Current Research in Toxicology最新文献

{"title":"Molecular response of Chironomus riparius to antibiotics","authors":"Judit Kalman ,&nbsp;Yolanda Valcárcel-Rivera ,&nbsp;José Luis Martínez-Guitarte","doi":"10.1016/j.crtox.2025.100239","DOIUrl":"10.1016/j.crtox.2025.100239","url":null,"abstract":"<div><div>Antibiotics, like other pharmaceuticals, are continuously released into the environment as a result of human activities. Although designed to target harmful bacteria, they can also affect non-target organisms in aquatic ecosystems. Standard toxicological tests often fail to detect the subtle or long term antibiotic-induced effects, but newer methods are providing valuable insights into the molecular pathways and physiological responses they affect. <em>Chironomus riparius</em>, a dipteran with aquatic larvae, is widely used in toxicological testing due to its sensitivity to various toxicants. However, little is known about the molecular effects of antibiotics on this species.</div><div>This study investigated the gene expression profile of <em>C. riparius</em> in response to antibiotics from three classes − aminoglycosides, fluoroquinolones and penicillin. Fourth instar larvae were exposed to concentrations of 0.001, 0.1 and 10 mg/L for 24 and 72 h. The expression of genes involved in hormonal regulation, detoxification, stress response and DNA repair was analysed. The results showed that all antibiotics altered mRNA levels, with three of the four (amoxicillin, neomycin and levofloxacin) downregulating genes at 24 h and upregulating them at 72 h. Genes affected by gentamicin showed the opposite trend.</div><div>These transcriptional changes in response to different antibiotics highlight the complexity of the regulatory mechanisms involved in development, detoxification, stress response and DNA repair in aquatic insects. Further research is needed to better understand the molecular effects of antibiotics on this species.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100239"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thallium (III) disrupts the cell cycle and induces oxidative DNA damage in human lymphocytes in vitro","authors":"Alejandra López-Lanuza ,&nbsp;Lucila Álvarez-Barrera ,&nbsp;Hugo López-Muñoz ,&nbsp;Rodrigo Aníbal Mateos-Nava ,&nbsp;Juan José Rodríguez-Mercado","doi":"10.1016/j.crtox.2025.100240","DOIUrl":"10.1016/j.crtox.2025.100240","url":null,"abstract":"<div><div>Thallium (Tl) is considered hazardous to health because of its high toxicity and is an emerging contaminant with two oxidation states: Tl (I) and Tl (III). However, the toxicity of Tl and its compounds can be influenced by the oxidation state of the metal. Tl (III) is the least studied oxidation state of Tl, although it may affect cell proliferation and has genotoxic potential. Therefore, the aim of the present study was to analyze the effects Tl (III) chloride (TlCl₃) on cell cycle progression, the induction of DNA damage, and oxidative stress in human lymphocytes <em>in vitro</em>. There were no changes in cell viability after treatment with different concentrations (0.1, 0.5, 1, 5, 10, and 50 μg/mL) of TlCl₃ for different exposure durations (1, 3, and 24 h), and a reduction in the number of viable cells was observed only after treatment with high concentrations (10 and 50 μg/mL) for 72 h. In addition, cells treated with 5–50 μg/mL TlCl₃ for 48 and 72 h arrested in G₁ phase. Moreover, TlCl₃ increased DNA damage by activating the enzyme formamidopyrimidine DNA-glycosylase (FPG), which oxidized DNA bases and increased the production of reactive oxygen species. In conclusion, TlCl₃ induces oxidative stress and DNA damage by oxidizing DNA bases, which may disrupt the cell cycle.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100240"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategy for reproductive and developmental toxicity (DART) studies for marketing applications in pharmaceutical development","authors":"Yusuke Kagawa ,&nbsp;Takuro Osawa ,&nbsp;Naomi Koyama ,&nbsp;Takashi Tanaharu ,&nbsp;Daisuke Kigami","doi":"10.1016/j.crtox.2025.100258","DOIUrl":"10.1016/j.crtox.2025.100258","url":null,"abstract":"<div><div>Studies on reproductive toxicity are conducted to assess the effects of chemicals and pharmaceuticals on the reproductive function and fetal development. However, depending on the indication or modality, Fertility and Early Embryonic Development (FEED), Embryo-Fetal Development (EFD), and Pre/Postnatal Development (PPND) studies which evaluate