Low-dose Exposure Research Articles

Developmental pyrethroid exposure in mouse leads to disrupted brain metabolism in adulthood.

Environmental and genetic risk factors, and their interactions, contribute significantly to the etiology of neurodevelopmental disorders (NDDs). Recent epidemiology studies have implicated pyrethroid pesticides as an environmental risk factor for autism and developmental delay. Our previous research showed that low-dose developmental exposure to the pyrethroid pesticide deltamethrin in mice caused male-biased changes in the brain and in NDD-relevant behaviors in adulthood. Here, we used a metabolomics approach to determine the broadest possible set of metabolic changes in the adult male mouse brain caused by low-dose pyrethroid exposure during development. Using a litter-based design, we exposed mouse dams during pregnancy and lactation to deltamethrin (3 mg/kg or vehicle every 3 days) at a concentration well below the EPA-determined benchmark dose used for regulatory guidance. We raised male offspring to adulthood and collected whole brain samples for untargeted high-resolution metabolomics analysis. Developmentally exposed mice had disruptions in 116 metabolites which clustered into pathways for folate biosynthesis, retinol metabolism, and tryptophan metabolism. As a cross-validation, we integrated metabolomics and transcriptomics data from the same samples, which confirmed previous findings of altered dopamine signaling. These results suggest that pyrethroid exposure during development leads to disruptions in metabolism in the adult brain, which may inform both prevention and therapeutic strategies.

Particulate matter exposure induces adverse effects on endometrium and fertility via aberrant inflammatory and apoptotic pathways in vitro and in vivo

This study aimed to evaluate the adverse effects of particulate matter (PM) exposure on endometrial cells and fertility and to identify possible underlying mechanisms. Thirteen women (aged 15–52 years) were included in this study. Enrolled patients underwent laparoscopic surgery at Gangnam Severance Hospital between 1 January and 31 December 2021. For in vivo experiments, 36 female and nine male C57BL/6 mice were randomly divided into control(vehicle), low-dose(10 mg/kg/d), and high-dose exposure groups(20 mg/kg/d). PM was inhaled nasally for four weeks and natural mating was performed. NIST® SRM® 1648a was used for PM exposure. qRT-PCR, western blotting and Masson's trichrome staining were performed. PM treatment in human endometrial stromal cells induced inflammation with significant upregulation of IL-1β, p–NF–kB, and p-c-Jun compared to those of controls. Additionally, PM treatment significantly increased apoptosis in human endometrial stromal cells by downregulating p-AKT and upregulating p-p53/p53, Cas-3, BAX/Bcl-2, p-AMPK, and p-ERK. After PM treatment, the relative expression of IL-1β, IL-6, TNF-α, p–NF–κB, p-c-Jun, and p-Nrf2/Nrf2 significantly increased in murine endometrium compared to those of the controls. Expression of apoptotic proteins p53, p27, and Cas-3, was also significantly elevated in murine endometrium of the PM exposure group compared to that of the controls. A significant increase in expression of procollagen Ⅰ, and Masson's trichrome staining scores in the murine endometrium was noted after PM treatment. PM treatment significantly decreased ERα expression. After natural mating, all 3 female mice in the control group gave birth to 25 offspring (mean 8.1), whereas in the low-dose PM treatment group, two of three female mice gave birth to nine offspring (mean 4.5). No pregnant mice or offspring was present in the high-dose PM treatment group. PM exposure induces adverse effects on the endometrium through aberrant activation of inflammatory and apoptotic pathways and is associated with detrimental effects on murine fertility.

