Environmental Toxins Research Articles

Fluoride induces pyroptosis via IL-17A-mediated caspase-1/11-dependent pathways and Bifidobacterium intervention in testis

Fluoride, a ubiquitous environmental pollutant, poses a significant public health threat. Our previous study revealed a correlation between fluoride-induced testicular pyroptosis and male reproductive dysfunction. However, the underlying mechanism remains unclear. Wild-type and interleukin 17 A knockout mice were exposed to sodium fluoride (100 mg/L) in deionized drinking water for 18 weeks. Bifidobacterium intervention (1 × 109 CFU/ml, 0.2 ml/day, administered via gavage) commenced in the 10th week. Sperm quality, testicular morphology, key pyroptosis markers, spermatogenesis key genes, IL-17A signaling pathway, and pyroptosis pathway related genes were determined. The results showed that fluoride reduced sperm quality, damaged testicular morphology, affected spermatogenesis, elevated IL-17A levels, and induced testicular pyroptosis. Bifidobacterium intervention alleviated adverse reproductive outcomes. Fluoride-activated testicular pyroptosis through both typical and atypical pathways, with IL-17A involvement. Bifidobacterium supplementation attenuated pyroptosis by downregulating IL-17A, inhibiting NLRP3 and PYRIN-mediated caspase-1 and caspase-11 dependent pathways in testis, thereby alleviating fluoride-induced male reproductive damage. In summary, this study uncovers the mechanism underlying fluorine-induced testicular pyroptosis and illustrates the novel protecting feature of Bifidobacterium against fluoride-induced harm to male reproduction, along with its potential regulatory mechanism. These results provide fresh perspectives on treating male reproductive dysfunction resulting from fluoride or other environmental toxins.

Farming activities and risk of inflammatory bowel disease: a French nationwide population-based cohort study.

Epidemiological data regarding inflammatory bowel disease (IBD) are lacking, in particular for occupationally exposed populations. We investigated whether, among the entire French farm manager (FM) workforce, certain agricultural activities are more strongly associated with IBD than others. Nationwide population-based insurance claims and electronic health records from all FMs that worked at least once over the period 2002-2016 were used (n=1088561, 69% males). The outcome measure was the association between 26 farming activities and the risk of IBD, Crohn's disease (CD), and ulcerative colitis (UC), measured as hazard ratios (HRs), after adjusting for age, sex, pre-existing medical comorbidities, and farm location. The time to first chronic disease declaration was used as the underlying timescale. A model was generated for every activity and disease, utilizing a reference group comprising all FMs who abstained from the specified activity from 2002 to 2016. There were 1752 IBD cases, with 704 CD (40.2%) and 1048 UC (59.8%) cases, respectively. Elevated HRs were observed for fruit arboriculture (HR from 1.17 to 1.52) and dairy farming (HR from 1.22 to 1.46) for all IBD, in crop farming for CD only (HR=1.26 [95CI%: 1.06-1.49]), and in shellfish farming (HR from 2.12 to 2.51) for both CD and IBD. Further research regarding specific farming activities and exposures likely to modify the microbiota (e.g., pesticides, pathogens) is required to identify potential occupational risk factors (agricultural exposome) for IBD. Exposure to Mycobacterium avium subspecies paratuberculosis, cryptosporidium, environmental toxins, micro/nanoplastics, and pesticides represents promising research avenues.

Impact of Quercetin and Omega-3 Fatty-Acid on Lead-Induced Alterations in Reproductive Parameters in Male Wistar Rats

