Chemico-Biological Interactions最新文献

{"title":"Glycerophospholipid metabolic disorders and gender difference of cantharidin-induced hepatotoxicity in rats: Lipidomics and MALDI mass spectrometry imaging analysis","authors":"Qiyi Wang ,&nbsp;Weina Cheng ,&nbsp;Tianmu He ,&nbsp;Shan Li ,&nbsp;Jingwen Ao ,&nbsp;Yanmei He ,&nbsp;Cancan Duan ,&nbsp;Xiaofei Li ,&nbsp;Jianyong Zhang","doi":"10.1016/j.cbi.2024.111314","DOIUrl":"10.1016/j.cbi.2024.111314","url":null,"abstract":"<div><div>The hepatotoxicity mechanism of cantharidin (CTD), a major active component of <em>Mylabris</em> was explored based on liver lipidome alterations and spatial distributions in female and male rats using lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). After oral CTD exposure, the livers of female rats were screened for 104 differential lipids including lysophosphatidylethanolamine(LysoPE)(20:2/0:0) and diacylglycerol(DG)(18:2/22:4), whereas the livers of male rats were screened for 76 differential lipids including fatty acid(FA)(24:6) and DG(18:0/22:4). According to the MALDI-MSI results, female rats exhibited 12 differential lipids with alteration in the abundance and spatial distribution of phosphatylcholine(PC), phosphatidylethanolamine(PE), lysophosphatidylcholine(LysoPC), and LysoPE in the liver lesion area. On the other hand, male rats exhibited 8 differential lipids with changes in the abundance and spatial distribution of PC, PE, and FA in the liver lesion area. The lipidomics- and MALDI-MSI-detected differential lipids strongly disrupted glycerophospholipid metabolism in both female and male rats. Additionally, phosphatidate phosphatase <strong>(</strong>Lipin1), choline/ethanolamine phosphotransferase 1 (CEPT1), and phosphatidylethanolamine N-methyltransferase (PEMT) were screened to distinguish CTD hepatoxicity in female and male rats. Western blotting analysis demonstrated a significant elevation in Lipin1 expression in female and male rat livers, accompanied by a decrease in PEMT expression. Furthermore, CEPT1 expression increased significantly in female rat livers and decreased significantly in male rat livers. These findings suggested that CTD could disrupt lipid metabolism in a gender-specific manner. Moreover, the combination of lipidomics and MALDI-MSI could offer valuable insights into CTD-induced hepatotoxicity in rats.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111314"},"PeriodicalIF":4.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copper oxide nanoparticles induced reactive oxygen species generation: A systematic review and meta-analysis","authors":"Srimathi Murugesan,&nbsp;Satheeswaran Balasubramanian,&nbsp;Ekambaram Perumal","doi":"10.1016/j.cbi.2024.111311","DOIUrl":"10.1016/j.cbi.2024.111311","url":null,"abstract":"<div><div>Copper oxide nanoparticles (CuO NPs) are widely employed in various industrial and biomedical applications owing to their enhanced physicochemical characteristics. However, concerns regarding their adverse effects on biological systems upon entering the environment remain unexplored. The generation of reactive oxygen species (ROS) is one of the primary mechanisms in CuO NPs induced toxicity. This meta-analysis was conducted to assess the associative link between CuO NPs exposure and ROS generation. A literature survey was performed in PubMed, Web of Science, Scopus, and Google Scholar, following PRISMA guidelines. After comprehensive initial and primary screening, 28 <em>in vitro</em> studies were selected for meta-analysis. Overall, our results show a substantial increase of ROS in the experimental group when compared to control (SMD = 3.3; 95 % CI: 2.82−3.77, p = 0.00001), with substantial heterogeneity (82 %). Subgroup analysis revealed that larger-sized NPs, higher dosages, and longer exposure duration were associated with ROS generation. Meta-regression analysis identified size, and dosage as significant factors influencing ROS levels. Sensitivity analysis revealed an outlier study and the funnel plot results suggested potential publication bias. Overall, our results provide valuable insights of CuO NPs induced ROS generation, and the relation of variables such as size, dose, and duration in nanotoxicity assessments.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111311"},"PeriodicalIF":4.