Current Research in Toxicology最新文献

{"title":"Crowdsourcing AOP development: Leveraging the thesis literature review to identify knowledge gaps and facilitate research translation","authors":"Jacob I. Reynolds ,&nbsp;Judy Choi ,&nbsp;Brian P. Johnson","doi":"10.1016/j.crtox.2024.100191","DOIUrl":"10.1016/j.crtox.2024.100191","url":null,"abstract":"<div><p>Chemical risk assessment still primarily relies on extrapolation of data from high-confidence <em>in vivo</em> studies. Emerging 21st Century Toxicology tools and approaches have potential to figure more prominently in chemical risk assessment, but many challenges in translating this research into assessments remain. One of these tools, the Adverse Outcome Pathway (AOP) Wiki provides a framework to map and evaluate adverse chemical dynamics, that is the biochemical and physiological effects that occur after chemical exposure. The AOP-guided targeted review of relevant literature, described here, shares similarities with a doctoral thesis or literature review but forces critical evaluation of each step in a pathway including those of central dogma. Additionally, it provides valuable translational regulatory relevance. Data gaps identified through this process can be targeted areas of study in the thesis itself to increase translational relevance. One of the challenges with this tool is that many AOPs are under- or undeveloped. To help fill this need, a concerted effort by subject matter experts to speed the development of AOPs supported under the Organization for Economic Cooperation and Development (OECD) framework would benefit this translational problem. As a case study, we present our experience developing AOP 460: Antagonism of Smoothened receptor leading to orofacial clefting (OECD AOP workplan project 1.101) as part of a graduate literature review. AOP development offers clear benefits to the regulatory and academic communities and increased dissemination of AOPs replete with the most current state of scientific knowledge will promote research translation and increased risk assessment capabilities.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100191"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000446/pdfft?md5=c2419829dcdc8264778e5365bcbe94c1&pid=1-s2.0-S2666027X24000446-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141953746","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":"Cytotoxicity and inhibitory potential of CUDC-101 in non-small cell lung cancer cells with rare EGFR L861Q mutation","authors":"Chunhong Chu ,&nbsp;Huixia Xu ,&nbsp;Chenxue Liu ,&nbsp;Xiangkai Wei ,&nbsp;Lanxin Li ,&nbsp;Rui Wang ,&nbsp;Wenrui Cui ,&nbsp;Guoliang Zhang ,&nbsp;Chenyang Liu ,&nbsp;Ke Wang ,&nbsp;Lei An ,&nbsp;Fei He","doi":"10.1016/j.crtox.2024.100194","DOIUrl":"10.1016/j.crtox.2024.100194","url":null,"abstract":"<div><div>The epidermal growth factor receptor (EGFR) represents an effective target for the treatment of non-small cell lung cancer. In the treatment of classical EGFR mutations, EGFR tyrosine kinase inhibitors have achieved desirable clinical efficacy. However, the effectiveness of tyrosine kinase inhibitors (TKIs) against the L861Q mutation has not been fully established. In this study, the four cell lines containing the L861Q mutation were constructed by CRISPR and the anti-tumour effects of CUDC-101 on them were investigated in vitro by various chemosensitivity methods, with afatinib serving as a positive control. The results demonstrated that CUDC-101 inhibited the proliferation and clonogenic capacity on the four cells through the ERK or AKT pathways, decreased the mitochondrial membrane potential of the cells, blocked the cell cycle and promoted apoptosis. Our findings suggest that CUDC-101 may be a promising treatment option for NSCLC patients with the EGFR exon 18 substitution mutation L861Q.