Mechanism Of Toxicity Research Articles

The effects of fumonisin B1 on intercellular communications and miRNA modulations: Non-genotoxic carcinogenesis mechanisms in human kidney cells

Fumonisin B1 (FB1), which is produced by Fusarium species, is one of the most prevalent mycotoxins known to exert several toxic effects, particularly nephrotoxicity. While its genotoxic carcinogenic mechanisms have been extensively studied, its influence on non-genotoxic pathways including intercellular communication and microRNA (miRNA) regulation remain underexplored. The present study investigates the effects of FB1 on gap junctions, miRNA expression profiles, and their relationship in human kidney cells (HK-2 and HEK293). Both cell lines showed increased apoptosis rates at 50 and 100 µM, while FB1 exposure significantly reduced gap junctional intercellular communication (GJIC) and decreased the expression levels of related genes, including Cx43, Cx45, e-cadherin, Cadherin-2, and β-catenin. After FB1 treatments alteration on the regulation of miRNAs including let-7a-5p, miR-125a-5p, miR-222–3p, miR-92a-3p, let-7b-5p, let-7e-5p, miR-21–5p, miR-155–5p, let-7i-5p, let-7d-5p, let-7f-5p, miR-181b-5p, miR-15b-5p, miR-23b-3p, miR-20b-5p, miR-196a-5p miRNAs have been shown. Let-7a-5p was selected among the altered miRNAs to elucidate the relationship between miRNAs and GJIC after FB1 exposure as it is one of the common miRNAs that changes in both cell lines and one of its target genes is Cx45, which is an important gene for GJIC. However, transfection analysis did not show any differences, resulting in Cx45 not being a direct target of let-7a-5p in HK-2 and HEK-293 cells. Through comprehensive analysis, we elucidated that FB1's impact on intercellular signaling cascades and its regulatory role on miRNA expression profiles, offering valuable insights into carcinogenesis beyond traditional genotoxic paradigms. Understanding these mechanisms is crucial for elucidating the mechanisms of FB1-induced toxicity.

Association between blood total mercury and psoriasis: The NHANES 2005-2006 and 2013-2014: A cross-sectional study.

An inflammatory skin condition called psoriasis results from immune system interactions that are out of balance. Reactive oxygen species are produced as a general mechanism of mercury toxicity. This study aimed to determine whether there was an association between blood total mercury and psoriasis in US adults. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2005-2006 and 2013-2014. NHANES is a national research survey program every two years to assess the population's nutritional and physical health. The relationship between blood total mercury and psoriasis was studied using multivariable logistic regression models and smooth curve fitting. Subgroup analysis and interaction tests were used to investigate if this association was stable across populations. After adjusting for several factors, we found a positive association between blood total mercury and psoriasis in 6086 participants. According to the fully adjusted model, each 1-unit increase in blood total mercury was associated with an 8% increase in the prevalence of psoriasis [1.08 (1.03, 1.14)]. The favorable association seems to be more pronounced in non-diabetes. Our research shows a positive association between psoriasis and blood total mercury in US adults. The results of this study need to be supported by additional prospective research.

Chemical screens for particle-induced macrophage death identifies kinase inhibitors of phagocytosis as targets for toxicity

BackgroundNanoparticles are increasingly being used in medicine, cosmetics, food, and manufacturing. However, potential toxicity may limit the use of newly engineered nanoparticles. Prior studies have identified particle characteristics that are predictive of toxicity, although the mechanisms responsible for toxicity remain largely unknown. Nanoparticle treatment in cell culture, combined with high-throughput chemical screen allows for systematic perturbations of thousands of molecular targets against potential pathways of toxicity. The resulting data matrix, called chemical compendium, can provide insights into the mechanism of toxicity as well as help classify nanoparticles based on toxicity pathway.ResultsWe performed unbiased screens of 1280 bioactive chemicals against a panel of four particles, searching for inhibitors of macrophage toxicity. Our hit compounds clustered upon inhibitors of kinases involved in phagocytosis, including focal adhesion kinase (FAK), with varying specificity depending on particles. Interestingly, known inhibitors of cell death including NLRP3 inflammasome inhibitor were unable to suppress particle-induced macrophage death for many of the particles. By searching for upstream receptors of kinases, we identified Cd11b as one of the receptors involved in recognizing a subset of particles. We subsequently used these hit compounds and antibodies to further characterize a larger panel of particles and identified hydrodynamic size as an important particle characteristic in Cd11b-mediated particle uptake and toxicity.ConclusionsOur chemical compendium and workflow can be expanded across cell types and assays to characterize the toxicity mechanism of newly engineered nanoparticles. The data in their current form can also be analyzed to help design future high-throughput screening for nanoparticle toxicity.Graphical abstract

