a major challenge to public health; hence, monitoring their manufacture, use, and disposal should be enforced. This would ensure reduced interaction between people and these toxic chemicals, thereby reducing the incidence and prevalence of T2DM. Full article

Among botanical insecticides based on essential oils (EOs) or their main components, Carlina acaulis EO and the aromatic polyacetylene carlina oxide, constituting more than 90% of its EO, were recently proven to be effective against the larvae and adults of some insect vectors and pests. In this study, the toxicity of C. acaulis EO and carlina oxide were tested on Bactrocera oleae adults using a protein bait formulation. The LC₅₀ values of the C. acaulis EO and carlina oxide were 706 ppm and 1052 ppm, respectively. Electroantennographic (EAG) tests on B. oleae adults showed that both carlina EO and oxide elicited EAG dose-dependent responses in male and female antennae. The responses to the EO were significantly higher than those to carlina oxide, indicating that other compounds, despite their lower concentrations, can play a relevant role. Moreover, Y-tube assays carried out to assess the potential attractiveness or repellency of carlina oxide LC₉₀ to B. oleae adults showed that it was unattractive to both males and females of B. oleae, and the time spent by both sexes in either the control or the treatment arm did not differ significantly. Overall, this study points out the potential use of C. acaulis EO and carlina oxide for the development of green and effective “lure-and-kill” tools. Full article

Persistent organic pollutants (POPs) are lipid-soluble toxins that are not easily degraded; therefore, they accumulate in the environment and the human body. Several studies have indicated a correlation between POPs and metabolic diseases; however, their effects on mitochondria as a central organelle in cellular metabolism and the usage of mitochondria as functional markers for metabolic disease are barely understood. In this study, a zebrafish model system was exposed to two subclasses of POPs, organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), under two different conditions (solitary OCPs or OCPs with PCBs (Aroclor 1254)), and changes in the oxidative stress marker levels and mitochondrial enzyme activities in the electron transport chain of the tail were measured to observe the correlation between POPs and representative biomarkers for metabolic disease. The results indicated different responses upon exposure to OCPs and OCPs with Aroclor 1254, and accelerated toxicity was observed following exposure to mixed POPs (OCPs with Aroclor 1254). Males were more sensitive to changes in the levels of oxidative stress markers induced by POP exposure, whereas females were more susceptible to the toxic effects of POPs on the levels of mitochondrial activity markers. These results demonstrate that the study reflects real environmental conditions, with low-dose and multiple-toxin exposure for a long period, and that POPs alter major mitochondrial enzymes’ functions with an imbalance of redox homeostasis in a sex-dependent manner. Full article