Absorption, distribution, metabolism, and elimination of epoxiconazole enantiomers in lizards (Eremias argus)

Epoxiconazole (EPX) is a world widely used chiral triazole fungicide in the agriculture field. The excessive application of this triazole may cause damage to lizards. However, limited information is known about the toxicokinetics of EPX on lizards. Our study aimed to investigate the enantioselective absorption, distribution, metabolism, and elimination (ADME) of EPX in lizards following low and high dose exposure (10 and 100 mg kg−1 bodyweitht (bw)). The results demonstrated that (+)-EPX was easier absorbed than (−)-EPX in lizard plasma. Both (+)-EPX and (−)-EPX were detected in the liver, gonad, kidney, skin, brain, and intestine, with (+)-EPX preferentially distributed in these tissues. The elimination of (−)-EPX was faster than that of (+)-EPX in lizard liver and kidney in the high dose groups. Chiral conversion was found between EPX enantiomers in lizard skin. Simultaneously, five metabolites including M2, M4, M10, M18 and M19 were detected in lizard liver and kidney after EPX enantiomers exposure. The relative concentrations of M2, M4, and M10 were higher in the liver and kidney of (−)-EPX groups than those produced from (+)-EPX groups. The metabolic enzymes CYP3A4 and SULT1A1 primarily mediated enantioselective metabolism of EPX. The conclusions drawn from this study significantly enhance our understanding of the enantioselective behaviors of chiral triazole fungicides in reptiles, offering essential guidance for assessing the risks associated with different enantiomers of triazole fungicides.

Estimating thoracic kyphosis without information on upper thoracic kyphosis: an observational study on 455 patients examined by EOS imaging

BackgroundPhysiological thoracic kyphosis (TK) allows sagittal balance of human body. Unlike lumbar lordosis (LL), TK has been relatively neglected in the literature. EOS is an imaging technique employing high-sensitivity xenon particles, featured by low-dose exposure combined with high accuracy compared to conventional radiography. The aim of this study was to investigate predictors of TK in patients with phyiological spine morphology using EOS imaging.MethodsEOS images of 455 patients without spinal anomalies were retrospectively assessed for TK (T1- T12), upper thoracic kyphosis (UTK, T1-T5), lower thoracic kyphosis (LTK, T5-T12), LL (L1-S1) and pelvic incidence (PI). The latter curves were measured by two researchers separately and the average of the two measurements was used for further analysis.Spearman non-parametric correlation was estimated for age, PI, LL, LTK, UTK and TK. Multiple robust linear regression analysis was employed to estimate TK, controlling for the effect of age, sex, LL and LTK.ResultsThe mean age of patients was 28.3 ± 19.2 years and 302 (66.4%) of them were females. The mean TK, UTK and LTK was 45.5° ± 9.3, 16 ± 7.4° and 29.7° ± 8.9, respectively. The mean UTK in people under 40 years of age was 17.0° ± 7.2, whereas for patients 40+ years old it was 13.6° ± 7.4. At univariable analysis TK positively correlated with UTK (p<0.001), LTK (p<0.001) an LL (p<0.001). At multivariable linear regression TK increased with LTK (RC = 0.67; 95%CI: 0.59; 0.75) or LL (RC = 0.12; 95%CI: 0.06; 0.18), whereas it decreased with age (RC = -0.06; 95%CI: -0.09;—0.02).ConclusionIf EOS technology is available, the above linear regression model could be used to estimate TK based upon information on age, sex, LL and LTK. Alternatively, TK could be estimated by adding to LTK 17.0° ± 7.4 for patients < 40 years of age, or 13.6° ± 7.4 in patients 40 + years old. The evidence from the present study may be used as reference for research purposes and clinical practice, including spine examination of particular occupational categories or athletes.

A comparative study on the dose–effect of low-dose radiation based on microdosimetric analysis and single-cell sequencing technology

The biological mechanisms triggered by low-dose exposure still need to be explored in depth. In this study, the potential mechanisms of low-dose radiation when irradiating the BEAS-2B cell lines with a Cs-137 gamma-ray source were investigated through simulations and experiments. Monolayer cell population models were constructed for simulating and analyzing distributions of nucleus-specific energy within cell populations combined with the Monte Carlo method and microdosimetric analysis. Furthermore, the 10 × Genomics single-cell sequencing technology was employed to capture the heterogeneity of individual cell responses to low-dose radiation in the same irradiated sample. The numerical uncertainties can be found both in the specific energy distribution in microdosimetry and in differential gene expressions in radiation cytogenetics. Subsequently, the distribution of nucleus-specific energy was compared with the distribution of differential gene expressions to guide the selection of differential genes bioinformatics analysis. Dose inhomogeneity is pronounced at low doses, where an increase in dose corresponds to a decrease in the dispersion of cellular-specific energy distribution. Multiple screening of differential genes by microdosimetric features and statistical analysis indicate a number of potential pathways induced by low-dose exposure. It also provides a novel perspective on the selection of sensitive biomarkers that respond to low-dose radiation.

