Microbial transformation of dietary xenobiotics shapes gut microbiome composition.

Diet is a major determinant of gut microbiome composition, and variation in diet-microbiome interactions may contribute to variation in their health consequences. To mechanistically understand these relationships, here we map interactions between ∼150 small-molecule dietary xenobiotics and the gut microbiome, including the impacts of these compounds on community composition, the metabolic activities of human gut microbes on dietary xenobiotics, and interindividual variation in these traits. Microbial metabolism can toxify and detoxify these compounds, producing emergent interactions that explain community-specific remodeling by dietary xenobiotics. We identify the gene and enzyme responsible for detoxification of one such dietary xenobiotic, resveratrol, and demonstrate that this enzyme contributes to interindividual variation in community remodeling by resveratrol. Together, these results systematically map interactions between dietary xenobiotics and the gut microbiome and connect toxification and detoxification to interpersonal differences in microbiome response to diet.

MAPK signaling pathway enhances tolerance of Mytilus galloprovincialis to co-exposure of sulfamethoxazole and polyethylene microplastics.

Microplastics (MPs) and antibiotics often coexist in complex marine environments, yet their combined detrimental effects on marine organisms remain underexplored. This study evaluated the effects of polyethylene microplastics (PE, 200 µg/L) and sulfamethoxazole (SMX, 50 µg/L), both individually and in combination, on Mytilus galloprovincialis. The exposure lasted 6 days, followed by a 6-day recovery period. Bioaccumulation, DNA damage, pollutants transport/metabolism related responses and responding alterations of mitogen-activated protein kinase (MAPK) signaling pathway were detected in gills and digestive glands. Bioaccumulation of SMX/PE in mussels occurred in a tissue-specific manner, co-exposure altered SMX contents in investigated tissues. Co-exposure did not induce extra DNA damage, elevated DNA damage was alleviated during the recovery period in all treated groups. The exposure of SMX/PE exerted different alterations in pollutants transport/metabolism related responses, characterized by multixenobiotic resistance and relative expression of key genes (cytochrome P450 monooxygenase, glutathione S-transferase, ATP-binding cassette transporters). Key molecules (p38 MAPK, c-jun N-terminal kinase, extracellular regulated protein kinase, nuclear factor-κB and tumor protein p53) in MAPK signaling pathway were activated at transcriptional and translational levels after SMX/PE and co-exposure. Co-regulation between MAPK members and pollutants transport/metabolism related factors was revealed, suggesting MAPK signaling pathway served as a regulating hub in exposed mussels to conquer SMX/PE stress. Overall, this study provides new insights on SMX/PE induced health risks in marine mussels and potential mechanism through MAPK cascades regulation.

A systematic review of the impact of chemical pollution on sea turtles: Insights from biomarkers of aquatic contamination.

Chemical anthropogenic contaminants in the marine environment pose a substantial threat to sea turtles. The current systematic review quantified the published literature on biomarkers of aquatic contamination in sea turtles. It examined the exposure and potential impacts of pollution at biochemical, molecular, and cellular levels, as indicated by these biomarkers. Eighty-seven primary peer-reviewed papers were included, most of which were published from 2013 onwards. Most studies focused on the species Chelonia mydas (n = 43 papers) and Caretta caretta (n = 36) and used blood samples for biomarker (n = 54) and chemical (n = 38) analyses. Chemical analyses were assessed alongside biomarker analyses in most studies (n = 71). Some studies indicated possible damage to the DNA, cells, oxidative balance, and reproduction of sea turtles associated with chemical contaminants as metals, emerging, and mixtures of organic pollutants. Research gaps and recommendations for future studies were addressed to help understand the toxicity of chemical pollutants in sea turtles. The purpose of this review is to contribute for supporting actions to mitigate the threats posed by pollution to these protected species, as well as to plan new studies in this research field for both conservation and biomonitoring purposes.

STAT5B, Akt and p38 Signaling Activate FTZ-F1 to Regulate the Xenobiotic Tolerance-Related Gene SlCyp9a75b in Spodoptera litura.