Exposure to environmental toxins like Lead has been associated with male infertility. Whether or not potent antioxidants like omega 3 Fatty acids and/or quercetin could reduce the effect of lead on male sexual functions deserve scientific investigation. Thirty-five (35) male albino Wistar rats were assigned into 7 groups: Group 1 (normal control), Group 2 (sham-control1), Group 3 (sham-control 2), Group 4 (Lead group), Group 5 (Lead + Omega-3), Group 6 (Lead + Quercetin) and Group 7 (Lead + Omega-3 + Quercetin). Lead was given orally at 20mg/kg bwt, quercetin 20mg/kg bwt s.c, Omega-3 14.29mg/kg bwt orally. The animals all had free access to rat food and water for 56 days. After which they were sacrificed, and semen and blood samples were collected for assay. The results showed no significant difference between normal control group and sham controls. Sperm function parameters (sperm count, motile, viable and normal sperms) in the lead treated group was significantly reduced compared to the control. Omega 3 and/or quercetin administration reversed the reductions in sperm function parameters to near control levels. Hormone levels (LH and Testosterone) were significantly reduced in lead group compared to the normal control but were reversed after quercetin and omega 3 treatment. However, there was no significant difference in the FSH level among experimental groups. Conclusively, omega 3 and/or quercetin ameliorates the harmful effects of lead on reproductive parameters by improving sperm functions (total sperm count, viability, motility, and morphology). A combination of both quercetin and omega 3 provided better ameliorative effect than either omega 3 or quercetin.

Case-control study of environmental toxins and risk of amyotrophic lateral sclerosis involving the national ALS registry

Objective: Neurotoxic chemicals are suggested in the etiology of amyotrophic lateral sclerosis (ALS). We examined the association of environmental and occupational risk factors including persistent organochlorine pesticides (OCPs) and ALS risk among cases from the Centers for Disease Control and Prevention National ALS Registry and age, sex, and county-matched controls. Methods: Participants completed a risk factor survey and provided a blood sample for OCP measurement. ALS cases were confirmed through the Registry. Conditional logistic regression assessed associations between ALS and risk factors including OCP levels. Results: 243 matched case-control pairs (61.7% male, mean [SD] age = 62.9 [10.1]) were included. Fifteen of the 29 OCPs examined had sufficient detectable levels for analysis. Modest correlations of self-reported years of exposure to residential pesticide mixtures and OCP serum levels were found (p<.001). Moreover, occupational exposure to lead including soldering and welding with lead/metal dust and use of lead paint/gasoline were significantly related to ALS risk (OR = 1.77, 95% CI: 1.11-2.83). Avocational gardening was a significant risk factor for ALS (OR = 1.57, 95% CI: 1.04-2.37). ALS risk increased for each 10 ng/g of α-Endosulfan (OR = 1.42, 95% CI: 1.14-1.77) and oxychlordane (OR = 1.24, 95% CI: 1.01-1.53). Heptachlor (detectable vs. nondetectable) was also associated with ALS risk (OR = 3.57, 95% CI: 1.50-8.52). Conclusion: This national case-control study revealed both survey and serum levels of OCPs as risk factors for ALS. Despite the United States banning many OCPs in the 1970s and 1980s, their use abroad and long half-lives continue to exert possible neurotoxic health effects.

The mussel larvae microbiome changes in response to a temperature rise

Ocean warming caused by global climate change influences the function, diversity, and community dynamics of commensal microorganisms, including the hemolymph and the gut microbiota in mussels. However, the microbiota in hard-shelled mussel (Mytilus coruscus) larvae and the effect of temperature on the microbial community structure have yet to be studied. Herein, we investigated the core microbiota of M. coruscus larvae and the impact of acute (4 h) and gradual (4 days) exposure to a rise in seawater temperature from 21 to 25 °C. Eleven core genera were identified in M. coruscus larvae by 16S rDNA gene sequencing: Alteromonas, Brevundimonas, Delftia, Microbacterium, Neptuniibacter, Neptunomonas, Pseudoalteromonas, Rhodococcus, Stenotrophomonas, Tenacibaculum, and Thalassotalea. The microbiota of larvae in the short exposure treatment was similar to the control. However, the abundance of Delftia, Neptunomonas, Pseudoalteromonadaceae, Rhodococcus, and Stenotrophomonas decreased significantly in the long-exposure larvae. In contrast, at the genus level, the abundance of Tenacibaculum increased significantly. Diversity and multivariate analyses confirmed that the microbiota patterns were linked to seawater warming over the long term. Microbiota diversity did not change significantly, regardless of whether the seawater temperature increased quickly or slowly; however, we observed a significant increase in the microbiota species abundance at higher temperatures. Among the altered bacterial genera, Delftia, Neptunomonas, and Rhodococcus function in the degradation of organic compounds; Pseudoalteromonas is closely associated with mussel attachment and metamorphosis, and Tenacibaculum is an opportunistic pathogen that can cause marine mollusk death. The results suggest that marine heat waves caused by climate change may reduce the ability of symbiotic bacteria to degrade environmental toxins, will affect mussel larvae metamorphosis, and increase the abundance of opportunistic pathogens, thereby increasing the risk of disease and death of mussel larvae.