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100194"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142531775","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":"Reproductive cytotoxic and genotoxic impact of polystyrene microplastic on Paracentrotus lividus spermatozoa","authors":"Filomena Mottola,&nbsp;Maria Carannante,&nbsp;Angela Barretta,&nbsp;Ilaria Palmieri,&nbsp;Lucia Rocco","doi":"10.1016/j.crtox.2024.100173","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100173","url":null,"abstract":"<div><p>In recent decades, industrialization, intensive agriculture, and urban development have severely impacted marine environments, compromising the health of aquatic and terrestrial organisms. Inadequate disposal results in hundreds of tons of plastic products released annually into the environment, which degrade into microplastics (MPs), posing health risks due to their ability to biomagnify and bioaccumulate. Among these, polystyrene MPs (PS-MPs) are significant pollutants in marine ecosystems, widely studied for their reproductive toxicological effects. This research aimed to evaluate the reproductive cytotoxic and genotoxic effects of PS-MPs on sea urchin (<em>Paracentrotus lividus</em>) spermatozoa <em>in vitro</em>. Results showed that PS-MPs significantly reduced sperm viability and motility without altering morphology, and induced sperm DNA fragmentation mediated by reactive oxygen species production. Furthermore, head-to-head agglutination of the spermatozoa was observed exclusively in the sample treated with the plastic agents, indicating the ability of microplastics to adhere to the surface of sperm cells and form aggregates with microplastics on other sperm cells, thereby impeding movement and reducing reproductive potential. These findings suggest that PS-MPs can adversely affect the quality of sea urchin sperm, potentially impacting reproductive events.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100173"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000264/pdfft?md5=9e1cb88ad35cf0ccec8deb87c4f72997&pid=1-s2.0-S2666027X24000264-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141090156","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":"Low-cost quantum mechanical descriptors for data efficient skin sensitization QSAR models","authors":"Davy Guan,&nbsp;Raymond Lui,&nbsp;Slade T. Mattthews","doi":"10.1016/j.crtox.2024.100183","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100183","url":null,"abstract":"<div><p>Quantitative Structure Activity Relationship modelling methodologies need to incorporate relevant mechanistic information to have high predictive performance and validity. Electrophilic reactivity is a common mechanistic feature of skin sensitization endpoints which could be concisely characterized with electronic descriptors which is key to enabling the modelling of small datasets in this domain. However, quantum mechanical methodologies have previously featured high computational costs which would exclude the use of large datasets. Consequently, we investigate the use of electronic descriptors calculated using the Hartree Fock with 3 corrections (Hf-3c) method, a low-cost <em>ab initio</em> methodology that has higher chemical accuracy than previous semiempirical methodologies for modelling <em>in vitro</em> skin sensitization assay outcomes. We also model the Ames assay as a surrogate for determining skin sensitization outcomes. The quantum chemical descriptors calculated using the Hf-3c method with conductor-like polarizable continuum model (CPCM) implicit solvation found improved QSAR model performance for the <em>in vitro</em> Ames (<em>n</em> = 6049, 0.770 AUC), KeratinoSens (<em>n</em> = 164, 0.763 AUC), and Direct Peptide Reactivity Assay (<em>n</em> = 122, 0.750 AUC) datasets, with their combination producing high predictive performance for unseen <em>in vivo</em> Local Lymph Node Assay (<em>n</em> = 86, 0.789 AUC) and Human Repeated Insult Patch Test (<em>n</em> = 86, 0.791 AUC) assay toxicant outcomes.