Pathway-based analyses of gene expression profiles at low doses of ionizing radiation.

Radiation exposure poses a significant threat to human health. Emerging research indicates that even low-dose radiation once believed to be safe, may have harmful effects. This perception has spurred a growing interest in investigating the potential risks associated with low-dose radiation exposure across various scenarios. To comprehensively explore the health consequences of low-dose radiation, our study employs a robust statistical framework that examines whether specific groups of genes, belonging to known pathways, exhibit coordinated expression patterns that align with the radiation levels. Notably, our findings reveal the existence of intricate yet consistent signatures that reflect the molecular response to radiation exposure, distinguishing between low-dose and high-dose radiation. Moreover, we leverage a pathway-constrained variational autoencoder to capture the nonlinear interactions within gene expression data. By comparing these two analytical approaches, our study aims to gain valuable insights into the impact of low-dose radiation on gene expression patterns, identify pathways that are differentially affected, and harness the potential of machine learning to uncover hidden activity within biological networks. This comparative analysis contributes to a deeper understanding of the molecular consequences of low-dose radiation exposure.

Factors Influencing Effects of Low-dose Radiation Exposure.

It is now well accepted that the mechanisms induced by low-dose exposures to ionizing radiation (LDR) are different from those occurring after high-dose exposures. However, the downstream effects of these mechanisms are unclear as are the quantitative relationships between exposure, effect, harm, and risk. In this paper, we will discuss the mechanisms known to be important with an overall emphasis on how so-called "non-targeted effects" (NTE) communicate and coordinate responses to LDR. Targeted deposition of ionizing radiation energy in cells causing DNA damage is still regarded as the dominant trigger leading to all downstream events whether targeted or non-targeted. We regard this as an over-simplification dating back to formal target theory. It ignores that last 100 y of biological research into stress responses and signaling mechanisms in organisms exposed to toxic substances, including ionizing radiation. We will provide evidence for situations where energy deposition in cellular targets alone cannot be plausible as a mechanism for LDR effects. An example is where the energy deposition takes place in an organism not receiving the radiation dose. We will also discuss how effects after LDR depend more on dose rate and radiation quality rather than actual dose, which appears rather irrelevant. Finally, we will use recent evidence from studies of cataract and melanoma induction to suggest that after LDR, post-translational effects, such as protein misfolding or defects in energy metabolism or mitochondrial function, may dominate the etiology and progression of the disease. A focus on such novel pathways may open the way to successful prophylaxis and development of new biomarkers for better risk assessment after low dose exposures.

Mycotoxins and Amyotrophic Lateral Sclerosis: Food Exposure, Nutritional Implications and Dietary Solutions.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder determined by a combination of both genetic and environmental factors. Despite wide investigations, the role of chronic exposure to environmental pollutants is still rather unknown. Among natural toxins, the mycotoxins have received major attention only in the last few years, due to both technical and scientific achievements that allowed to disentangle many important features of the complex fungal biology. Whereas the effects of acute and high-dose mycotoxin exposure are well known, the potential effects of chronic and low-dose exposure on neurodegeneration have not been broadly elucidated. In this review, we have summarized all the studies concerning environmental exposure to unknown substances that caused ALS outbreaks all over the world, reinterpreting in light of the new scientific acquisitions and highlighting the potential and neglected role of mycotoxins. Then, we focused on recent papers about food exposure to mycotoxin, mycobiome and fungal infections in ALS and other neurodegenerative diseases. We analyzed the gaps of current literature that lead to an undervaluation of mycotoxins as detrimental molecules. By listing all the most important mycotoxins and analyzing all the biological pathways that they can affect, we explained the reasons why they need to be considered in the next epidemiological studies on ALS and other neurodegenerative and neuroinflammatory diseases. In conclusion, after suggesting some possible solutions to mitigate mycotoxin exposure risk, we affirm that future collaborations between scientists and policymakers are important to develop sustainable interventions and promote health through dietary diversity.