The Prospect of Biomimetic Immune Cell Membrane-Coated Nanomedicines for Treatment of Serious Bacterial Infections and Sepsis.

Invasive bacterial infections and sepsis are persistent global health concerns, complicated further by the escalating threat of antibiotic resistance. Over the past 40 years, collaborative endeavors to improve the diagnosis and critical care of septic patients have improved outcomes, yet grappling with the intricate immune dysfunction underlying the septic condition remains a formidable challenge. Anti-inflammatory interventions that exhibited promise in murine models failed to manifest consistent survival benefits in clinical studies through recent decades. Novel therapeutic approaches that target bacterial virulence factors, for example with monoclonal antibodies, aim to thwart pathogen-driven damage and restore an advantage to the immune system. A pioneering technology addressing this challenge is biomimetic nanoparticles-a therapeutic platform featuring nanoscale particles enveloped in natural cell membranes. Borne from the quest for a durable drug delivery system, the original red blood cell-coated nanoparticles showcased a broad capacity to absorb bacterial and environmental toxins from serum. Tailoring the membrane coating to immune cell sources imparts unique characteristics to the nanoparticles suitable for broader application in infectious disease. Their capacity to bind both inflammatory signals and virulence factors assembles the most promising sepsis therapies into a singular, pathogen-agnostic therapeutic. This review explores the ongoing work on immune cell-coated nanoparticle therapeutics for infection and sepsis. Significance Statement In the quest to combat antibiotic-resistant bacterial infections and sepsis, an innovative approach has emerged in which nanoscale particles are enveloped in natural cell membranes purified from human blood cells. Since this technology shows the ability to (a) neutralize bacterial toxins that injure host cells and (b) quell the exaggerated septic inflammation that leads to deadly organ system failure, these novel nanomedicines may represent a versatile strategy to complement antibiotics and vaccines in the ongoing battle against infectious diseases.

Neurotoxic effects of home radon exposure on oscillatory dynamics serving attentional orienting in children and adolescents

Radon is a naturally occurring gas that contributes significantly to radiation in the environment and is the second leading cause of lung cancer globally. Previous studies have shown that other environmental toxins have deleterious effects on brain development, though radon has not been studied as thoroughly in this context. This study examined the impact of home radon exposure on the neural oscillatory activity serving attention reorientation in youths. Fifty-six participants (ages 6–14 years) completed a classic Posner cuing task during magnetoencephalography (MEG), and home radon levels were measured for each participant. Time-frequency spectrograms indicated stronger theta (3–7 Hz, 300–800 ms), alpha (9–13 Hz, 400–900 ms), and beta responses (14–24 Hz, 400–900 ms) during the task relative to baseline. Source reconstruction of each significant oscillatory response was performed, and validity maps were computed by subtracting the task conditions (invalidly cued – validly cued). These validity maps were examined for associations with radon exposure, age, and their interaction in a linear regression design. Children with greater radon exposure showed aberrant oscillatory activity across distributed regions critical for attentional processing and attention reorientation (e.g., dorsolateral prefrontal cortex, and anterior cingulate cortex). Generally, youths with greater radon exposure exhibited a reverse neural validity effect in almost all regions and showed greater overall power relative to peers with lesser radon exposure. We also detected an interactive effect between radon exposure and age where youths with greater radon exposure exhibited divergent developmental trajectories in neural substrates implicated in attentional processing (e.g., bilateral prefrontal cortices, superior temporal gyri, and inferior parietal lobules). These data suggest aberrant, but potentially compensatory neural processing as a function of increasing home radon exposure in areas critical for attention and higher order cognition.