Toxicity of parental co-exposure of microplastic and bisphenol compounds on adult zebrafish: Multi-omics investigations on offspring

In recent years, the widespread use of bisphenol compounds and microplastics (MP) have attracted attention due to their harmful effects. Here, individual and combined effects of MP and bisphenol compounds, were assessed on adult zebrafish after co-exposure of bisphenol A (BPA) or bisphenol S (BPS) and 25 μm polyethylene MP. Impacts on their offspring (the F1 generation) were also investigated. The reproductive toxicity in adult zebrafish impacted exerted by bisphenol compounds were aggravated by the co-presence of MP. Transcriptomics and metabolomics further showed single or co-exposure of bisphenol compounds and MP could together regulate apoptosis, calcium signaling pathway and glycerophospholipid signaling pathways. Our results also showed the different toxicity mechanisms on transcriptional and metabolic profiles in the combination effects of bisphenol compounds and MP. The co-exposure of BPA and MP predominantly influenced neurotoxicity via the MAPK signaling pathway and voltage-dependent calcium channels, whereas the co-exposure of BPS and MP principally affected visual development through phototransduction and retinol metabolism. The co-exposure of BPA and MP, as well as BPS and MP, specifically regulate lipid metabolism and carbohydrate metabolism in zebrafish offspring, respectively. Overall, this study provided a deep understanding of the toxicity differences between co-exposure and single exposure of bisphenol compound and MP in zebrafish, as well as the transgenerational effects and potential molecular mechanisms of bisphenol compounds and MP in zebrafish offspring.

Metabolomic Profiling and Network Toxicology: Mechanistic Insights into Effect of Gossypol Acetate Isomers in Uterine Fibroids and Liver Injury

Objective: Gossypol is a natural polyphenolic dialdehyde product that is primarily isolated from cottonseed. It is a racemized mixture of (−)-gossypol and (+)-gossypol that has anti-infection, antimalarial, antiviral, antifertility, antitumor and antioxidant activities, among others. Gossypol optical isomers have been reported to differ in their biological activities and toxic effects. Method: In this study, we performed a metabolomics analysis of rat serum using 1H-NMR technology to investigate gossypol optical isomers’ mechanism of action on uterine fibroids. Network toxicology was used to explore the mechanism of the liver injury caused by gossypol optical isomers. SD rats were randomly divided into a normal control group; model control group; a drug-positive group (compound gossypol acetate tablets); high-, medium- and low-dose (−)-gossypol acetate groups; and high-, medium- and low-dose (+)-gossypol acetate groups. Result: Serum metabolomics showed that gossypol optical isomers’ pharmacodynamic effect on rats’ uterine fibroids affected their lactic acid, cholesterol, leucine, alanine, glutamate, glutamine, arginine, proline, glucose, etc. According to network toxicology, the targets of the liver injury caused by gossypol optical isomers included HSP90AA1, SRC, MAPK1, AKT1, EGFR, BCL2, CASP3, etc. KEGG enrichment showed that the toxicity mechanism may be related to pathways active in cancer, such as the PPAR signaling pathway, glycolysis/glycolysis gluconeogenesis, Th17 cell differentiation, and 91 other closely related signaling pathways. Conclusions: (−)-gossypol acetate and (+)-gossypol acetate play positive roles in the treatment and prevention of uterine fibroids. Gossypol optical isomers cause liver damage through multiple targets and pathways.