Unraveling paraquat-induced toxicity on mouse neural stem cells: Dose-response metabolomics insights and identification of sensitive biomarkers for risk assessment

Exposure to pesticide could contribute to neurodevelopmental and neurodegenerative disorders. Notably, research suggests that prenatal or early postnatal exposure to paraquat (PQ), an herbicide, might trigger neurodevelopmental toxicity in neural stem cells (NSCs) via oxidative stress. However, the molecular mechanisms of PQ-induced perturbations in NSCs, particularly at the metabolite level, are not fully understood. Using a dose-response metabolomics approach, we examined metabolic changes in murine NSCs exposed to different PQ doses (0, 10, 20, 40 μM) for 24h. At 20 μM, PQ treatment led to significant metabolic alterations, highlighting unique toxic mechanisms. Metabolic perturbations, mainly affecting amino acid metabolism pathways (e.g., phenylalanine, tyrosine, arginine, tryptophan, and pyrimidine metabolism), were associated with oxidative stress, mitochondrial dysfunction, and cell cycle dysregulation. Dose-response models were used to identify potential biomarkers (e.g., Putrescine, L-arginine, ornithine, L-histidine, N-acetyl-L-phenylalanine, thymidine) reflecting early damage from low-dose PQ exposure. These biomarkers could be used as points of departure (PoD) for characterizing PQ exposure hazard in risk assessment. Our study offers insights into mechanisms and risk assessment related to PQ-induced neurotoxicity in NSCs.

Toxicity of bisphenol S on human normal ovarian epithelial cells mediated by ERβ-MAPK signaling pathway

To investigate the effects of long-term(7 days and 14 days) bisphenol S(BPS) exposure on the ERβ-MAPK signaling pathway, hormone secretion phenotype and cell cycle in human normal ovarian epithelial cells IOSE 80 at actual human exposure level. Physiologically based pharmacokinetic model combined with BPS levels in the serum of women along the Yangtze River in China was used to determine the dosing concentrations of BPS, and vehicle control and 17 β-estradiol(E_2) control were used. Complete medium with corresponding concentrations(0, 6.79×10~(-6), 6.79×10~(-4), 6.79×10~(-2), 6.79 μmol/L BPS and 10 nmol/L E_2) was replaced every 2 days. mRNA expressions of estrogen receptor(ERβ and GPR30), key genes in MAPK signaling pathway(P38/JNK/ERK signaling pathway) and gonadotropin-releasing hormone-related genes(GnRH-I, GnRH-II and GnRH-R) were measured by qPCR. The ERβ-MAPK signaling pathway inhibitors were employed to detect the effect of long-term exposure to BPS on the cell cycle by flow cytometry. Dose-response relationship analysis was performed to calculate the benchmark does lower confidence limits. Compared to the vehicle control, after 7 days exposure to BPS, the ratio of G_2/M phase was significantly increased(P&lt;0.05), and the mRNA expressions of GnRH-I, GnRH-II and GnRH-R were significantly decreased(P&lt;0.05); after 14 days exposure to BPS, the mRNA expressions of ESR2, MAPK3, and MAPK9 were significantly increased(P&lt;0.05), and the mRNA expressions of GnRH-II and GnRH-R were significantly decreased(P&lt;0.05). The GnRH-II mRNA expression level of BPS treatment for 7 days; the G_0/G_1 phase ratio, MAPK3 and MAPK8 mRNA expression level of BPS exposure for 14 days; and the GnRH-I mRNA expression level after BPS treatment for 7 days and 14 days showed a good dose-response relationship but with poor fit. Long-term low-dose exposure to BPS may cause cell cycle arrest by activating the ERβ-MAPK signaling pathway, and may lead to changes in the hormone secretion of IOSE 80 cells.