INDIVIDUAL ARTICLE: Sugar Sag: What Is Skin Glycation and How Do You Combat It?

Skin aging is influenced by various exogenous and endogenous factors, ranging from ultraviolet (UV) light exposure and environmental toxins to biological sources, such as those that arise from normal metabolic processes (eg, free radicals). Glycation is the normal process by which glucose and other reducing sugars react with proteins to form an array of heterogeneous biomolecular structures known as advanced glycation end-products (AGEs) over time. However, AGEs are toxic to human cells and are implicated in the acceleration of inflammatory and oxidative processes, with their accumulation in the skin being associated with increased skin dulling and yellowing, fine lines, wrinkles, and skin laxity. Clinicians should become cognizant of how AGEs develop, what their biological consequences are, and familiarize themselves with available strategies to mitigate their formation. J Drugs Dermatol.&nbsp; 2024;23:4(Suppl 1):s5-10.

Breaking Down Resistance: Verapamil-Derived Compounds Augment Antibiotic Activity against Streptococcus Pneumonia via MATE Transporter Interference.

Pneumonia, an infectious lung disease, is a significant global health concern, claiming the lives of 740,180 children in 2019, which accounts for 14% of pediatric deaths. Recently, the management of pediatric pneumonia has become complex due to exposure to indoor and outdoor environmental toxins. Notably, exposure to pollutants and antibiotic-resistant bacteria during community and hospital-acquired pneumonia poses a serious threat to patient outcomes. The development of antibiotic resistance against Streptococcus pneumoniae is driven by the DinF efflux pump protein, which expels antibiotics from bacterial cells, leading to multidrug resistance. Therefore, blocking DinF could serve as a strategy to combat antibiotic resistance. This study aimed to identify DinF inhibitors from compounds analogous to verapamil, a well-known DinF inhibitor, through computational techniques including molecular docking, molecular dynamics simulations, ADMET analysis, MMGBSA, quantum mechanics, and Network Pharmacology. After considering docking scores, results of MMGBSA, quantum mechanics, Molecular Dynamics Simulations, ADMET analysis and network pharmacology profiling four compounds namely netarsudil, rimegepant, GSK-1521498 and tariquidar were found as the most promising DinF inhibitors. Therefore, these compounds hold a great promise as leads to the development of potent DinF inhibitors; however, further studies are needed to warrant their clinical uses against antibiotic resistant Streptococcus pneumonia-induced pneumonia.

123 Utilizing Project ECHO to mitigate environmental impacts on health through collaborative provider education

OBJECTIVES/GOALS: Launch a case-based learning collaborative on best practices that meet social, emotional and physical health needs of underserved communities as they relate to environmental toxins—specifically those related to the train derailment in OH. Topics discussed could also include disasters and spills, air quality, extreme heat, and water. METHODS/STUDY POPULATION: In response to a call for action delivered by PA’s Acting Secretary of Health, we established a partnership between Penn State CTSI, Project ECHO at Penn State, and Primary Health Network (PHN). PHN is the largest Federally Qualified Health Center in PA, making it uniquely qualified to reach rural providers diagnosing and treating patients impacted by environmental events. Utilizing the ECHO model, we are hosting monthly, 1-hour sessions on environmental determinants of health starting October 2023. Experts in pulmonology, toxicology, atmospheric science, and rural medicine (whom many participants would have limited access to outside of the ECHO platform) and participants have the opportunity to share and learn from their varied experiences exemplifying a culture of ‘all teach, all learn’. RESULTS/ANTICIPATED RESULTS: Project ECHO is an ideal model for upscaling workforce quickly, allowing participants to be responsive in the care of their community, regardless of location and access to specialty clinics. 74 participants across 26 PA counties registered for the series, ranging from PCPs, medical directors, and state officials. Upon registration, nearly half of our direct patient-care participants do not routinely conduct an environmental exposure history and almost 70% report receiving questions from their patients related to how the environment might impact their health. More than half of those providers reported feeling unprepared to answer patients’ questions related to the environment’s impact on their health. Evaluation data will be collected at enrollment, after each session, and post-series. DISCUSSION/SIGNIFICANCE: This series could result in: * Reduction of health disparities caused by environmental events (no cost, virtual learning) * Increased preparedness to quickly address health questions/symptoms related to environmental exposures * Increased awareness of the environmental impacts on health. * Improved testing/treatment for patients

Exploring the Hawaiian Ala Wai Watershed with Zebrafish.