Chemical Characteristics of Zirconium Chloride and Zirconium Oxide Nanoparticles Driving Toxicity on Lemna minor

The increasing global production and utilization of zirconium (Zr) compounds, including zirconium chloride (ZrCl4) and zirconium oxide nanoparticles (NPs-ZrO2), raises concerns about their potential environmental impact. This study investigated the toxicity mechanisms of ZrCl4 and NPs-ZrO2 on the aquatic plant Lemna minor. The physicochemical properties of NPs-ZrO2 in the test medium were characterized, revealing concentration-dependent changes in the hydrodynamic diameter, zeta potential, and solubility over time. The analysis of Zr speciation showed the predominance of Zr(OH)4(aq) species from ZrCl4. Plants of L. minor exposed to ZrCl4 and NPs-ZrO2 exhibited differential Zr bioaccumulation, growth inhibition, oxidative stress, and antioxidant responses. ZrCl4 induced a higher toxicity than NPs-ZrO2, with bioaccumulation strongly correlating with adverse effects. The differential toxicity impact between these two Zr-compounds was also determined by the lowest observed-effect doses for growth and biochemical parameters. The scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy confirmed internalization of NPs-ZrO2 and Zr uptake in the L. minor plant. Therefore, these findings highlighted the importance of chemical speciation, environmental transformations, and biological responses in assessing the ecological impact of Zr-compounds for effective risk assessment and management strategies for protecting aquatic ecosystems.

Unraveling the risks of nAl2O3 on harmful algal blooms: Insights from paralytic shellfish toxins production of Alexandrium tamarense

As one of the commonly used and cost-effective nanomaterials, nanosized aluminum oxide (nAl2O3) posses unique properties and chemical stability. However, its extensive use and resultant dissemination into aquatic ecosystems prompt concerns over the proliferation and repercussions of harmful algal blooms, particularly those caused by dinoflagellates producing toxins. This study investigated the sub-chronic effects of nAl2O3 on growth, physiological activities, and paralytic shellfish toxins (PSTs) production in Alexandrium tamarense. Results showed dose-dependent inhibition in growth (EC50 = 20.6 mg L−1), esterase activity, and photosynthetic efficiency (Fv/Fm) during the sub-chronic exposure (13-day). The internalization of nAl2O3 in microalgal cells and the significant decrease in the total cellular PSTs content were observed under high nAl2O3 concentrations (>40 mg L−1). The study also demonstrated a clear decrease in the content of some derivatives of PSTs (GTX5, C1/2, and GTX2/3) with the increase in nAl2O3 concentrations, accompanied by the induction of an unknown derivative. Excessive ROS production, dissolved Al, and physical inhibition were suggested as potential mechanisms for nAl2O3 toxicity and changes in PSTs toxin profile. Overall, this research enhances our understanding of the potentiated risks and threats on the possible concurrent events of toxic dinoflagellate, such as Alexandrium species and nanoparticles in aquatic environments.

Sight of Aged Microplastics Adsorbing Heavy Metal Exacerbated Intestinal Injury: A Mechanistic Study of Autophagy-Mediated Toxicity Response.

Contaminant-bearing polystyrene microplastics (PSMPs) may exert significantly different toxicity profiles from their contaminant-free counterparts, with the role of PSMPs in promoting contaminant uptake being recognized. However, studies investigating the environmentally relevant exposure and toxic mechanisms of aged PSMPs binding to Cr are limited. Here, we show that loading of chromium (Cr) markedly alters the physicochemical properties and toxicological profiles of aged PSMPs. Specifically, Cr-bearing aged PSMPs induced severe body weight loss, oxidative stress (OS), autophagy, intestinal barrier injury, inflammation-pyroptosis response, and enteropathogen invasion in mice. Mechanistic investigations revealed that PSMPs@Cr exacerbated the OS, resulting in intestinal barrier damage and inflammation-pyroptosis response via overactivated Notch signaling and autophagy/cathepsin B/IL-1β pathway, respectively, which ultimately elevated mortality related to bacterial pathogen infection. In vitro experiments confirmed that autophagy-mediated reactive oxygen species (ROS) overproduction resulted in severe pyroptosis and impaired intestinal stem cells differentiation alongside the overactivation of Notch signaling in PSMPs@Cr-exposed organoids. Overall, our findings provide an insight into autophagy-modulated ROS overproduction within the acidic environment of autophagosomes, accelerating the release of free Cr from PSMPs@Cr and inducing secondary OS, revealing that PSMPs@Cr is a stable hazard material that induces intestinal injury. These findings provided a potential therapeutic target for environmental MPs pollution caused intestinal disease in patients.