Cytochrome P450 monooxygenases in insects have been verified to implicated in insecticide and phytochemical detoxification metabolism. However, the regulation of P450s, which are modulated by signal-regulated transcription factors (TFs), is less well studied in insects. Here, we found that the Malpighian tubule specific P450 gene SlCYP9A75b in Spodoptera litura is induced by xenobiotics. The transgenic Drosophila bioassay and RNAi results indicated that this P450 gene contributes to α-cypermethrin, cyantraniliprole, and nicotine tolerance. In addition, functional analysis revealed that the MAPKs p38, PI3K/Akt, and JAK-STAT activate the transcription factor fushi tarazu factor 1 (FTZ-F1) to regulate CYP9A75b expression. These findings provide mechanistic insights into the contributions of CYP9A genes to xenobiotic detoxification and support the possible involvement of different signaling pathways and TFs in tolerance to xenobiotics in insects.

Laboratory and physiological aspects of substitute metazoan models for in vivo pharmacotoxicological analysis.

New methods are essential to characterize the performance of substitute procedures for detecting therapeutic action(s) of a chemical or key signal of toxicological events. Herein, it was discussed the applications and advantages of using arthropods, worms, and fishes in pharmacological and/or toxicology assessments. First of all, the illusion of similarity covers many differences between humans and mice, remarkably about liver injury and metabolism of xenobiotics. Using invertebrates, especially earthworms (Eisenia fetida), brine shrimps (Artemia salina, Daphnia magna), and insects (Drosophila melanogaster) and vertebrates as small fishes (Oryzias latipes, Pimephales promelas, Danio rerio) has countless advantages, including fewer ethical conflicts, short life cycle, high reproduction rate, simpler to handle, and less complex anatomy. They can be used to find contaminants in organic matters and water and are easier genetically engineered with orthologous-mutated genes to explore specific proteins involved in proliferative and hormonal disturbances, chemotherapy multidrug resistance, and carcinogenicity. As multicellular embryos, larvae, and mature organisms, they can be tested in bigger-sized replication platforms with 24-, 96-, or 384-multiwell plates as cheaper and faster ways to select hit compounds from drug-like libraries to predict acute, subacute or chronic toxicity, pharmacokinetics, and efficacy parameters of pharmaceutical, cosmetic, and personal care products. Meanwhile, sublethal exposures are designed to identify changes in reproduction, body weight, DNA damages, oxidation, and immune defense responses in earthworms and zebrafishes, and swimming behaviors in A. salina and D. rerio. Behavioral parameters also give specificities on sublethal effects that would not be detected in zebrafishes by OECD protocols.

Pregnenolone 16-Alpha Carbonitrile, an Agonist of Rodent Pregnane X Receptor, Regulates Testosterone Biosynthesis in Rodent Leydig Cells.

Leydig cells (LCs) in the testes produce the male sex hormone testosterone (T). Several xenobiotics, including clinical drugs, supplements, and environmental chemicals, are known to disrupt T homeostasis. Notably, some of these xenobiotics are known to activate the pregnane X receptor (PXR), a ligand-dependent nuclear receptor. However, it is currently unknown whether PXR is expressed in LCs and whether PXR activation alters T synthesis in rodent LCs. Therefore, in this study, we sought to determine whether PXR is expressed in rodent LCs and whether pregnenolone 16-alpha carbonitrile (PCN), the prototype agonist of rodent PXR, regulates T biosynthesis in rodent LCs. Hormonal as well as protein and gene expression analyses were conducted in rat primary LCs and MA-10 mouse Leydig cells. Results showed that PXR was expressed at the mRNA and protein level in both rat primary LCs and MA-10 cells. Incubation of rat primary LCs with PCN resulted in a significant decrease in T secretion. This PCN-induced decrease in T secretion was associated with decreased protein expression of key steroidogenic enzymes such as 3ß-HSD and CYP17A1. RNA-seq results from MA-10 cells showed that PCN down-regulated the transcripts of steroidogenic enzymes and proteins involved in the T synthesis pathway. Together, these results suggest that PCN, an agonist of rodent PXR, can regulate T biosynthesis in rodent LCs by down-regulating the expression of the steroidogenic enzymes involved in T biosynthesis. Our results are significant as they provide a potential novel mechanism for disruption of testosterone homeostasis by a variety of xenobiotics.