Post-Irradiation Behavior of Colored PVA-Based Films Containing Ag Nanoparticles as Radiation Detectors/Exposure Indicators.

Ionizing radiation covers a broad spectrum of applications. Since radioactive/radiation pollution is directly related to radiation risk, radiation levels should be strictly controlled. Different detection methods can be applied for radiation registration and monitoring. In this paper, radiation-induced variations in the optical properties of silver-enriched PVA-based hydrogel films with and without azo dye (Toluidine blue O, TBO, and Methyl red, MR) additives were investigated, and the feasibility of these free-standing films to serve as radiation detectors/exposure indicators was assessed. AgNO3 admixed with PVA gel was used as a source for the radiation-induced synthesis of silver nanoparticles (AgNPs) in irradiated gel films. Three types of sensors were prepared: silver-enriched PVA films containing a small amount of glycerol (AgPVAGly); silver-enriched PVA films with toluidine blue adducts (AgPVAGlyTBO); and silver-enriched PVA films with methyl red additives (AgPVAGlyMR). The selection of TBO and MR was based on their sensitivity to irradiation. The irradiation of the samples was performed in TrueBeam2.1 (VARIAN) using 6 MeV photons. Different doses up to 10 Gy were delivered to the films. The sensitivity of the films was assessed by analyzing the characteristic UV-Vis absorbance peaks on the same day as irradiation and 7, 30, 45, 90, and 180 days after irradiation. It was found that the addition of azo dyes led to an enhanced radiation sensitivity of the AgNPs containing films (0.6 Gy-1 for AgPVAGlyTBO and 0.4 Gy-1 for AgPVAGlyMR) irradiated with <2 Gy doses, indicating their applicability as low-dose exposure indicators. The irradiated films were less sensitive to higher doses. Almost no dose fading was detected between the 7th and 45th day after irradiation. Based on the obtained results, competing AgNP formation and color-bleaching effects in the AgPVAGly films with dye additives are discussed.

Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure

Lead is a neurotoxic contaminant that exists widely in the environment. Although lead neurotoxicity has been found to be tightly linked to gut microbiota disturbance, the effect of host metabolic disorders caused by gut microbiota disturbance on lead neurotoxicity has not been investigated. In this work, the results of new object recognition tests and Morris water maze tests showed that chronic low-dose lead exposure caused learning and memory dysfunction in mice. The results of 16 S rRNA sequencing of cecal contents and fecal microbiota transplantation showed that the neurotoxicity of lead could be transmitted through gut microbiota. The results of untargeted metabolomics and bile acid targeted metabolism analysis showed that the serum bile acid metabolism profile of lead-exposed mice was significantly changed. In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity.

Impact of vacuum ultraviolet photons on ultrathin polymethylmethacrylate during plasma etching

State-of-the-art extreme ultraviolet lithography requires the use of ultrathin photoresists (or resists) due to pattern stability concerns and reduced depth of focus of the extreme ultraviolet lithography scanners. Current resists for extreme ultraviolet lithography are less than 50 nm thick. These ultrathin resists further complicate pattern transfer as unintended plasma-induced damage during dry etching is more pronounced. A better understanding of the interaction of plasma species with ultrathin resists is critical for enabling pattern transfer of sub-10 nm features. Here, we study the impact of vacuum ultraviolet photons, argon ions, and argon plasma on a 40 nm thick polymethylmethacrylate film. Using a deuterium lamp, an industrial ion beam etch tool, and an industrial inductively coupled plasma etch tool, we exposed the polymer to photons, ions, and plasma, respectively. The exposed samples were then analyzed for chemical and physical changes using different characterization techniques. It was observed that the vacuum ultraviolet photons interact with the entire bulk of polymer film, while the ions only affect the surface and subsurface region. The photon exposed samples formed smaller polymer fragments at low exposure doses and further started to cross-link at high doses. In contrast, the ion modification leads to carbonization of only the top few nanometers of the polymer film, leaving the bottom bulk intact. The plasma exposed sample showed changes characteristic to both vacuum ultraviolet photons and ions and their synergism. It was stratified with a 1.34 ± 0.03 nm thick ion-caused carbonized layer on top of a 13.25 ± 0.12 nm photon-induced cross-linked layer. By studying the impact of plasma photons on ultrathin polymethylmethacrylate, we were able to establish a baseline for a testing methodology that can be extended to novel ultrathin resist platforms.