The Ala Wai Canal is an artificial waterway in the tourist district of Waikiki in Honolulu, HI. Originally built to collect runoff from industrial, residential, and green spaces dedicated to recreation, the Ala Wai Canal has since experienced potent levels of toxicity due to this runoff entering the watershed and making it hazardous for both marine life and humans at current concentration, including Danio rerio (zebrafish). A community of learners at educations levels from high school to postbaccalaureate from Oahu, HI was connected through the Consortium for Increasing Research and Collaborative Learning Experiences (CIRCLE) distance research program. This team conducted research with an Investigator and team from Mayo Clinic in Rochester, MN, with the Ala Wai Canal as its primary subject. Through CIRCLE, research trainees sent two 32 oz bottles of Ala Wai- acquired water to a partnered laboratory at the Mayo Clinic in which zebrafish embryos were observed at differing concentrations of the sampled water against a variety of developmental and behavioral assays. Research trainees also created atlases of developmental outcomes in zebrafish following exposure to environmental toxins and tables of potential pesticide contaminants to enable the identification of the substances linked to structural defects and enhanced stress during Ala Wai water exposure experiments.

Butylparaben induced zebrafish (Danio rerio) kidney injury by down-regulating the PI3K-AKT pathway

Butylparaben, a common endocrine disruptor in the environment, is known to be toxic to the reproductive system, heart, and intestines, but its nephrotoxicity has rarely been reported. In order to study the nephrotoxicity and mechanism of butylparaben, we examined the acute and chronic effects on human embryonic kidney cells (HEK293T) and zebrafish. Additionally, we assessed the potential remedial effects of salidroside against butylparaben-induced nephrotoxicity. Our in vitro findings demonstrated oxidative stress and cytotoxicity to HEK293T cells caused by butylparaben. In the zebrafish model, the concentration of butylparaben exposure ranged from 0.5 to 15 μM. An assortment of experimental techniques was employed, including the assessment of kidney tissue morphology using Hematoxylin-Eosin staining, kidney function analysis via fluorescent dextran injection, and gene expression studies related to kidney injury, development, and function. Additionally, butylparaben caused lipid peroxidation in the kidney, thereby damaging glomeruli and renal tubules, which resulted from the downregulation of the PI3K-AKT signaling pathway. Furthermore, salidroside ameliorated butylparaben-induced nephrotoxicity through the PI3K-AKT signaling pathway. This study reveals the seldom-reported kidney toxicity of butylparaben and the protective effect of salidroside against toxicological reactions related to nephrotoxicity. It offers valuable insights into the risks to kidney health posed by environmental toxins.

Ochratoxin A (OTA) causes intestinal aging damage through the NLRP3 signaling pathway mediated by calcium overload and oxidative stress.

Ochratoxin A (OTA) is a widespread environmental toxin that poses a serious threat to human and animal health. OTA has been shown to cause cellular and tissue damage and is a global public health problem. However, the effects of OTA on gastrointestinal aging have not been reported. The aim of this study was to investigate the effects of OTA on intestinal aging in vitro and in vivo. In vitro experiments showed that OTA induced cellular inflammation through calcium overload and oxidative stress, significantly up-regulated the expression of P16, P21, and P53 proteins, markedly increased senescence-associated β-galactosidase activity (SA-β-gal) positive cells, and obviously decreased the expression of proliferating cell nuclear antigen (PCNA) proteins, which led to intestinal cell senescence. Meanwhile, we found that treatment with β-carotene ameliorated OTA-induced intestinal cell senescence. Consistent with the results of the in vitro experiments, in vivo studies showed that the intestinal aging of mice fed OTA was significantly higher than that of the control group. In conclusion, OTA may induce intestinal aging through calcium overload, oxidative stress and inflammation. This study lays a foundation for further research on the toxicological effects of OTA.