Pesticides in the population of European hedgehogs (Erinaceus europaeus) in Denmark.

European hedgehogs (Erinaceus europaeus) inhabit most of Denmark, except for a few smaller islands. Research from other European countries has shown that the hedgehog populations are in decline. The exposure to chemicals might contribute to this development, although their role is currently unknown. Our research studied the occurrence of 19 selected pesticides in the Danish hedgehog population as well as factors potentially explaining the levels of chemicals detected. We analysed 115 liver samples obtained from dead hedgehogs in 2016 for seven rodenticides, four insecticides and eight herbicides commonly used in Denmark at the time of sampling, applying a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. Detection frequencies varied between 0.9% for fluroxypyr and trans-permethrin and 79% for bromadiolone. Rodenticides, insecticides and herbicides were detected in 84, 43, and 50% of the samples, respectively. The compounds most frequently detected included the insecticide imidacloprid (35%), the herbicide metamitron (29%) and the rodenticide bromadiolone (79%). Individual concentrations varied between non-detected to >2 µg/g. A total of 79% of the 115 hedgehogs contained more than one detectable pesticide, with up to nine of the 19 compounds detected in one individual. The detection frequencies were found to differ significantly between the Eastern and Western part of Denmark for difenacoum, difethialone and imidacloprid. However, no associations were found with sex, age, habitat type or the prevalence of mecC-MRSA and endoparasites in the hedgehogs tested. Whether or not the pesticide levels detected carry a health risk for the hedgehogs remains unknown as no adverse effect levels have yet been established for European hedgehogs for single compounds or pesticide mixtures.

Deciphering the ecological impact of azo dye pollution through microbial community analysis in water-sediment microcosms.

The uncontrolled release of untreated dyeing wastewater into aquatic ecosystems poses global environmental risks. It alters native microbial communities and associated ecological processes, often going unnoticed. Therefore, the influence of acid orange 7 dye (AO7) contamination on the natural microbial community was investigated using a water-sediment microcosm. Compared to sterile microcosms, complete dye decolourization in natural microcosms showed microbial communities' significance in combating xenobiotic contamination. Proteobacteria dominated the water community, whereas Firmicutes dominated the sediment. AO7 exposure induced notable shifts in the structural composition of the bacterial community in both water and sediment. Niveispirillum exhibited a marked decrease, and Pseudomonas demonstrated a notable increase. The - 9.0 log2FC in Niveispirillum, a nitrogen-fixing bacterium, from 24.4% in the control to 0.1% post-treatment, may disrupt nutrient balance, plant growth, and ecosystem productivity. Conversely, elevated levels of Pseudomonas sp. resulting from azo dye exposure demonstrate its ability to tolerate and bioremediate organic pollutants, highlighting its resilience. Functional profiling via KEGG pathway analysis revealed differential expression patterns under AO7 stress. Specifically, valine, leucine, and isoleucine degradation pathways in water decreased by 52.2%, and cysteine and methionine metabolism ceased expression entirely, indicating reduced protein metabolism and nutrient bioavailability under dye exposure. Furthermore, in sediment, glutathione metabolism ceased, indicating increased oxidative stress following AO7 infusion. However, C5-branched dibasic acid metabolism and limonene and pinene degradation were uniquely expressed in sediment. Decreased methane metabolism exacerbates the effects of global warming on aquatic ecosystems. Further, ceased-butanoate metabolic pathways reflect the textile dye wastewater-induced adverse impact on ecological processes, such as organic matter decomposition, energy flow, nutrient cycling, and community dynamics that help maintain self-purification and ecological balance in river ecosystems. These findings underscore the critical need for more comprehensive environmental monitoring and management strategies to mitigate ecological risks posed by textile dyes in aquatic ecosystems, which remain unnoticed.

Is There an Interplay between Environmental Factors, Microbiota Imbalance, and Cancer Chemotherapy-Associated Intestinal Mucositis?