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100183"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000367/pdfft?md5=d5bfc894935ff6bbfb35bf0733792275&pid=1-s2.0-S2666027X24000367-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141439237","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":"Hydrogen sulfide donor NaHS inhibits formaldehyde-induced epithelial-mesenchymal transition in human lung epithelial cells via activating TGF-β1/Smad2/3 and MAPKs signaling pathways","authors":"Haopei Wang ,&nbsp;Miaomiao Jia ,&nbsp;Yuxin Chang,&nbsp;Xingwei Ling,&nbsp;Wenyan Qi,&nbsp;Hongtao Chen,&nbsp;Feipeng Chen,&nbsp;Haiyang Bai,&nbsp;Yuhan Jiang,&nbsp;Chengfan Zhou","doi":"10.1016/j.crtox.2024.100199","DOIUrl":"10.1016/j.crtox.2024.100199","url":null,"abstract":"<div><div>Formaldehyde (FA) long term exposure leads to abnormal pulmonary function and small airway obstruction of the patients. Hydrogen sulfide (H₂S) is one of the recognized gaseous transmitters involved in a wide range of cellular functions. It is unknown the involvement of H₂S in FA-induced lung injury. The purpose of this study is to investigate the therapeutic potential and mechanism of H₂S on FA-induced epithelial-mesenchymal transition (EMT) of human lung epithelial cells. The cell viability of Beas2B and A549 cells after FA treatment were assessed using MTT assay. The endogenous H₂S was visualized by fluorescence microscopy using of the 7-azido-4-methylcoumarin (AzMC). Cell morphology was observed under phase contrast microscope. The mRNAs and proteins level were evaluated by reverse transcription-polymerase chain reaction and western blotting assays. FA treatment downregulated the endogenous H₂S levels and the mRNAs and proteins level of H₂S synthesizing enzymes, such as cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in Beas2B and A549 cells. FA treatment changed the cell morphology of Beas2B cells from cuboid to a spindle-shape, while declined the protein level of E-cadherin and increased the protein level of Vimentin. Moreover, FA treatment increased the proteins level of transforming growth factor-β1 (TGF-β1), phosphorylated-Smad2 (p-Smad2), phosphorylated-Smad3 (p-Smad3), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-c-Jun N-terminal kinase (p-JNK), and phosphorylated-P38 (p-P38). Furthermore, the inhibitors of TGF-β receptor type 1 (TGFβRI) and mitogen-activated protein kinases (MAPKs) signaling pathways reversed FA-induced decrease in E-cadherin expression and increase in Vimentin expression in Beas2B cells. Sodium hydrogen sulfide (NaHS) increased the level of H₂S, while reversed FA-induced the low expression of E-cadherin and the high expression of Vimentin, TGF-β1, p-Smad2, p-Smad3, p-ERK, p-JNK, and p-P38. These findings indicates FA treatment downregulating the endogenous H₂S in human lung epithelial cells. NaHS may inhibit FA-induced EMT in human lung epithelial cells via modulating TGF-β1/Smad2/3 and MAPKs signaling pathways. Therefore, we demonstrated that supplementation of exogenous H₂S may inhibit FA-induced lung injury.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100199"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142531776","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":"Cytoprotective effects of α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol on 7-ketocholesterol – Induced oxiapoptophagy: Major roles of PI3-K / PDK-1 / Akt signaling pathway and glutathione peroxidase activity in cell rescue","authors":"Aline Yammine ,&nbsp;Imen Ghzaiel ,&nbsp;Vivien Pires ,&nbsp;Amira Zarrouk ,&nbsp;Omar Kharoubi ,&nbsp;Hélène Greige-Gerges ,&nbsp;Lizette Auezova ,&nbsp;Gérard Lizard ,&nbsp;Anne Vejux","doi":"10.1016/j.crtox.2024.100153","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100153","url":null,"abstract":"<div><p>On murine N2a cells, 7-ketocholesterol induced an oxiapotophagic mode of cell death characterized by oxidative stress (reactive oxygen species overproduction on whole cells and at the mitochondrial level; lipid peroxidation), apoptosis induction (caspase-9, −3 and −7 cleavage, PARP degradation) and autophagy (increased ratio LC3-II / LC3-I). Oxidative stress was strongly attenuated by diphenyleneiodonium chloride which inhibits NAD(P)H oxidase. Mitochondrial and peroxisomal morphological and functional changes were also observed. Down regulation of PDK1 / Akt signaling pathways as well as of GSK3 / Mcl-1 and Nrf2 pathways were simultaneously observed in 7-ketocholesterol-induced oxiapoptophagy. These events were prevented by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol. The inhibition of the cytoprotection by LY-294002, a PI3-K inhibitor, demonstrated an essential role of PI3-K in cell rescue. The rupture of oxidative stress in 7-ketocholesterol-induced oxiapoptophagy was also associated with important modifications of glutathione peroxidase, superoxide dismutase and catalase activities as well as of glutathione peroxidase-1, superoxide dismutase-1 and catalase level and expression. These events were also counteracted by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol. The inhibition of the cytoprotection by mercaptosuccinic acid, a glutathione peroxidase inhibitor, showed an essential role of this enzyme in cell rescue. Altogether, our data support that the reactivation of PI3-K and glutathione peroxidase activities by α-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, oleic acid and α-tocopherol are essential to prevent 7KC-induced oxiapoptophagy.