Synthesis of chlorotoxin functionalized metallic nanoparticles and their in vitro evaluation of cytotoxic effects in nervous system cancer cell lines

The treatment of glioblastoma (GB) and neuroblastoma (NB) remains a challenge, as current chemotherapies are plagued with systemic toxicity, drug resistance, and inadequate blood–brain barrier (BBB) penetration. Therefore, novel therapeutic strategies with high specificity and the capacity to bypass the BBB are required. Chlorotoxin (CTX) selectively targets gliomas and neuroectodermal tumors, hence the use of CTX-targeted nanoparticles (NPs) represents a promising therapeutic approach for nervous system (NS) cancers. Bimetallic NPs composed of two metals such as gold-platinum NPs (AuPtNPs) exhibit enhanced anticancer properties compared to single-metal NPs, however their application in studying NS tumors has been relatively limited. CTX-functionalized monometallic gold NPs (CTX-AuNPs) and bimetallic gold-platinum NPs (CTX-AuPtNPs) were synthesized in this study. The NPs were characterized by Ultraviolet-Visible Spectroscopy (UV–vis), Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM) and Fourier Transform Infra-Red Spectroscopy (FTIR). Cytotoxicity of NPs was investigated in cancer (U87 and SH-SY5Y) and non-cancer (KMST-6) cells using the water-soluble tetrazolium (WST)-1 assay. The CTX-AuNPs and CTX-AuPtNPs had a core size of ∼5 nm. The CTX-AuPtNPs showed significant anticancer activity in U87 cells possibly due to the synergistic effects of combined metals. Findings obtained from this study demonstrated that CTX can be used to target NS cancers and that bimetallic NPs could be effective in their treatment. More studies are required to investigate the mechanisms of NPs toxicity, and further explore the hyperthermia treatment of NS cancer using the CTX-AuPtNPs.

Response and adaptation of Chlorella pyrenoidosa to 6PPD: Physiological and genetic mechanisms

The extensive contamination of the tire antidegradant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) in aquatic environments have raised concerns about its potential threats to aquatic organisms. Here, the responses of green algae Chlorella pyrenoidosa (C. pyrenoidosa) to 6PPD exposure were investigated for the first time. The growth of C. pyrenoidosa experienced three sequential phases, including inhibition, recovery and stimulation. Physiological and transcriptome analysis suggested that the growth inhibition was associated with the suppressed nitrogen assimilation and amino acid biosynthesis pathways, among which nitrate transporter (NRT) 2.1 was a key target of 6PPD. Molecular docking revealed the steadily binding of 6PPD to the substrate entry region of NRT 2.1 via hydrogen bonds and π − cation interaction, blocking the acquisition of extracellular inorganic nitrogen. Along with the removal of 6PPD through abiotic processes and biodegradation, an adaptive metabolic shift in cells not only facilitated growth recovery but also triggered a compensatory stimulation phase. With regard to microalgal adaptation, upregulated DNA replication and repair pathways served to maintain the integrity of the genetic information, enhanced photosynthesis cascades and central carbon metabolism improved carbon flux and energy conversion to microalgal biomass, recovered amino acid biosynthesis produced essential proteins for multiple metabolisms. The results provide new insights into microalgal molecular responses to 6PPD exposure, facilitating a better understanding of ecological consequences of 6PPD in the environment.

Meet-in-metabonomics: Insights into associations between hair heavy metal and adverse child growth in e-waste recycling area