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the nephrotoxicity and molecular mechanisms of Di-2-ethylhexyl phthalate: A comprehensive review","authors":"Yun Liu ,&nbsp;Xu Zhang ,&nbsp;Ruhan Yi ,&nbsp;Qing Tian ,&nbsp;Jiawei Xu ,&nbsp;Xinyu Yan ,&nbsp;Jiaxuan Ma ,&nbsp;Shaopeng Wang ,&nbsp;Guang Yang","doi":"10.1016/j.cbi.2024.111310","DOIUrl":"10.1016/j.cbi.2024.111310","url":null,"abstract":"<div><div>Di-2-ethylhexyl phthalate (DEHP), a widely applied plasticizer in various products, can be absorbed into the human body through several channels and accumulate in the lungs, liver, testes, and kidneys, potentially impairing the function of these organs. Recently, the nephrotoxicity of DEHP has received heightened attention. Numerous epidemiologic findings have demonstrated that DEHP exposure may contribute to renal damage, leading to structural and functional abnormalities and exacerbating the progression of kidney disease. Recent research has discovered the mechanisms behind DEHP-induced nephrotoxicity may involve a variety of pathways, including apoptosis, autophagy, ferroptosis, oxidative stress, inflammation, DNA damage, and lipid metabolism disorders. This review discusses the impact of DEHP on kidney function and delves into the molecular mechanisms of nephrotoxicity mediated by DEHP in recent years. In addition, the review examines evidence for the antioxidant and anti-inflammatory capacities of lycopene, green tea polyphenols, and quercetin in ameliorating DEHP-induced renal injury is reviewed, providing a basis for further research.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111310"},"PeriodicalIF":4.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sevoflurane postconditioning mitigates neuronal hypoxic-ischemic injury via regulating reactive astrocytic STAT3 protein modification","authors":"Yufei Jia,&nbsp;Yanhong Song,&nbsp;Hang Xue,&nbsp;Xingyue Li,&nbsp;Yinong Zhang,&nbsp;Shiyue Fan,&nbsp;Xu Yang,&nbsp;Zixuan Ding,&nbsp;Yue Qiu,&nbsp;Ziyi Wu,&nbsp;Ping Zhao","doi":"10.1016/j.cbi.2024.111308","DOIUrl":"10.1016/j.cbi.2024.111308","url":null,"abstract":"<div><div>Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 min of 2.5 % sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111308"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicological effects and potential reproductive risk of microplastic-induced molecular changes in protamine-like proteins and their DNA binding","authors":"Carmela Marinaro ,&nbsp;Giulia Scarciello ,&nbsp;Anna Rita Bianchi ,&nbsp;Bruno Berman,&nbsp;Teresa Chianese,&nbsp;Rosaria Scudiero,&nbsp;Luigi Rosati ,&nbsp;Anna De Maio ,&nbsp;Gennaro Lettieri,&nbsp;Marina Piscopo","doi":"10.1016/j.cbi.2024.111309","DOIUrl":"10.1016/j.cbi.2024.111309","url":null,"abstract":"<div><div>Today, plastic pollution is a widespread problem in all ecosystems and has a particularly severe impact on marine ecosystems and external fertilisers such as the mussel <em>Mytilus galloprovincialis</em>. The present study aims to assess the toxicological reproductive health effects in this organism following exposure to two concentrations of polystyrene microplastics (PS-MPs) (0.5 and 1 μg/L), representative of conditions in the Mediterranean Sea. After exposure, the electrophoretic pattern of protamine-like (PL) proteins, the major basic protein component of <em>Mytilus galloprovincialis</em> sperm chromatin, was analysed. Compared to the unexposed condition, differences were observed by SDS-PAGE and an increased ability of PL to bind and protect DNA from oxidative damage was then measured, particularly for PL from mussels exposed to 1 μg/L PS-MPs. At this dose of PS-MPs, a reduced release of all PLs from the sperm nuclei was also observed, whereas the digestion by micrococcal nuclease did not show any significant differences between the exposed and the unexposed conditions. Finally, the possibility of poly(ADP)-ribosylation of the PLs was investigated. PL-II showed an increase in poly(ADP)-ribosylation after PS-MPs exposure, which may account for the difference in the ability of the PLs to bind DNA. In conclusion, while all the results might suggest a molecular mechanism of gametic plasticity occurring upon exposure of mussels to PS-MPs 1 μg/L, they also indicate that this dose of exposure could be extremely detrimental to the reproductive health of <em>Mytilus galloprovincialis</em> because it could prevent the release of basic nuclear proteins from the sperm DNA at fertilisation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111309"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diosgenin attenuates