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100153"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000069/pdfft?md5=cc94eed3c51e0bb23ed2a0f7ac637582&pid=1-s2.0-S2666027X24000069-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139737550","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":"Estrogen replacement therapy reverses spatial memory loss and pyramidal cell neurodegeneration in the prefrontal cortex of lead-exposed ovariectomized Wistar rats","authors":"Abiodun Shukrat Lasisi-Sholola ,&nbsp;Sodiq Opeyemi Hammed ,&nbsp;Richard Adedamola Ajike ,&nbsp;Roland Eghoghosoa Akhigbe ,&nbsp;Oladele Ayobami Afolabi","doi":"10.1016/j.crtox.2024.100200","DOIUrl":"10.1016/j.crtox.2024.100200","url":null,"abstract":"<div><h3>Background</h3><div>Although menopause is a component of chronological aging, it may be induced by exposure to heavy metals like lead. Interestingly, lead exposure, just like the postmenopausal state, has been associated with spatial memory loss and neurodegeneration; however, the impact of hormone replacement therapy (HRT) on menopause and lead-induced spatial memory loss and neurodegeneration is yet to be reported.</div></div><div><h3>Aim</h3><div>The present study investigated the effect and associated mechanism of HRT on ovariectomized-driven menopausal state and lead exposure-induced spatial memory loss and neurodegeneration.</div></div><div><h3>Materials and methods</h3><div>Thirty adult female Wistar rats were randomized into 6 groups (n = 5 rats/group); the sham-operated vehicle-treated, ovariectomized (OVX), OVX + HRT, lead-exposed, OVX + lead, and OVX + Lead + HRT groups. Treatment was daily via gavage and lasted for 28 days.</div></div><div><h3>Results</h3><div>Ovariectomy and lead exposure impaired spatial memory deficit evidenced by a significant reduction in novel arm entry, time spent in the novel arm, alternation, time exploring novel and familiar objects, and discrimination index. These findings were accompanied by a marked distortion in the histology of the prefrontal cortex, and a decline in serum dopamine level and pyramidal neurons. In addition, ovariectomy and lead exposure induced metabolic disruption (as depicted by a marked rise in lactate level and lactate dehydrogenase and creatinine kinase activities), oxidative stress (evidenced by a significant increase in MDA level, and decrease in GSH level, and SOD and catalase activities), inflammation (as shown by significant upregulation of myeloperoxidase activity, and TNF-α and IL-1β), and apoptosis (evidenced by a rise in caspase 3 activity) of the prefrontal cortex. The observed biochemical and histological perturbations were attenuated by HRT.</div></div><div><h3>Conclusions</h3><div>This study revealed that HRT attenuated ovariectomy and lead-exposure-induced spatial memory deficit and pyramidal neurodegeneration by suppressing oxidative stress, inflammation, and apoptosis of the prefrontal cortex.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100200"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142657175","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":"Placental transfer of tofacitinib in the ex vivo dual-side human placenta perfusion model","authors":"Gaby A.M. Eliesen ,&nbsp;Milou Fransen ,&nbsp;Hedwig van Hove ,&nbsp;Petra H.H. van den Broek ,&nbsp;Rick Greupink","doi":"10.1016/j.crtox.2024.100149","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100149","url":null,"abstract":"<div><p>Tofacitinib is a small molecule Janus kinase (JAK) inhibitor, introduced to the European market in 2017, for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the