Subclinical immune responses to nickel in sensitized individuals-a dose-response study.

Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high. To investigate the clinical and subclinical immune response to low-dose nickel exposure on nickel pre-exposed skin to assess the adequacy of current regulatory limits. Nickel-allergic and healthy controls were patch tested with nickel twice with a 3-4 weeks interval. The first exposure used the diagnostic concentration of 2000 μg/cm2 nickel sulphate, and the same skin areas were then re-exposed to 0.2, 0.5, 12.8 and 370 μg/cm2 nickel sulphate. After 48 h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction. Two nickel-allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2/0.5 μg/cm2) following re-exposure. There was immune activation in all skin areas following re-exposure to nickel, predominantly mediated by up-regulation of cytokines and chemokines. In all nickel re-exposed skin areas, 81 genes were up-regulated independent from the clinical response. In skin areas exposed to 0.2 μg/cm2, 101 immune-related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up-regulation of three genes in response to nickel re-exposures without any clinical reactions. Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low-dose exposures.

Chronic inhalation of H2S in low concentration induces immunotoxicity and inflammatory effects in lung tissue of rats

Hydrogen sulfide (H2S) is a typical odour compound mainly causing respiratory and central nervous system symptoms. However, the immunotoxicity of inhaled H2S and the underlying mechanisms remain largely unknown. In this study, a low-dose inhalation exposure to H2S was arranged to observe inflammatory response and immunotoxicity in lung tissue of rats. Low concentrations of H2S exposure affected the immune level of pulmonary tissue and peripheral blood. Significant pathological changes in lung tissue in the exposure group were observed. At low concentration, H2S not only induced the upregulation of AQP-4 and MMP-9 expression but also stimulated immune responses, initiating various anti-inflammatory and inflammatory factors, altering tissue homeostatic environments. The TNF and chemokine signaling pathway played an important role which can promote the deterioration of pulmonary inflammatory processes and lead to lung injury and fibrosis. Excessive immune response causes an inflammatory effect and blood-gas barrier damage. These data will be of value in evaluating future occupational health risks and providing technical support for the further development of reliable, sensitive, and easy-to-use screening indicators of exposure injury.

Updated Estimates of Radiation Risk for Cancer and Cardiovascular Disease: Implications for Cardiology Practice.

This review aims to furnish an updated assessment of the societal healthcare load, including cancer and cardiovascular disease resulting from diagnostic radiologic operations. The previously projected additional cancer risk of 0.9% in a United States 2004 study referred to radiological conditions in 1996 with an X-ray exposure of 0.50 millisievert (mSv) per capita annually. Radiological exposure (radiology + nuclear medicine) has escalated to 2.29 mSv (2016) per capita per year. Low-dose exposures were previously assumed to have a lower biological impact, since they allow the DNA repair system to mitigate molecular damage. However, epidemiological data matured and disproved this assumption, as shown by updated cancer risk assessments derived from the World Health Organization 2013 and the German Institute of Radioprotection 2014 data. The risk of cardiovascular disease aligns within the same order of magnitude as cancer risk and compounds it, as shown by a comprehensive meta-analysis of 93 studies. The collective societal burden arising from the augmented risks of cancer and cardiovascular disease attributable to diagnostic radiology and nuclear medicine is higher than previously thought.