nonalcoholic fatty liver disease through mTOR-mediated inhibition of lipid accumulation and inflammation","authors":"Guoliang Yin ,&nbsp;Hongyi Liang ,&nbsp;Yiran Cheng ,&nbsp;Suwen Chen ,&nbsp;Xin Zhang ,&nbsp;Decheng Meng ,&nbsp;Wenfei Yu ,&nbsp;Hongshuai Liu ,&nbsp;Chaoyuan Song ,&nbsp;Fengxia Zhang","doi":"10.1016/j.cbi.2024.111306","DOIUrl":"10.1016/j.cbi.2024.111306","url":null,"abstract":"<div><div>Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms <em>in vitro</em> and in vivo were examined using quantitative polymerase chain reaction and Western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111306"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the mechanism of ursolic acid in preventing liver fibrosis and improving intestinal microbiota based on NOX2/NLRP3 inflammasome signaling pathway","authors":"Qi Liu ,&nbsp;Lin-Xiang Liu ,&nbsp;Bi-Min Li ,&nbsp;Wang Zhang ,&nbsp;Yue Zhang ,&nbsp;Peng Chen ,&nbsp;Chen-Kai Huang ,&nbsp;Yuan Nie ,&nbsp;Xuan Zhu","doi":"10.1016/j.cbi.2024.111305","DOIUrl":"10.1016/j.cbi.2024.111305","url":null,"abstract":"<div><div>Early-stage liver fibrosis can be reversed; however, the underlying mechanisms remain incompletely understood. The intestinal tract hosts a substantial and diverse microbiota involved in various physiological activities and is closely linked to chronic liver disease. Previous studies have indicated that ursolic acid (UA), derived from herbal plants, possesses anti-inflammatory and antifibrotic properties; however, its precise mechanism remains to be elucidated. Consequently, liver fibrosis models were constructed utilizing both the methionine/choline deficieny (MCD) diet and carbon tetrachloride (CCl4) intraperitoneal injections. 16S rRNA was conducted to analyze the intestinal microbiota. Results indicated that UA attenuated liver injury and fibrosis, reduced indices related to liver fibrosis, and decreased the expression levels of NADPH oxidase 2 (NOX2) and NOD like receptor protein 3 (NLRP3). Hepatic fibrosis was alleviated in post-model NOX2 and NLRP3 gene knockout (NOX2^−/− and NLRP3^−/−) mice in comparison to post-model wild-type (WT) mice. Nonetheless, neither UA treatment nor control treatment significantly improved liver fibrosis in comparison to post-model knockout mice. Furthermore, the liver of NOX2^−/− mice exhibited lower levels of NLRP3 expression. Importantly, knockout mice displayed a higher diversity of intestinal microbiota, characterized by an increased presence of beneficial bacteria and a reduced presence of harmful bacteria compared to WT mice. In conclusion, UA exerts antifibrotic effects through the inhibition of the NOX2/NLRP3 inflammasome signaling pathway. UA has the potential to reverse liver fibrosis by modulating this signaling pathway, thereby enhancing the gut microbiota.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111305"},"PeriodicalIF":4.7,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic analysis of Lewisite exposed human dermal equivalent tissues","authors":"Elizabeth S. Dhummakupt,&nbsp;Conor C. Jenkins,&nbsp;Gabrielle M. Rizzo,&nbsp;Allison E. Clay,&nbsp;Jennifer R. Horsmon,&nbsp;Tyler D.P. Goralski,&nbsp;Julie A. Renner,&nbsp;Daniel J. Angelini","doi":"10.1016/j.cbi.2024.111295","DOIUrl":"10.1016/j.cbi.2024.111295","url":null,"abstract":"<div><div>Lewisite (Military Code: L) is an arsenical vesicant chemical warfare agent (CWA) that was developed in the United States during World War I. Even though its use has not been documented in warfare, large stockpiles were created and still exist in various locations around the world. Given that large quantities exist as well as the relative straightforward process for its creation, Lewisite still presents itself as a serious threat agent. In this study, we examined the effects of Lewisite on human dermal equivalent tissues (EpiDerm™/EpiDerm™-FT) through the evaluation of cellular viability, histology, and multiomic analysis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111295"},"PeriodicalIF":4.