Abstract 883: Genetic characteristics between males and females with urothelial bladder cancer

Abstract Urothelial bladder cancer (UBC) affects the epithelial cells of the urinary tract and is the most common type of bladder cancer worldwide. Statistically, males are four times more likely to develop UBC than females. It is known that decreased expression of the KDM6A gene, coded on the X chromosome, corresponds with a higher incidence of UBC. KDM6A mutations are known to be more prevalent in females with non-muscle-invasive UBC. These mutations are targetable by inhibiting EZH2, an enzyme coded by its namesake gene. On the environmental side, males are at a higher risk of developing carcinogenic complications due to smoking and environmental toxins. However, this discrepancy fails to exist when comparing males and females who smoke similar levels. Though environmental factors may play a role in influencing behavior and altering levels of risk to develop UBC, research suggests that they do not single-handedly explain sex-based disparities in UBC. In this study, we characterize the molecular mechanisms associated with altered overall survival by uncovering previously unreported data on the expression of KDM6A and FGFR3, a commonly altered oncogene, in UBC patients. Our in silico approach consisted of broad survival data analysis through cBioPortal (n=1486), sequencing-based gene expression data through ICGC Portal (n=295), and single nucleotide polymorphism identification with the PLCO Atlas (n=69,429). The 5-year overall survival (OS) curves of 13 therapeutic and/or significantly altered genes between males and females were analyzed. BRCA2 was the only gene associated with worse survival for females with alterations. Interestingly, males with alterations to the following genes had significantly better OS outcomes: ERCC2, KDM6A, BRCA2, FGFR3. However, there was no gene whose alterations were associated with significantly better OS outcomes for females. KDM6A and FGFR3, two genes whose alterations are typically associated with worse OS outcomes in males, exhibit the opposite effect. Additionally, males exhibited significantly worse OS outcomes when presenting with CDKN2A and CDKN2B alterations, while females exhibited significantly worse OS outcomes when presenting with CDKN2A and NTRK1. A majority of European males had SNPs on the following genes: CDKN2B, ERBB2, CREBBP, while a majority of European females had SNPs on BRCA2. Differential expression also revealed 714 genes that were significantly expressed in one sex when compared to the other. Therefore, we suggest that there are unique molecular differences between sex that conflict with previous analyses; further research should be conducted to explore the effect of sex via the tumor-suppressive characteristics of KDM6A as well as oncogenic properties of FGFR3. Citation Format: Rishi Nair, Roy Khalife, Anthony Magliocco. Genetic characteristics between males and females with urothelial bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 883.

Abstract 1477: Acrylamide exposure in obesity enhances mammary epithelial DNA damage via the activity of its metabolite, glycidamide, and increased oxidative stress