Heavy metal pollution from informal e-waste recycling may adversely affect child growth. However, the potential toxic mechanisms from a population perspective remain unknown. Herein, 18 hair heavy metals, urinary metabolomics, and three child growth indices [i.e., weight-for-age Z-score (WAZ), height-for-age Z-score (HAZ), and BMI Z-score (BMIZ)] were measured in children from e-waste recycling (ER, N = 426) and control areas (CR, N = 247). We examined longitudinal changes in heavy metal exposure and child growth after e-waste control to further elucidate causal relationships. Results showed that children in regulated ER site were still exposed to higher levels of several heavy metals and experienced poorer growth compared to those in control areas. Elevated exposure to heavy metals like tin, antimony, lead, cadmium, and cobalt correlated with poor child growth, particularly affecting girls and younger children. Tin, rather than traditionally concerning heavy metals, exhibited the most crucial role in driving the adverse effects of metal mixtures on child growth. Reducing heavy metal exposure through e-waste control could notably improve child growth, confirming the causal relationship between heavy metal exposure and poor child growth and underscoring the health benefits of e-waste regulation. Our research identified the roles of steroid biosynthesis, folate biosynthesis, amino acid metabolism, and purine metabolism in mediating the effects of metal exposure on child growth. Testosterone glucuronide, riboflavin, folic acid, xanthosine, and xanthine emerged as key mediators, potentially serving as metabolic signatures of heavy metal exposure. These findings illuminate the toxic mechanisms underlying poor child growth resulted from heavy metal exposure, offering important insights from a population-based perspective. In addition to lead and cadmium, monitoring and regulating tin and antimony are crucial to mitigate their negative impact on child growth in e-waste recycling areas.

Untargeted Metabolite Profiling Reveals Acute Toxicity of Pentosidine on Adipose Tissue of Rats.

Background: Pentosidine is an advanced glycation end product that is commonly found in heat-processed foods. Pentosidine has been involved in the occurrence and development of some chronic diseases. It was reported that pentosidine exposure can impair the function of the liver and kidneys. Adipose tissue, as an active endocrine organ, plays an important role in maintaining the normal physiological function of cells. However, the metabolic mechanism that causes pentosidine to induce toxicity in adipose tissue remains unclear. Methods: In the study, thirty male Sprague-Dawley rats were divided into a normal diet group, low dose group, and high dose group. A non-targeted metabolomics approach was used to compare the metabolic profiles of adipose tissue between the pentosidine and normal diet groups. Furthermore, histopathological observation and body weight change analysis were performed to test the results of the metabolomics analysis. Results: A total of forty-two differential metabolites were identified. Pentosidine mainly disturbed twelve metabolic pathways, such as ascorbate and aldarate metabolism, glycine, serine, and threonine metabolism, sulfur metabolism, pyruvate metabolism, etc. Additionally, pyruvic acid was identified as a possible key upregulated metabolite involved in thirty-four metabolic pathways. α-Ketoglutaric acid was named as a probable key downregulated metabolite involved in nineteen metabolic pathways based on enrichment network analysis. In addition, histopathological analysis and body weight changes confirmed the results of the metabolomics analysis. Conclusions: These results provided a new perspective for the molecular mechanisms of adipose tissue toxicity induced by pentosidine.

A tiered toxicity testing strategy for assessing early life stage toxicity in estuarine fish (Mugilogobius chulae): A case study on tris (1-chloro-2-propyl) phosphate ester

The estuarine ecological environment faces significant threats from contaminants of emerging concern (CECs); yet, the risk posed by CECs to resident organisms remains poorly understood. Here, we employed tiered toxicity testing to investigate the adverse effects and potential mechanisms of tris (1-chloro-2-propyl) phosphate (TCPP) on the early life stages of an estuarine fish, Mugilogobius chulae. TCPP affected the development of M. chulae embryos, including survival, morphology, hatching, and behavior. A concentration-dependent transcriptomic analysis showed that TCPP disrupted 12 neurodevelopment-related KEGG pathways in M. chulae embryos, with five of the 30 % top-ranked pathways related to neurotransmitter signaling. Besides the cholinergic synapse signaling pathway, the glutamatergic signaling pathway (including NMDAR and AMPAR subtypes) may also mediate TCPP-induced neurodevelopmental toxicity. The NMDAR subtype GRIN2B was downregulated at high concentrations. Molecular dynamics simulations revealed a strong interaction between TCPP and GRIN2B, with TCPP binding to the residues Ile153 and Ile188. The results suggest that NMDARs play a crucial role in TCPP-induced neurodevelopmental toxicity toward M. chulae. AOP network analysis predicted that TCPP may impact cognitive functions and memory. Our study provides a novel testing strategy for identifying the mechanisms of toxicity of CECs, a crucial component of ecological risk assessment.

New Insights into the Mechanisms of Toxicity of Aging Microplastics.