Interindividual variation in drug efficacy and toxicity is a significant problem, potentially leading to adverse clinical and economic public health outcomes. While pharmacogenetics and pharmacogenomics have long been considered the primary causes of such heterogeneous responses, pharmacomicrobiomics has recently gained attention. The microbiome, a community of microorganisms living in or on the human body, is a critical determinant of drug response and toxicity. Factors such as diet, lifestyle, exposure to xenobiotics, antibiotics use, illness, and genetics can influence the composition of the microbiota. Changes in the intestinal microbiota are particularly influential in drug responsiveness, especially in cancer chemotherapy. The microbiota can modulate an individual's response to a drug, affecting its bioavailability, clinical effect, and toxicity, affecting treatment outcomes and patient quality of life. For instance, the microbiota can convert drugs into active or toxic metabolites, influencing their efficacy and side effects. Alternatively, chemotherapy can also alter the microbiota, creating a bidirectional interplay. Probiotics have shown promise in modulating the microbiome and ameliorating chemotherapy side effects, highlighting the potential for microbiota-targeted interventions in improving cancer treatment outcomes. This opinion paper addresses how environmental factors and chemotherapy-induced dysbiosis impact cancer chemotherapy gastrointestinal toxicity.

Diethyl phthalate and dibutyl phthalate disrupt sirtuins expression in the HepG2 cells.

Background: Phthalates are additives used as plasticizers among other uses, classified as endocrine disruptors and may contribute to some metabolic disorders. The aim of this work was to determine the effect of the exposure of diethyl phthalate (DEP) and dibutyl phthalate (DBP) on cell viability and reactive oxygen species (ROS) production, as well as the regulation of sirloins in HepG2 cells. Methods: HepG2 cells were exposed to DEP or DBP at 0.1, 1, 10 and 100 µg/mL, and after 48 or 72 h the gene and protein expression of sirtuins was quantified by qRT-PCR and Western-Blot, respectively. Results: Results showed that even at a low concentration of 0.1 µg/mL DEP affected the expression of Sirt3 and Sirt4, whereas DBP at 0.1 µg/mL affected Sirt3 and Sirt5 gene expression. Protein analysis showed a reduction in Sirt1 levels at a DEP concentration of 1 µg/mL and higher, while DBP at higher dose (100 µg/mL) decreased Sirt3 protein levels. Cell viability decreased by 20% only at higher dose (100 µg/mL) and ROS production increased at 10 and 100 µg/mL for both phthalates. Conclusion: These findings indicate that exposure to low concentrations (0.1 µg/mL) of DEP or DBP can negatively influence the expression of some sirtuins.

Synthesis and Reactivity of Masked Organic Sulfates.

Nature offers a variety of structurally unique, sulfated endobiotics including sulfated glycosaminoglycans, sulfated tyrosine peptides, sulfated steroids/bile acids/catecholamines. Sulfated molecules display a large number of biological activities including antithrombotic, antimicrobial, anticancer, anti-inflammatory, and others, which arise from modulation of intracellular signaling and enhanced in vivo retention of certain hormones. These characteristics position sulfated molecules very favorably as drug-like agents. However, few have reached the clinic. Major hurdles exist in realizing sulfated molecules as drugs. This state-of-the-art has been transformed through recent works on the development of sulfate masking technologies for both alkyl (sulfated carbohydrates, sulfated steroids) and aryl (sTyr-bearing peptides/proteins, sulfated flavonoids) sulfates. This review compiles the literature on different strategies implemented for different types of sulfate groups. Starting from early efforts in protection of sulfate groups to the design of newer SuFEx, trichloroethyl, and gem-dimethyl-based protection technologies, this review presents the evolution and application of concepts in realizing highly diverse, sulfated molecules as candidate drugs and/or prodrugs. Overall, the newer strategies for sulfate masking and demasking are likely to greatly enhance the design and development of sulfated molecules as non-toxic drugs of the future.

A Malpighian Tubule-Specific P450 Gene SlCYP9A75a Contributes to Xenobiotic Tolerance in Spodoptera litura.