all reproductive stages or EFD studies in a second species may not be necessary. Therefore, based on the Common Technical Document (CTD), PMDA review reports, and other documents of drugs with new active ingredients approved in Japan, we aimed to investigate the implementation status of DART studies by classifying the studies into FEED, EFD, and PPND types, and summarizing the reasons for not conducting the studies. This survey was conducted by the Reproductive and Developmental Toxicity Team of the Japan Pharmaceutical Manufacturers Association (JPMA) to address issues related to DART studies conducted as non-clinical studies for drug development. Of the three DART studies, 35% of drugs received marketing application without conducting EFD studies in at least one species. Among the three study types, PPND studies were the second most frequently waivered, with 36% not conducted. FEED studies had the lowest implementation rate among the three types of studies, with 40% not conducted. The primary reason for waiving at least one study was compliance with ICH S5, S6, S9, and M3 guidelines. In conclusion, the necessity of DART studies varied depending on the applicable ICH guideline and the characteristics of the drug, including therapeutic indication, target, endogenous substances, low exposure, and ADA formation. This suggests that the need for DART studies may be waived because of various reasons, each of which should be justified based on scientific rationale and risk analysis.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100258"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145104416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating open access new approach methods (NAM) to assess biological points of departure: A case study with 4 neurotoxic pesticides","authors":"Marilyn H. Silva","doi":"10.1016/j.crtox.2024.100156","DOIUrl":"10.1016/j.crtox.2024.100156","url":null,"abstract":"<div><p>Open access new approach methods (NAM) in the US EPA ToxCast program and NTP Integrated Chemical Environment (ICE) were used to investigate activities of four neurotoxic pesticides: endosulfan, fipronil, propyzamide and carbaryl. Concordance of <em>in vivo</em> regulatory points of departure (POD) adjusted for interspecies extrapolation (AdjPOD) to modelled human Administered Equivalent Dose (AED_Human) was assessed using 3-compartment or Adult/Fetal PBTK <em>in vitro</em> to <em>in vivo</em> extrapolation. Model inputs were from Tier 1 (High throughput transcriptomics: HTTr, high throughput phenotypic profiling: HTPP) and Tier 2 (single target: ToxCast) assays. HTTr identified gene expression signatures associated with potential neurotoxicity for endosulfan, propyzamide and carbaryl in non-neuronal MCF-7 and HepaRG cells. The HTPP assay in U-2 OS cells detected potent effects on DNA endpoints for endosulfan and carbaryl, and mitochondria with fipronil (propyzamide was inactive). The most potent ToxCast assays were concordant with specific components of each chemical mode of action (MOA). Predictive adult IVIVE models produced fold differences (FD) &lt; 10 between the AED_Human and the measured <em>in vivo</em> AdjPOD. The 3-compartment model was concordant (i.e., smallest FD) for endosulfan, fipronil and carbaryl, and PBTK was concordant for propyzamide. The most potent AED_Human predictions for each chemical showed HTTr, HTPP and ToxCast were mainly concordant with <em>in vivo</em> AdjPODs but assays were less concordant with MOAs. This was likely due to the cell types used for testing and/or lack of metabolic capabilities and pathways available <em>in vivo</em>. The Fetal PBTK model had larger FDs than adult models and was less predictive overall.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100156"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000094/pdfft?md5=31c931d7a1bcb728b57343cdc6471724&pid=1-s2.0-S2666027X24000094-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139873916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer's disease: In silico study of rosemary diterpenes activities","authors":"Zakariae Abbaoui ,&nbsp;Mohammed Merzouki ,&nbsp;Imane Oualdi ,&nbsp;Abdelhamid Bitari ,&nbsp;Abdelouhed Oussaid ,&nbsp;Allal Challioui ,&nbsp;Rachid Touzani ,&nbsp;Belkheir Hammouti ,&nbsp;Wilson Agerico Diño","doi":"10.1016/j.crtox.2024.100159","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100159","url":null,"abstract":"<div><p>The global surge in Alzheimer's disease poses a significant public health concern. In