Nowadays, synthetic polymer (plastic) particles are ubiquitous in the environment. It is known that for several decades microplastics (MPs) have been accumulating in the World Ocean, becoming available to a large variety of marine organisms. Particularly alarming is the accumulation of aging plastic particles, as the degradation processes of such particles increase their toxicity. The diverse display of negative properties of aging MPs and its effect on biota are still poorly understood. In this study, in vitro experiments modeling the interaction of pristine and UV-irradiated aging polypropylene (PP) fragments with hemocytes and mitochondria of bivalve mollusks Mytilus sp. were performed. The appearance of free radicals in the environment was recorded by spectral characteristics of indicator dyes-methylene blue (MB) and nitroblue tetrazolium (NBT). It was found that due to photooxidation, aging PP fragments sorbed more than threefold MB on their modified surface compared to pristine samples of this polymer. Using NBT, the formation of reactive oxygen species in seawater in the presence of pristine and photoactivated PP was recorded. It was also found that photodegraded PP fragments largely stimulated the development of lipid peroxidation processes in mitochondrial membranes and reduced the stability of hemocyte lysosome membranes compared to pristine PP fragments. In general, the results obtained concretize and supplement with experimental data the previously stated hypothesis of toxicity of aging MPs.

Flavor compound geraniol induces inhibited nutrient utilization and developmental toxicity on embryonic–larval zebrafish

AbstractFlavors are widely utilized in the food and oral pharmaceutical industry, particularly in products for children, to enhance palatability and promote ingestion willingness. The complex compositions of flavors potentially induce severer toxicity especially in children. In this study, zebrafish embryos are applied for toxicity screening of flavor and its compounds by immersing in flavor solutions followed by the assessment of morphology of zebrafish larvae. Geraniol is identified as the prominent toxic compound and is considered highly toxic to zebrafish embryo. In further toxicology study, geraniol demonstrates the concentration‐dependent developmental toxicity as the obvious reduction of body and eye lengths, as well as the increased prevalence of tail deformities, pericardial edema, and spine deformation. Zebrafish larvae treated with geraniol exhibit reduction in liver area and exocrine pancreas length, increase in yolk sac area, as well as elevation of triglycerides and total cholesterol, which indicate the inhibited nutrient utilization. Transcriptome analysis reveals that under geraniol treatment, 248 differentially expressed genes (DEGs) are downregulated, whereas 23 DEGs are upregulated, and 110 DEGs are related to metabolic process. Biological processes of lipid metabolism, carbohydrate metabolism, protein hydrolysis, and transmembrane transport, including their involved functional genes, are all downregulated. These findings reveal the developmental toxicity of geraniol by affecting the nutrient utilization‐related organs development and biological processes. This study establishes an efficient screening model for identifying toxic flavor compounds during developing stages, thereby elucidating the potential safety risks of geraniol exposure in zebrafish and providing a comprehensive understanding of its potential toxicity mechanism.

Ozone-Induced Lung Injury are Mediated Via PPAR-Mediated Ferroptosis in Mice.

In recent years, the concentration of PM2.5 in China has decreased, while the concentration of ozone remains rising. Exposure to ozone contributes to respiratory illnesses; however, little is known about the underlying molecular mechanisms. The present study established an ozone-induced lung injury mice model to investigate potential molecular biomarkers and toxic mechanisms. Collected and analyzed the ozone pollution data in Xinxiang city from 2015 to 2022. At the same time, 24 male C57BL/6 mice were randomly assigned to control group and ozone exposure group. The ozone exposure concentration is 1ppm, with 4h of daily exposure for 33 consecutive days. HE staining was used to assess lung histological alterations and lung injury. High-throughput sequencing performed on the lung tissues of mice was used to analyze the differential expressed genes and signal transduction pathways. Xinxiang city is suffering from ozone pollution, especially in summer. HE staining showed that the ozone exposure could induce obvious inflammatory cell infiltration, alveolar wall thickening, or fracture. Transcriptome data revealed that there is a 145 differentially expressed genes between two groups and the genes enriched in PPAR signaling pathway, ferroptosis. The pivotal genes in the PPAR pathway including Adipoq, Lpl, Pck1, and Plin1 expression were significantly reduced. Additionally, the expression of Acsl6 and Scl7a11, which are close to PPAR pathway and ferroptosis has decreased. Ozone exposure could disrupt the lipid metabolism balance via downregulating lipid peroxidation-related genes through the PPAR signaling pathway, which further induced lung cell ferroptosis and aggravated lung injury in mice.