Phytophagous insects are more predisposed to evolve insecticide resistance than other insect species due to the "preadaptation hypothesis". Cytochrome P450 monooxygenases have been strongly implicated in insecticide and phytochemical detoxification in insects. In this study, RNA-seq results reveal that P450s of Spodoptera litura, especially the CYP3 clan, are dominant in cyantraniliprole, nicotine, and gossypol detoxification. The expression of a Malpighian tubule-specific P450 gene, SlCYP9A75a, is significantly upregulated in xenobiotic treatments except α-cypermethrin. The gain-of-function and loss-of-function analyses indicate that SlCYP9A75a contributes to cyantraniliprole, nicotine, and α-cypermethrin tolerance, and SlCYP9A75a is capable of binding to these xenobiotics. This study indicates the roles of inducible SlCYP9A75a in detoxifying man-made insecticides and phytochemicals and may provide an insight into the development of cross-tolerance in omnivorous insects.

Aldo-keto reductases: Role in cancer development and theranostics.

Aldo-keto reductases (AKRs) are a superfamily of enzymes that play crucial roles in various cellular processes, including the metabolism of xenobiotics, steroids, and carbohydrates. A growing body of evidence has unveiled the involvement of AKRs in the development and progression of various cancers. AKRs are aberrantly expressed in a wide range of malignant tumors. Dysregulated expression of AKRs enables the acquisition of hallmark traits of cancer by activating oncogenic signaling pathways and contributing to chemoresistance. AKRs have emerged as promising oncotherapeutic targets given their pivotal role in cancer development and progression. Inhibition of aldose reductase (AR), either alone or in combination with chemotherapeutic drugs, has evolved as a pragmatic therapeutic option for cancer. Several classes of synthetic aldo-keto reductase (AKR) inhibitors have been developed as potential anticancer agents, some of which have shown promise in clinical trials. Many AKR inhibitors from natural sources also exhibit anticancer effects. Small molecule inhibitors targeting specific AKR isoforms have shown promise in preclinical studies. These inhibitors disrupt the activation of oncogenic signaling by modulating transcription factors and kinases and sensitizing cancer cells to chemotherapy. In this review, we discuss the physiological functions of human AKRs, the aberrant expression of AKRs in malignancies, the involvement of AKRs in the acquisition of cancer hallmarks, and the role of AKRs in oncogenic signaling, and drug resistance. Finally, the potential of aldose reductase inhibitors (ARIs) as anticancer drugs is summarized.

Gut microbial metalloproteins and its role in xenobiotics degradation and ROS scavenging.

The gut microbial metalloenzymes play an important role in maintaining the balance between gut microbial ecosystem, human physiologically processes and immune system. The metals coordinated into active site contribute in various detoxification and defense strategies to avoid unfavourable environment and ensure bacterial survival in human gut. Metallo-ß-lactamase is a potent degrader of antibiotics present in periplasmic space of both commensals and pathogenic bacteria. The resistance to anti-microbial agents developed in this enzyme is one of the global threats for human health. The organophosphorus eliminator, organophosphorus hydrolases have evolved over a course of time to hydrolyze toxic organophosphorus compounds and decrease its effect on human health. Further, the redox stress responders namely superoxide dismutase and catalase are key metalloenzymes in reducing both endogenous and exogenous oxidative stress. They hold a great importance for pathogens as they contribute in pathogenesis in human gut along with reduction of oxidative stress. The in-silico study on these enzymes reveals the importance of point mutation for the evolution of these enzymes in order to enhance their enzyme activity and stability. Various mutation studies were conducted to investigate the catalytic activity of these enzymes. By using the "directed evolution" method, the enzymes involved in detoxification and defense system can be engineered to produce new variants with enhance catalytic features, which may be used to predict the severity due to multi-drug resistance and degradation pattern of organophosphorus compounds in human gut.

Persistent organic pollutants disrupt the oxidant/antioxidant balance of INS-1E pancreatic ß-cells causing their physiological dysfunctions.