response, we study the efficacy of carnosic acid and related abietane-type diterpenes extracted from rosemary as acetylcholinesterase (AChE) inhibitors. Our analyses, using in silico techniques, encompassed all the compounds within this extract. Through molecular docking, we explored how these compounds interact with the active site of the AChE protein. The docking scores, ranging from −5.560 Kcal/mol to −7.270 Kcal/mol, indicate robust binding affinities. Assessment of the ADME/T (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) properties and pharmacokinetics of these compounds reveal favorable profiles for all the tested substances. These encouraging results suggest the potential of these compounds as candidates for further development to prevent and/or treat Alzheimer's disease. Among these compounds, we find rosmanol as the most likely candidate for further research and clinical trials to validate their efficacy.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100159"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000124/pdfft?md5=a81cfe8a39de5357800a7a007141150a&pid=1-s2.0-S2666027X24000124-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140030287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcellular expression of CYP2E1 in HepG2 cells impacts response to free oleic and palmitic acid","authors":"Zaria K. Killingsworth ,&nbsp;Kelly R. Misare ,&nbsp;Abigail S. Ryan ,&nbsp;Elizabeth A. Ampolini ,&nbsp;Tsultrim T. Mendenhall ,&nbsp;Melinda A. Engevik ,&nbsp;Jessica H. Hartman","doi":"10.1016/j.crtox.2024.100195","DOIUrl":"10.1016/j.crtox.2024.100195","url":null,"abstract":"<div><h3>Aims</h3><div>Cytochrome P450 2E1 (CYP2E1) is a mammalian monooxygenase expressed at high levels in the liver that metabolizes low molecular weight pollutants and drugs, as well as endogenous fatty acids and ketones. Although CYP2E1 has been mainly studied in the endoplasmic reticulum (ER, microsomal fraction), it also localizes in significant amounts to the mitochondria, where it has been far less studied. We investigated the effects of CYP2E1 expression in mitochondria, endoplasmic reticulum, or both organelles in transgenic HepG2 cells exposed to free oleic and palmitic acid, including effects on cytotoxicity, lipid storage, respiration, and gene expression.</div></div><div><h3>Results</h3><div>We found that HepG2 cells expressing CYP2E1 in both the ER and mitochondria have exacerbated levels of palmitic acid cytotoxicity and inhibited respiration. CYP2E1 expression did not impact lipid accumulation from fatty acid exposures, but mitochondrial CYP2E1 expression promoted lipid droplet depletion during serum starvation. In contrast to HepG2 cells, differentiated HepaRG cells express abundant CYP2E1, but they are not sensitive to palmitic acid cytotoxicity. Oleic acid exposure prompted less cytotoxicity, and CYP2E1 expression in the ER prevented an oleic-acid-induced increase in respiration. HepG2 cells exposed to mixtures of palmitic and oleic acid are protected from palmitic acid cytotoxicity. Additionally, we identified that CYP2E1 was decreased at the gene and protein level in hepatocellular carcinoma. Moreover, patients with tumors that had higher CYP2E1 expression had a better prognosis compared to patients with lower CYP2E1 expression.</div></div><div><h3>Innovation</h3><div>This study has demonstrated that transgenic CYP2E1 subcellular localization plays an important role in sensitivity to cytotoxicity, lipid storage, and respiration in the hepatoma cell line HepG2 exposed to palmitic and oleic acid. HepaRG cells, in contrast, were insensitive to palmitic acid. This work demonstrates the clear importance of CYP2E1 in dictating lipotoxicity and differential roles for the mitochondrial and ER forms of the enzyme. Additionally, our data supports a potentially unique role for CYP2E1 in cancer cells.</div></div><div><h3>Conclusion</h3><div>There lies a role for CYP2E1 in altering lipotoxicity, and since CYP2E1 is known to be upregulated in both liver disease and hepatocellular carcinoma, it is important to better define how the role of CYP2E1 changes during disease progression.