Chronic low-dose chromium VI exposure induces oxidative stress and apoptosis with altered expressions of DNA repair genes and promoter hypermethylation in the liver of Swiss albino mice.

The present investigation dealt with harmful effects of hexavalent chromium (Cr [VI]) on liver of Swiss albino mice. This variant exhibited cytotoxicity, mutagenicity, and carcinogenicity. Our study focused on elucidating the hepatotoxic effects of chronic low-dose exposure to Cr (VI) (2, 5, and 10ppm) administered via drinking water for 4 and 8months. The observed elevation in SGPT, ALP, and SGOT and increased oxidative stress markers unequivocally confirmed the severe disruption of liver homeostasis at these low treatment doses. Noteworthy alterations in histoarchitecture, body weight, and water intake provided further evidences of the harmful effects of Cr (VI). Production of reactive oxygen species (ROS) during metabolism led to DNA damages. Immunohistochemistry and qRT-PCR analyses revealed that chronic low-dose exposure of Cr (VI) induced apoptosis in liver tissue. Our study exhibited alterations in the expression pattern of DNA repair genes (Rad51, Mutyh, Mlh1, and Ogg1), coupled with promoter hypermethylation of Mutyh and Rad51, leading to transcriptional inhibition. Our findings underscored the potential of low-dose Cr (VI) exposure on hepatotoxicity by the intricate interplay between apoptosis induction and epigenetic alterations of DNA repair genes.

Abstract 1478: Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal cancer cells

Abstract Background: Chronic exposure to long-term exposures to per- and polyfluoroalkyl substances (PFAS), widely known as “forever chemicals”, has been associated with multiple negative health outcomes including increased risk of cancer. Perfluorooctanesulfonic acid (PFOS), a “long-chain” subtype of PFAS, has high bioaccumulation potential with a long elimination half-life. PFOS is frequently detected in drinking water leading to its high absorption through the gastrointestinal tract. Recent studies demonstrate that PFAS exposures promote intestinal inflammation and gut barrier dysfunction. However, how a long-term PFOS exposure affects colorectal cancer (CRC) progression is not known. Therefore, the purpose of this study is to delineate the effect of PFOS exposure on CRC cell proliferation and test the potential mitigation strategy for the harmful effects of PFOS. Methods: SW480 and HCT116 cells have been treated with 1 ug/mL PFOS and proliferation was measured at 1, 2, and 3 months using the Presto Blue Cell Viability Reagent fluorescence assay. Proliferation markers were assessed by qPCR and Western blot. Control and PFOS exposed cells were treated with sulforaphane, a nuclear factor erythroid 2-related factor 2 (Nrf-2) inducer, at concentration 5, 10 and 20 uM for 72 hours. Results: We show that chronic, low-dose PFOS exposure promotes proliferation of SW480 and HCT116 cell lines starting at 3 months since the first exposure. The increase in proliferation is associated with upregulation of Cyclin D, pAkt and FASN. We also show that sulforaphane significantly decreases proliferation of HCT116 and SW480 cells, and its efficacy is significantly higher in PFOS exposed CRC cells. The current studies show no effect on sulforaphane on normal colon epithelium cells. Conclusion: Our studies suggest that chronic PFOS exposure promotes proliferation of CRC cells by increasing pro-carcinogenic gene expression and signaling. Furthermore, our findings suggest that supplementation of diet sulforaphane can potentially mitigate the harmful effects from PFOS exposure. Our studies warrant further investigation of the mechanisms behind the effect of PFOS exposure on cancer progression that would guide development of effective intervention strategies to mitigate the harmful effects of the exposure to “forever chemicals”. Citation Format: Jerika Durham, Josiane Weber Tessmann, Bernhard Hennig, Yekaterina Zaytseva. Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal cancer cells [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 1478.