Abstract Obesity is a world-wide epidemic, with 39% of adults considered overweight and 13% obese, and rates are rising. Obese women are at greater risk for developing breast cancer than lean women, however the mechanisms of how obesity increases breast cancer risk are not well understood. There is also limited knowledge on how environmental toxins may interact with obesity to promote breast cancer. Acrylamide, a probable carcinogen, is a biproduct in starchy foods cooked at high temperatures, which are prevalent in the obesity-inducing Western diet. Acrylamide is metabolized by the CYP2E1 enzyme into the epoxide, glycidamide, which is known to induce DNA damage. CYP2E1 activity is elevated in obesity, which could enhance DNA damage in obese individuals. Acrylamide exposure is associated with an increased risk of breast cancer in epidemiologic studies, but the evidence has been contradictory. To investigate how acrylamide impacts DNA damage in the obese mammary gland, three-week-old FVB female mice were randomized to receive a low-fat (LFD; 16% kcal from fat) or high-fat diet (HFD; 60% kcal from fat) and either 0.7 mM acrylamide water or control water. HFD-fed mice gained significantly more weight than LFD-fed mice, and exposure to acrylamide did not impact weight gain compared to respective controls. Mammary epithelial cells from acrylamide-treated mice had increased DNA damage compared to controls measured by COMET assays, with the highest DNA damage present in epithelial cells from obese acrylamide-treated mice. Mammary epithelial cells from acrylamide-treated mice also had enhanced oxidative DNA damage, measured by 8-OHdG adducts, and an additive effect was observed between acrylamide exposure and obesity. To investigate the impact of acrylamide in vitro, COMMA-D mammary epithelial cells were treated with vehicle, 9.8 µM acrylamide, or 0.5 mM glycidamide for 24 hours, then COMET assays and immunohistochemistry for markers of DNA damage were performed. COMMA-D cells treated with acrylamide-metabolite glycidamide showed significantly increased double strand DNA breaks compared to vehicle-treated cells, however acrylamide-treated cells did not. Interestingly, acrylamide-treated cells demonstrated significantly higher levels of intracellular reactive oxygen species compared to both glycidamide and vehicle-treated cells. These studies suggest acrylamide exposure enhances DNA damage in mammary epithelial cells via conversion to the genotoxic metabolite glycidamide and through generation of oxidative stress, which is exacerbated by obese conditions. These studies suggest that long-term acrylamide exposure through foods common in the Western diet may enhance DNA damage in mammary epithelial cells, potentially enhancing obesity-induced breast cancer risk. Citation Format: Brenna Walton, Lisa Arendt. Acrylamide exposure in obesity enhances mammary epithelial DNA damage via the activity of its metabolite, glycidamide, and increased oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1477.

Digging Deeper: What Can We Really Learn about Dementia from History?

In response to Finch and Burstein's provocative argument that the advanced dementias may result from environmental toxins and lifestyle factors associated with post-industrial societies, we call for a more rigorous historical approach, emphasizing the importance of situating ancient texts more fully in their historical and cultural context. Such an approach would also entail consideration of the declining relative rates of dementia in Western countries, which have been linked to population health-level factors and policies that appear to have reduced the risk of dementia by directly and indirectly influencing the social determinants of brain health.

Di (2-ethylhexyl) phthalate and polystyrene microplastics co-exposure caused oxidative stress to activate NF-κB/NLRP3 pathway aggravated pyroptosis and inflammation in mouse kidney

Polystyrene microplastic (PS-MPs) contamination has become a worldwide hotspot of concern, and its entry into organisms can cause oxidative stress resulting in multi-organ damage. The plasticizer di (2-ethylhexyl) phthalate (DEHP) is a common endocrine disruptor, these two environmental toxins often occur together, but their combined toxicity to the kidney and its mechanism of toxicity are unknown. Therefore, in this study, we established PS-MPS and/or DEHP-exposed mouse models. The results showed that alone exposure to both PS-MPs and DEHP caused inflammatory cell infiltration, cell membrane rupture, and content spillage in kidney tissues. There were also down-regulation of antioxidant enzyme levels, increased ROS content, activated of the NF-κB pathway, stimulated the levels of heat shock proteins (HSPs), pyroptosis, and inflammatory associated factors. Notably, the co-exposure group showed greater toxicity to kidney tissues, the cellular assay further validated these results. The introduction of the antioxidant n-acetylcysteine (NAC) and the NLRP3 inhibitor (MCC950) could mitigate the changes in the above measures. In summary, co-exposure of PS-MPs and DEHP induced oxidative stress that activated the NF-κB/NLRP3 pathway and aggravated kidney pyroptosis and inflammation, as well as that HSPs are also involved in this pathologic injury process. This study not only enriched the nephrotoxicity of plasticizers and microplastics, but also provided new insights into the toxicity mechanisms of multicomponent co-pollution in environmental.

HFE Mutations in Neurodegenerative Disease as a Model of Hormesis.