8421 The Effect of Dietary Glycotoxins on Insulin Resistance in Polycystic Ovary Syndrome

Abstract Disclosure: A. Weidner: None. K. Vann: None. J. Zhang: None. A. Roy: None. O. Astapova: None. Polycystic ovary syndrome (PCOS) is a chronic systemic disorder that affects both metabolism and reproduction. PCOS is characterized by hyperandrogenism and insulin resistance, which are closely intertwined in this disease pathophysiology. PCOS affects an estimated 10% of people with ovaries and increases risk of endometrial cancer, type 2 diabetes, and major cardiovascular events. Furthermore, treatment options are generally poorly tolerated. Despite its prevalence, severity, and enormous public health burden, the etiology of PCOS is not well-understood. Insulin resistance likely plays a central role in PCOS pathogenesis, and often leads to hyperinsulinemia as the pancreas attempts to compensate for insulin’s decreased efficacy in the body. Moreover, the Western diet is becoming increasingly rich in advanced glycation end products (AGEs): non-enzymatically modified biomolecules that have recently been found to have a harmful effect on insulin sensitivity and are associated with diabetes, aging, and oxidative stress. Serum AGE levels have been reported to be higher in both lean and obese PCOS patients, regardless of PCOS subtype. We have also found higher levels of AGE precursors in the serum of our chronic dihydrotestosterone-induced mouse model of PCOS. Using this mouse model, we have shown that ovarian granulosa cells (GCs) remain insulin-sensitive despite systemic insulin resistance and hyperinsulinemia, manifested by impaired glucose tolerance and increased HOMA-IR. To assess whether GCs respond to insulin through alternative receptor pathways, we knocked down insulin receptor in human granulosa-derived KGN cells and found that insulin-stimulated AKT phosphorylation was only minimally reduced, suggesting that insulin may signal in large part through the insulin-like growth factor 1 receptor (IGF1R) in these cells. Therefore, we believe that compensatory hyperinsulinemia plays a key role in chronic GC hyperstimulation, possibly by rerouting the insulin signal through IGF1R to overcome the resistance to insulin receptor activation, suggesting a mechanism for AGE toxicity in PCOS. We hypothesize that in PCOS, this results in impaired GC function and exacerbation of ovarian dysfunction. We will use our PCOS mouse model to study the effects of a reduced-AGE diet in ameliorating the reproductive and metabolic phenotype of an androgenized PCOS mouse. In preliminary experiments, we have found that a low-AGE diet results in lower fasting glucose in C57BL/6J mice after only 4 weeks. We expect that reproductive symptoms, such as estrous cyclicity, and metabolic symptoms, such as GTT and circulating insulin, will improve in our PCOS mouse model when mice are fed a low-AGE diet throughout development and adulthood. This project has significant clinical implications, as reducing dietary AGEs could provide an effective, tolerable, non-drug therapy option for patients with PCOS. Presentation: 6/3/2024

Adverse Outcomes Following Exposure to Perfluorooctanesulfonamide (PFOSA) in Larval Zebrafish (Danio rerio): A Neurotoxic and Behavioral Perspective.

Toxicity mechanisms of per- and polyfluoroalkyl substances (PFASs), a chemical class present in diverse ecosystems, as well as many of their precursors, have been increasingly characterized in aquatic species. Perfluorooctanesulfonamide (PFOSA, C8H2F17NO2S) is a common precursor of perfluorooctane sulfonic acid (PFOS), a long-chain PFAS. Here, we assessed sub-lethal endpoints related to development, oxidative stress, transcript levels, and distance moved in zebrafish embryos and larvae following continuous exposure to PFOSA beginning at 6 h post-fertilization (hpf). PFOSA decreased survival in fish treated with 1 µg/L PFOSA; however, the effect was modest relative to the controls (difference of 10%). Exposure up to 10 µg/L PFOSA did not affect hatch rate, nor did it induce ROS in 7-day-old larvae fish. The activity of larval fish treated with 100 µg/L PFOSA was reduced relative to the solvent control. Transcripts related to oxidative stress response and apoptosis were measured and BCL2-associated X, apoptosis regulator (bax), cytochrome c, somatic (cycs), catalase (cat), superoxide dismutase 2 (sod2) were induced with high concentrations of PFOSA. Genes related to neurotoxicity were also measured and transcript levels of acetylcholinesterase (ache), elav-like RNA binding protein 3 (elavl3), growth-associated protein 43 (gap43), synapsin II (syn2a), and tubulin 3 (tubb3) were all increased in larval fish with higher PFOSA exposure. These data improve our understanding of the potential sub-lethal toxicity of PFOSA in fish species.