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100195"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protective effects of amphetamine and methylphenidate against dopaminergic neurotoxicants in SH-SY5Y cells","authors":"Patrícia Carneiro ,&nbsp;Mariana Ferreira ,&nbsp;Vera Marisa Costa ,&nbsp;Félix Carvalho ,&nbsp;João Paulo Capela","doi":"10.1016/j.crtox.2024.100165","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100165","url":null,"abstract":"<div><p>Full treatment of the second most common neurodegenerative disorder, Parkinson’s disease (PD), is still considered an unmet need. As the psychostimulants, amphetamine (AMPH) and methylphenidate (MPH), were shown to be neuroprotective against stroke and other neuronal injury diseases, this study aimed to evaluate their neuroprotective potential against two dopaminergic neurotoxicants, 6-hydroxydopamine (6-OHDA) and paraquat (PQ), in differentiated human dopaminergic SH-SY5Y cells.</p><p>Neither cytotoxicity nor mitochondrial membrane potential changes were seen following a 24-hour exposure to either therapeutic concentration of AMPH or MPH (0.001–10 μM). On the other hand, a 24-hour exposure to 6-OHDA (31.25–500 μM) or PQ (100–5000 μM) induced concentration-dependent mitochondrial dysfunction, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and lysosomal damage, evaluated by the neutral red uptake assay. The lethal concentrations 25 and 50 retrieved from the concentration-toxicity curves in the MTT assay were 99.9 µM and 133.6 µM for 6-OHDA, or 422 µM and 585.8 µM for PQ. Both toxicants caused mitochondrial membrane potential depolarization, but only 6-OHDA increased reactive oxygen species (ROS). Most importantly, PQ-induced toxicity was partially prevented by 1 μM of AMPH or MPH. Nonetheless, neither AMPH nor MPH could prevent 6-OHDA toxicity in this experimental model.</p><p>According to these findings, AMPH and MPH may provide some neuroprotection against PQ-induced neurotoxicity, but further investigation is required to determine the exact mechanism underlying this protection.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100165"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000185/pdfft?md5=e8feb0868f6d3c35be317d1482d07e68&pid=1-s2.0-S2666027X24000185-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acceleration of benzo(a)pyrene-induced colon carcinogenesis by Western diet in a rat model of colon cancer","authors":"Kelly L. Harris ,&nbsp;Kenneth J. Harris ,&nbsp;Leah D. Banks ,&nbsp;Samuel E. Adunyah,&nbsp;Aramandla Ramesh","doi":"10.1016/j.crtox.2024.100162","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100162","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is the third leading cause of cancer-related mortalities in the USA and around 52,550 people were expected to die from this disease by December 2023. The objective of this study was to investigate the effect of diet type on benzo(a)pyrene [B(a)P]-induced colon cancer in an adult male rat model, the Polyposis In the Rat Colon (PIRC) kindred type. Groups of PIRC rats (n = 10) were fed with AIN-76A regular diet (RD) or Western diet (WD) and received 25, 50 and 100 µg B(a)P/kg body wt. via oral gavage for 60 days. Rats fed diets alone, but no B(a)P, served as controls. After exposure, rats were euthanized; colon and liver samples were analyzed for activation of drug metabolizing enzymes (DMEs) CYP1A1, CYP1B1, SULT and GST. Plasma and tissue samples were analyzed by reverse phase-HPLC for B(a)P metabolites. In addition to these studies, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the ³²P-postlabeling method using a thin-layer chromatography system. Western diet consumption resulted in a marked increase in DME expression and B(a)P metabolite concentrations in rats that were administered 100 µg/kg B(a)P + WD (p &lt; 0.05) compared to other treatment groups. Our findings demonstrate that WD accelerates the development of colon tumors induced by B(a)P through enhanced biotransformation, and the products of this process (metabolites) were found to bind with DNA and form B(a)P-DNA adducts, which may have given rise to colon polyps characterized by gain in tumor number, sizes, and dysplasia.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100162"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400015X/pdfft?md5=fa6e9e7a98636748599bec26e093a373&pid=1-s2.0-S2666027X2400015X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140096236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Environmental cadmium-induced circRNA-miRNA-mRNA network regulatory mechanism in human normal liver cell model","authors":"Zhi Qu ,&nbsp;Lugang Deng ,&nbsp;Chunqian Feng ,&nbsp;Peisen Guo ,&nbsp;Peixi Wang ,&nbsp;Nan Liu","doi":"10.1016/j.crtox.2024.100192","DOIUrl":"10.1016/j.crtox.2024.100192","url":null,"abstract":"<div><p>At present, hundreds