BACKGROUND: Persistent organic pollutants (POPs) have emerged as potent diabetogenic agents, but their mechanisms of action remain poorly identified. OBJECTIVES: In this study, we aim to determine the mechanisms regulating the damaging effects of POPs in pancreatic ß-cells, which have a central role in the development of diabetes. METHODS: We treated INS-1E pancreatic ß-cells with PCB-153, p,p'-DDE, PCB-126, or TCDD at doses ranging from 1 × 10-15to 5 × 10-6M. We measured insulin content and secretion, cell viability and assessed the mRNA expression of the xenobiotic nuclear receptors Nr1i2 and Nr1i3, and the aryl hydrocarbon receptor (Ahr). In addition, we evaluated the antioxidant defense and production of reactive oxygen species (ROS). Finally, we studied the ability of the antioxidant N-acetyl-L-cysteine (NAC) to counteract the effects of POPs in INS-1E cells. RESULTS: When exposed to environmental POP levels, INS-1E cells had impaired production and secretion of insulin. These defects were observed for all tested POPs and were paralleled by reduced Ins1 and Ins2 mRNA expression. While POP treatment for 3 days did not affect INS-1E cell viability, longer treatment progressively killed the cells. Furthermore, we found that the xenobiotic detoxification machinery is poorly expressed in the INS-1E cells, as characterized by the absence of Nr1i2 and Nr1i3 and their respective downstream targets Cyp3a1/Cyp3a2 and Cyp2b1/Cyp2b3, and the weak functionality of the Ahr/Cyp1a1 signaling. Interestingly, POPs dysregulated key antioxidant enzymes such as glutathione peroxidases, peroxiredoxins, thioredoxins, and catalases. In parallel, the production of intracellular ROS, including superoxide anion (O2•-) and hydrogen peroxide (H2O2), was increased by POP exposure. Improving the oxidant scavenging capacity of INS-1E cells by NAC treatment restored the production and secretion of insulin. CONCLUSION: By promoting oxidative stress and impairing the ability of INS-1E cells to produce and secrete insulin, this study reveals how POPs can mechanistically act as diabetogenic agents, and provides new scientific evidence supporting the concept that POPs are fueling the diabetes epidemics.

Diverse mechanisms by which chemical pollutant exposure alters gut microbiota metabolism and inflammation.

The human gut microbiome, the host, and the environment are inextricably linked across the life course with significant health impacts. Consisting of trillions of bacteria, fungi, viruses, and other micro-organisms, microbiota living within our gut are particularly dynamic and responsible for digestion and metabolism of diverse classes of ingested chemical pollutants. Exposure to chemical pollutants not only in early life but throughout growth and into adulthood can alter human hosts' ability to absorb and metabolize xenobiotics, nutrients, and other components critical to health and longevity. Inflammation is a common mechanism underlying multiple environmentally related chronic conditions, including cardiovascular disease, multiple cancer types, and mental health. While growing research supports complex interactions between pollutants and the gut microbiome, significant gaps exist. Few reviews provide descriptions of the complex mechanisms by which chemical pollutants interact with the host microbiome through either direct or indirect pathways to alter disease risk, with a particular focus on inflammatory pathways. This review focuses on examples of several classes of pollutants commonly ingested by humans, including (i) heavy metals, (ii) persistent organic pollutants (POPs), and (iii) nitrates. Digestive enzymes and gut microbes are the first line of absorption and metabolism of these chemicals, and gut microbes have been shown to alter compounds from a less to more toxic state influencing subsequent distribution and excretion. In addition, chemical pollutants may interact with or alter the selection of more harmful and less commensal microbiota, leading to gut dysbiosis, and changes in receptor-mediated signaling pathways that alter the integrity and function of the gut intestinal tract. Arsenic, cadmium, and lead (heavy metals), influence the microbiome directly by altering different classes of bacteria, and subsequently driving inflammation through metabolite production and different signaling pathways (LPS/TLR4 or proteoglycan/TLR2 pathways). POPs can alter gut microbial composition either directly or indirectly depending on their ability to activate key signaling pathways within the intestine (e.g., PCB-126 and AHR). Nitrates and nitrites' effect on the gut and host may depend on their ability to be transformed to secondary and tertiary metabolites by gut bacteria. Future research should continue to support foundational research both in vitro, in vivo, and longitudinal population-based research to better identify opportunities for prevention, gain additional mechanistic insights into the complex interactions between environmental pollutants and the microbiome and support additional translational science.

AI-driven discovery of blood xenobiotic biomarkers in neovascular age-related macular degeneration using iterative random forests.