Acute toxicity of salicylic acid and its derivatives on the diatom Phaeodactylum tricornutum: Physico-Biochemical and transcriptomic insights

Salicylate pollutants (SAs) poses a serious threat to marine ecosystems as emerging contaminants. However, the toxic effects of SAs on marine phytoplankton, as well as the potential mechanisms and their ecological risks linked with them, are remain largely unknown. In this study, we aimed to evaluate the toxic effects of salicylic acid (SA) and its 5-substituted derivatives (5-sSA) on the marine diatom Phaeodactylum tricornutum, as well as the potential molecular mechanism involved in the toxicity. Physiological assays conducted on P. tricornutum revealed significant changes in photosynthetic pigments, chlorophyll fluorescence parameters, and antioxidant enzyme activities. The results showed that exposure of P. tricornutum to SAs caused a significant decline in chlorophyll contents and damage to the photosystem II (PSII) core resulting in the decline of photosynthesis. Although the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were enhanced, oxidative damage occurred. Transcriptome analysis showed that a large number of differentially expresses genes (DEGs) were significantly enriched in metabolic pathways such as porphyrin metabolism, terpenoid backbone biosynthesis, and carbon fixation in photosynthetic organisms after SA and 5-BrSA treatments. In addition, key genes in transcriptomic metabolic pathways were further analyzed and validated using weighted correlation network analysis (WGCNA) and real-time fluorescence quantitative PCR (qPCR). Considering the above results, SAs mainly inhibit the processes of photosynthesis by repressing the expression of genes involved in secondary metabolite synthesis and photosynthetic carbon sequestration pathways, thus exerting toxic effects on algal cells. The results of the study will provide key data for understanding the ecological risk and toxicity mechanisms of SA pollutants.

Cytotoxic Potencies of Zinc Oxide Nanoforms in A549 and J774 Cells.

Zinc oxide nanoparticles (NPs) are used in a wide range of consumer products and in biomedical applications, resulting in an increased production of these materials with potential for exposure, thus causing human health concerns. Although there are many reports on the size-related toxicity of ZnO NPs, the toxicity of different nanoforms of this chemical, toxicity mechanisms, and potency determinants need clarification to support health risk characterization. A set of well-characterized ZnO nanoforms (e.g., uncoated ca. 30, 45, and 53 nm; coated with silicon oil, stearic acid, and (3-aminopropyl) triethoxysilane) were screened for in vitro cytotoxicity in two cell types, human lung epithelial cells (A549), and mouse monocyte/macrophage (J774) cells. ZnO (bulk) and ZnCl2 served as reference particles. Cytotoxicity was examined 24 h post-exposure by measuring CTB (viability), ATP (energy metabolism), and %LDH released (membrane integrity). Cellular oxidative stress (GSH-GSSG) and secreted proteins (targeted multiplex assay) were analyzed. Zinc oxide nanoform type-, dose-, and cell type-specific cytotoxic responses were seen, along with cellular oxidative stress. Cell-secreted protein profiles suggested ZnO NP exposure-related perturbations in signaling pathways relevant to inflammation/cell injury and corresponding biological processes, namely reactive oxygen species generation and apoptosis/necrosis, for some nanoforms, consistent with cellular oxidative stress and ATP status. The size, surface area, agglomeration state and metal contents of these ZnO nanoforms appeared to be physicochemical determinants of particle potencies. These findings warrant further research on high-content "OMICs" to validate and resolve toxicity pathways related to exposure to nanoforms to advance health risk-assessment efforts and to inform on safer materials.