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rosavin regulates bone homeostasis through HDAC1-induced epigenetic regulation of EEF2","authors":"Wenhao Zhang ,&nbsp;Leilei Yu ,&nbsp;Fang Wang,&nbsp;Minjie Chen,&nbsp;Hui Li","doi":"10.1016/j.cbi.2023.110696","DOIUrl":"https://doi.org/10.1016/j.cbi.2023.110696","url":null,"abstract":"<div><p>Bioactive constituents from Rhodiola rosea<span><span><span> L. show a myriad of pharmacological effects on diverse diseases. Rosavin has been linked to reduced osteoclastogenesis, while its role in regulating osteogenesis remains unclear. The present study investigated whether and how Rosavin alleviates ovariectomy (OVX)-induced osteoporosis (OP) in mice. Rosavin had a therapeutic effect on OP in ovariectomized mice and inhibited osteoclast viability and promoted osteoblast viability. Integrated </span>transcriptome sequencing, GO enrichment analysis, and PPI network construction revealed that the HDAC1/EEF2 axis was an important axis of gene action for Rosavin treatment. Mechanistically, </span>HDAC1<span> suppressed EEF2 expression through histone<span> deacetylation. Rescue experiments exhibited that HDAC1 promoted osteoclast viability, while EEF2 reversed the action of HDAC1 to restore bone homeostasis<span>. In mice with OP, HDAC1 mitigated the effects of Rosavin, resulting in enhanced bone resorption<span> and diminished bone formation, while EEF2 contributed to reduced bone resorption and elevated bone formation in mice. NF-κB and MAPK pathways were inhibited by Rosavin, enhanced by HDAC1, and blocked again by EEF2. To summarize, our results proved that Rosavin maintained bone homeostasis in OP via regulation of histone acetylation of EEF2, thus playing a key role as a therapeutic candidate for OP treatment.</span></span></span></span></span></p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"384 ","pages":"Article 110696"},"PeriodicalIF":5.1,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6713464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk assessment of parabens in a transcriptomics-based in vitro test","authors":"Florian Seidel ,&nbsp;Franziska Kappenberg ,&nbsp;Susann Fayyaz ,&nbsp;Andreas Scholtz-Illigens ,&nbsp;Anna Cherianidou ,&nbsp;Katharina Derksen ,&nbsp;Patrick Nell ,&nbsp;Rosemarie Marchan ,&nbsp;Karolina Edlund ,&nbsp;Marcel Leist ,&nbsp;Agapios Sachinidis ,&nbsp;Jörg Rahnenführer ,&nbsp;Reinhard Kreiling ,&nbsp;Jan G. Hengstler","doi":"10.1016/j.cbi.2023.110699","DOIUrl":"https://doi.org/10.1016/j.cbi.2023.110699","url":null,"abstract":"<div><p><span><span><span>Parabens have been used for decades as preservatives in food, drugs and cosmetics. The majority however, were banned in 2009 and 2014 leaving only methyl-, ethyl-, propyl-, and butyl-derivates available for subsequent use. Methyl- and </span>propylparaben have been extensively tested in vivo, with no resulting evidence for developmental and </span>reproductive toxicity<span> (DART). In contrast, ethylparaben has not yet been tested for DART in animal experiments, and it is currently debated if additional animal studies are warranted. In order to perform a comparison of the four currently approved parabens, we used a previously established in vitro test based on human induced pluripotent stem cells (iPSC) that are exposed to test substances during their differentiation to neuroectodermal cells. EC</span></span>₅₀<span><span> values for cytotoxicity were 906 μM, 698 μM, 216 μM and 63 μM for methyl-, ethyl-, propyl- and butylparaben<span>, respectively, demonstrating that cytotoxicity increases with increasing alkyl chain length. Genome-wide analysis demonstrated that FDR-adjusted significant gene expression changes occurred only at cytotoxic or close to cytotoxic concentrations, for example 1720 differentially expressed genes (DEG) at 1000 μM ethylparaben, 1 DEG at 316 μM, and no DEG at 100 μM or lower concentrations. The highest concentration of ethylparaben that did not induce any cytotoxicity nor DEG was 1670-fold above the highest concentration reported in biomonitoring studies (60 nM ethylparaben in cord blood). In conclusion, cytotoxicity and gene expression alterations of ethylparaben occurred at concentrations of approximately three orders of magnitude above human blood concentrations; moreover, the substance fitted well into a scenario where toxicity increases with the alkyl chain length, and gene expression changes only occur at cytotoxic or close to cytotoxic concentrations. Therefore, no evidence was obtained suggesting that in vivo DART with ethylparaben would lead to different results as the methyl- or </span></span>propyl derivates.</span></p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"384 ","pages":"Article 110699"},"PeriodicalIF":5.1,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"6713460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}