of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been confirmed to be related to the toxicity of cadmium (Cd). However, the role of circular RNAs (circRNAs) in the toxicity of Cd and the underlying regulatory mechanisms remain unclear. In this study, we chose human normal liver cells (L-02) as a model to investigate changes in transcriptome expression levels following exposure to Cd. Total RNA of each sample was extracted by Trizol method, and the expression profiles of circRNAs, miRNAs and mRNAs of each sample were determined by microarray hybridization and scanning. After standardizing the data, differential circRNAs, miRNAs, and mRNAs associated with the toxic effects of Cd were identified. By screening the predicted circRNAs, miRNAs, and mRNAs, we constructed a competing endogenous RNA (ceRNA) network, and predicted the main biological functions and metabolic pathways influenced by Cd toxicity. Our comprehensive screening strategy led to the identification of 266 different circRNAs, 223 different miRNAs and 519 different mRNAs exhibiting differential expression. Following further screening, even circRNAs, 10 miRNAs and 97 mRNAs were incorporated into the ceRNA network. After performing GO enrichment and KEGG pathway analyses on the 97 mRNAs within the ceRNA network, which indicated that the circRNAs in the ceRNA network are poised to modulate key cellular processes, including cell proliferation, apoptosis, oxidative stress and inflammatory responses under the toxic effects of Cd-induced damage in L-02 cells.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100192"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000458/pdfft?md5=ff0fa6c687127d74e562c5fe0095d0dd&pid=1-s2.0-S2666027X24000458-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142075899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethylene dimethanesulfonate effects on gene promoter activities related to the endocrine function of immortalized Leydig cell lines R2C and MA-10","authors":"Jorge W.F. de Barros ,&nbsp;Kenley Joule Pierre ,&nbsp;Wilma De G. Kempinas ,&nbsp;Jacques J. Tremblay","doi":"10.1016/j.crtox.2023.100147","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100147","url":null,"abstract":"<div><p>Ethylene dimethanesulfonate (EDS) is a molecule with known selective cytotoxicity on adult Leydig cells. A single intraperitoneal injection in rats but not mice, leads to male androgen deprivation and infertility. <em>In vitro</em> studies using rat and mouse immortalized Leydig cell lines, showed similar effects of cell death promoted by EDS in rat cells as seen <em>in vivo</em>, and suggest that EDS affects gene transcription, which could firstly compromise steroidogenesis before the apoptosis process. Using gene reporter assay, this study aimed to investigate EDS effects on the promoter activity of genes important for endocrine function (<em>Star</em>, <em>Insl3</em>) and response to toxic agents (<em>Gsta3</em>) in immortalized Leydig cell lines (rat R2C and mouse MA-10 cells), as well as identify possible EDS-responsive elements in the <em>Star</em> gene promoter. EDS exposure of R2C and MA-10 Leydig cells increased <em>Gsta3</em> promoter activity after 4 h of treatment and decreased <em>Insl3</em> promoter activity only in R2C cells after 24 h of treatment. EDS also decreased <em>Star</em> promoter activity in both Leydig cell lines. Using R2C cells, the EDS-responsive region in the <em>Star</em> promoter was located between −400 and −195 bp. This suggests that this region and the associated transcription factors, which include MEF2, might be targeted by EDS. Additional somatic gonadal cell lines expressing <em>Star</em> were used and EDS did not affect <em>Star</em> promoter activity in DC3 granulosa cells while <em>Star</em> promoter activity was increased in MSC-1 Sertoli cells after 24 h of treatment. This study contributes to the knowledge regarding the mechanism of EDS action in Leydig cells, and in other gonadal cell lineages, and brings new light regarding the rats and mice differential susceptibility to EDS effects, in addition to providing new avenues for experimental approaches to better understand Leydig cell function and dynamics in different rodent species.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100147"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000452/pdfft?md5=7638e3700b61387d77ad30d1e6ae81c8&pid=1-s2.0-S2666027X23000452-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139108115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}