Common variants in the iron regulatory protein HFE contribute to systematically increased iron levels, yet the effects in the brain are not fully characterized. It is commonly believed that iron dysregulation is a key contributor to neurodegenerative disease due to iron's ability to catalyze reactive oxygen species production. However, whether HFE variants exacerbate or protect against neurodegeneration has been heavily debated. Some claim that mutated HFE exacerbates oxidative stress and neuroinflammation, thus predisposing carriers to neurodegeneration-linked pathologies. However, H63D HFE has also been shown to slow the progression of multiple neurodegenerative diseases and to protect against environmental toxins that cause neurodegeneration. These conflicting results showcase the need to further understand the contribution of HFE variants to neurodegenerative disease heterogeneity. Data from mouse models consistently demonstrate robust neuroprotection against toxins known to increase the risk of neurodegenerative disease. This may represent an adaptive, or hormetic, response to increased iron, which leaves cells better protected against future stressors. This review describes the current research regarding the contribution of HFE variants to neurodegenerative disease prognosis in the context of a hormetic model. To our knowledge, this is the first time that a hormetic model for neurodegenerative disease has been presented.

Influence of irrigation water and soil on annual mercury dynamics in Sacramento Valley rice fields.

Methylmercury (MeHg) is a human and environmental toxin produced in flooded soils. Little is known about MeHg in rice (Oryza Sativa L.) fields in Sacramento Valley, California. The objectives of this study were to quantify mercury fractions in irrigation water and within rice fields and to determine their mercury pools in surface water, soil, and grain. Soil, grain, and surface water (dissolved and particulate) MeHg and total mercury (THg) were monitored in six commercial rice fields throughout a winter fallow season and subsequent growing season. Both dissolved and particulate mercury fractions were higher in fallow season rice field water. Total suspended solids and particulate mercury concentrations were positively correlated (r=0.99 and 0.98 for THg and MeHg, respectively), suggesting that soil MeHg was suspended in the water column and potentially exported. Dissolved THg and MeHg concentrations were positively correlated with absorbance at 254nm (r=0.47 and 0.58, respectively) in fallow season field water. In the growing season, fields with higher irrigation water MeHg concentrations (due to recycled water use) had elevated field-water MeHg (r=0.86) and grain MeHg concentrations (r=0.96). Based on a mass balance analysis, soil mercury pools were orders of magnitude larger than surface water or grain mercury pools; however, fallow season drainage and grain harvest were the primary pathways for MeHg export. Based on these findings, reducing (1) discharge when water is turbid, (2) straw inputs, and (3) use of recycled irrigation water could help reduce mercury exports in rice field drainage water.

Prenatal exposure to environmental toxins and comprehensive dental findings in a population cohort of children.

Environmental toxins are known to have many impacts on growth and development in humans, starting in utero. Alterations in amelogenesis, caused by chemical and physical trauma that occur during the antenatal, perinatal and postnatal time periods, may result in developmental defects in deciduous and permanent tooth enamel, as demonstrated in animal studies. These defects can be clinically visible and result in a variety of morphological and functional problems in the dentition. Since enamel does not remodel after formation, it may serve as a permanent record of insults during organ development.Our primary purpose was to investigate any possible relationship between intrauterine exposure to endocrine disrupting chemicals (phenols and phthalates) and developmental defects in enamel in children, while also accounting for fluoride exposure. Our secondary purpose was to report descriptively on findings from comprehensive dental examinations performed on 356 children that were drawn from the general paediatric population. A cohort of children from the Utah Children's Project (N = 356) that had full medical exams, comprehensive medical and family histories and available biospecimens were given extraoral and intraoral examinations. They also completed an oral health questionnaire. Standardized intraoral photographs were taken of the teeth and viewed by standardised examiners and the dental observations were recorded for a full inventory of findings, including: tooth morphology, caries, restorations, colorations, attrition, erosion, fractures and hypomineralization. Perinatal maternal urine samples were assessed for the concentration of fluoride, phenols and phthalates, including bisphenol A (BPA).Pairwise statistical analyses were done to correlate the dental findings with one another and with the presence of environment chemicals found in the urine samples. Hypomineralization was the most common finding (96% of children; 37% of deciduous teeth, 42% of permanent teeth), consistent with molar incisor hypomineralization (MIH) described in other human populations. No consistent correlations were seen between dental findings and the presence of phenols and phthalates in prenatal urine, but the number of samples available for the assessment was limited (n = 35).In conclusion, we found a high proportion of dental hypomineralization in a population based paediatric cohort, but did not find an association with prenatal exposure to phenols and phthalates.