Cadmium Exposure Impairs Development, Detoxification Mechanisms and Gene Expression of Glyphodes pyloalis Walker (Lepidoptera: Pyralidae)

Cadmium (Cd) is the most serious heavy metal pollutant in the agricultural soil of China and can transfer and accumulate through the food chain and affect the growth, development and physiological processes of phytophagous insect. Glyphodes pyloalis Walker (G. pyloalis) is one of the most important pests of mulberry, and there are few studies on the adverse effects of heavy metals on insects, especially mulberry pests. To understand the toxicology of Cd exposure on G. pyloalis, we investigated the effects of three different concentrations of Cd (0, 3.89 and 51.69 mg/kg, labeled as control check (CK), low dose (LD) and high dose (HD)) on the development and detoxification mechanism of G. pyloalis and explored the molecular mechanism of Cd on G. pyloalis larvae using RNA-seq technology. Transcriptome analysis showed that compared with the CK, a total of 63 differentially expressed genes (DEGs) were identified in LD exposure, including 24 upregulated and 39 downregulated candidates. In CK versus HD groups, 395 upregulated DEGs and 436 downregulated DEGs were identified and the expression patterns of 12 genes related to detoxification and metabolism were verified using qPCR. These DEGs were relevant to multiple specific peroxisome and drug metabolism-cytochrome P450 pathways. Gene annotation and quantitative real-time PCR revealed that a high concentration of Cd significantly stimulated the expression of metabolic detoxification enzyme genes. The results revealed that Cd exposure changed the pupal weight, adult emergence rate and the activities of AKP, ACP and GST in G. pyloalis and induced notable adverse effects at the molecular level on detoxification and metabolism such as concentration and time differences. In addition, we silenced CYP12A2 by RNA interference. Bioassays showed that after silencing CYP12A2, the survival rate of G. pyloalis under Cd exposure was lower than that of the control group.

A generalisation of the method of regression calibration and comparison with Bayesian and frequentist model averaging methods

For many cancer sites low-dose risks are not known and must be extrapolated from those observed in groups exposed at much higher levels of dose. Measurement error can substantially alter the dose–response shape and hence the extrapolated risk. Even in studies with direct measurement of low-dose exposures measurement error could be substantial in relation to the size of the dose estimates and thereby distort population risk estimates. Recently, there has been considerable attention paid to methods of dealing with shared errors, which are common in many datasets, and particularly important in occupational and environmental settings. In this paper we test Bayesian model averaging (BMA) and frequentist model averaging (FMA) methods, the first of these similar to the so-called Bayesian two-dimensional Monte Carlo (2DMC) method, and both fairly recently proposed, against a very newly proposed modification of the regression calibration method, the extended regression calibration (ERC) method, which is particularly suited to studies in which there is a substantial amount of shared error, and in which there may also be curvature in the true dose response. The quasi-2DMC with BMA method performs well when a linear model is assumed, but very poorly when a linear-quadratic model is assumed, with coverage probabilities both for the linear and quadratic dose coefficients that are under 5% when the magnitude of shared Berkson error is large (50%). For the linear model the bias is generally under 10%. However, using a linear-quadratic model it produces substantially biased (by a factor of 10) estimates of both the linear and quadratic coefficients, with the linear coefficient overestimated and the quadratic coefficient underestimated. FMA performs as well as quasi-2DMC with BMA when a linear model is assumed, and generally much better with a linear-quadratic model, although the coverage probability for the quadratic coefficient is uniformly too high. However both linear and quadratic coefficients have pronounced upward bias, particularly when Berkson error is large. By comparison ERC yields coverage probabilities that are too low when shared and unshared Berkson errors are both large (50%), although otherwise it performs well, and coverage is generally better than the quasi-2DMC with BMA or FMA methods, particularly for the linear-quadratic model. The bias of the predicted relative risk at a variety of doses is generally smallest for ERC, and largest for the quasi-2DMC with BMA and FMA methods (apart from unadjusted regression), with standard regression calibration and Monte Carlo maximum likelihood exhibiting bias in predicted relative risk generally somewhat intermediate between ERC and the other two methods. In general ERC performs best in the scenarios presented, and should be the method of choice in situations where there may be substantial shared error, or suspected curvature in the dose response.