PURPOSE: To investigate the xenobiotic profiles of patients with neovascular age-related macular degeneration (nAMD) undergoing anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy (IVT) to identify biomarkers indicative of clinical phenotypes through advanced AI methodologies. METHODS: In this cross-sectional observational study, we analyzed 156 peripheral blood xenobiotic features in a cohort of 46 nAMD patients stratified by choroidal neovascularization (CNV) control under anti-VEGF IVT. We employed Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for measurement and leveraged an AI-driven iterative Random Forests (iRF) approach for robust pattern recognition and feature selection, aligning molecular profiles with clinical phenotypes. RESULTS: AI-augmented iRF models effectively refined the metabolite spectrum by discarding non-predictive elements. Perfluorooctanesulfonate (PFOS) and Ethyl ß-glucopyranoside were identified as significant biomarkers through this process, associated with various clinically relevant phenotypes. Unlike single metabolite classes, drug metabolites were distinctly correlated with subretinal fluid presence. CONCLUSIONS: This study underscores the enhanced capability of AI, particularly iRF, in dissecting complex metabolomic data to elucidate the xenobiotic landscape of nAMD and environmental impact on the disease. The preliminary biomarkers discovered offer promising directions for personalized treatment strategies, although further validation in broader cohorts is essential for clinical application.

Mitochondrial injury induced by triclopyr in the rat liver.

The herbicide triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) is already considered an environmental problem due to damage caused by incorrect disposal, leaching, and aerial dispersion, which may pose risks to the environment and human health. Studies have evaluated metabolism, absorption, excretion, and active transport but there is no clear information about its mode of action (MoA) and its cytotoxic action potential remains unknown. In this context, mitochondria have been used to assess the toxicity of xenobiotics, for this reason, to identify the toxic mechanism of triclopyr, hepatic mitochondria from Wistar rats were exposed in vitro to different concentrations of triclopyr (0.5-500 µM). There was neither formation/accumulation of reactive oxygen and nitrogen species, nor lipid peroxidation or changes in the mitochondrial antioxidant system, in addition to proper functioning of oxidative phosphorylation and ATP production. Changes were found in NAD(P)H oxidation, membrane potential dissipation and mitochondrial calcium gradient. These results demonstrate that mitochondria suffer damage related to their bioenergetics and redox status but not to their structure when exposed to concentrations of triclopyr considered higher than those described as found in the environment so far.HighlightsTriclopyr has a low mitochondrial uncoupling potential.The damage caused to the bioenergetics and redox state of the mitochondria is related to concentrations considered higher than those found in the environment.Even at high concentrations, triclopyr was not able to change the structure of the organelle after exposure.Oxidative phosphorylation and ATP production were not impaired after exposure.NAD(P)H oxidation resulted in potential membrane dissipation and mitochondrial calcium gradient dissipation.Triclopyr does not have RONS-forming properties, as well as it does not peroxide membrane lipids, it preserves membrane sulfhydryl groups and maintains the normality of the GSH/GSSG ratio.

Microbial Symbiont-Based Detoxification of Different Phytotoxins and Synthetic Toxic Chemicals in Insect Pests and Pollinators.

Insects are the most diverse form of life, and as such, they interact closely with humans, impacting our health, economy, and agriculture. Beneficial insect species contribute to pollination, biological control of pests, decomposition, and nutrient cycling. Pest species can cause damage to agricultural crops and vector diseases to humans and livestock. Insects are often exposed to toxic xenobiotics in the environment, both naturally occurring toxins like plant secondary metabolites and synthetic chemicals like herbicides, fungicides, and insecticides. Because of this, insects have evolved several mechanisms of resistance to toxic xenobiotics, including sequestration, behavioral avoidance, and enzymatic degradation, and in many cases had developed symbiotic relationships with microbes that can aid in this detoxification. As research progresses, the important roles of these microbes in insect health and function have become more apparent. Bacterial symbionts that degrade plant phytotoxins allow host insects to feed on otherwise chemically defended plants. They can also confer pesticide resistance to their hosts, especially in frequently treated agricultural fields. It is important to study these interactions between insects and the toxic chemicals they are exposed to in order to further the understanding of pest insect resistance and to mitigate the negative effect of pesticides on nontarget insect species like Hymenopteran pollinators.