treatment of women with autoimmune diseases, pregnancy is a relevant issue, as such diseases typically affect women in their reproductive years. Currently, there is limited data on the use of tofacitinib during pregnancy. To estimate the extent of placental transfer in the absence of clinical data, we conducted <em>ex vivo</em> dual-side perfused human placental cotyledon perfusions. Term placentas were perfused for 180 min with tofacitinib (100 nM, added to the maternal circuit) in a closed-closed configuration. At the end of the perfusions, drug concentrations in the maternal and fetal reservoirs were near equilibrium, at 35.6 ± 5.5 and 24.8 ± 4.7 nM, respectively. Transfer of tofacitinib was similar to that observed for the passive diffusion marker antipyrine (100 µg/mL, added to the maternal reservoir). Final antipyrine maternal and fetal concentrations amounted to 36.9 ± 3.0 and 36.7 ± 1.3 µg/mL, respectively. In conclusion, in the <em>ex vivo</em> perfused placenta tofacitinib traverses the placental barrier rapidly and extensively. This suggests that substantial fetal tofacitinib exposure will take place after maternal drug dosing.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100149"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000021/pdfft?md5=750bbc6c92fbedeaeb8bafe931bcf4db&pid=1-s2.0-S2666027X24000021-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139419305","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":"3D human stem-cell-derived neuronal spheroids for in vitro neurotoxicity testing of methylglyoxal, highly reactive glycolysis byproduct and potent glycating agent","authors":"Teresa Coccini ,&nbsp;Francesca Caloni ,&nbsp;Luciana Alessandra Russo ,&nbsp;Laura Villani ,&nbsp;Davide Lonati ,&nbsp;Uliana De Simone","doi":"10.1016/j.crtox.2024.100176","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100176","url":null,"abstract":"<div><p>Human-derived three-dimensional (3D) <em>in vitro</em> models are advanced <em>human cell-based</em> model for their complexity, relevance and application in toxicity testing. Intracellular accumulation of methylglyoxal (MGO), the most potent glycating agent in humans, mainly generated as a by-product of glycolysis, is associated with age-related diseases including neurodegenerative disorders.</p><p>In our study, 3D human stem-cell-derived neuronal spheroids were set up and applied to evaluate cytotoxic effects after short-term (5 to 48 h) treatments with different MGO concentrations, including low levels, taking into consideration several biochemical endpoints.</p><p>In MGO-treated neurospheroids, reduced cell growth proliferation and decreased cell viability occurred early from 5-10 μM, and their compactness diminished starting from 100 μM, apparently without affecting spheroid size. MGO markedly caused loss of the neuronal markers MAP-2 and NSE from 10-50 μM, decreased the detoxifying Glo1 enzyme from 50 μM, and activated NF-kB by nuclear translocation.</p><p>The cytochemical evaluation of the 3D sections showed the presence of necrotic cells with loss of nuclei. Apoptotic cells were observed from 50 μM MGO after 48 h, and from 100 μM after 24 h. MGO (50–10 µM) also induced modifications of the cell–cell and cell-ECM interactions. These effects worsened at the higher concentrations (300–500 µM).</p><p>In 3D neuronal spheroids, MGO tested concentrations comparable to human samples levels measured in MGO-associated diseases, altered neuronal key signalling endpoints relevant for the pathogenesis of neurodegenerative diseases and aging. The findings also demonstrated that the use of 3D neuronal spheroids of human origin can be useful in a strategy <em>in vitro</em> for testing MGO and other dicarbonyls evaluation.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100176"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400029X/pdfft?md5=215eca89a24ba4180c3d12b699dc970d&pid=1-s2.0-S2666027X2400029X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141308252","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":"Using targeted fetal rat testis genomic and endocrine alterations to predict the effects of a phthalate mixture on the male reproductive tract","authors":"L. Earl Gray Jr ,&nbsp;Christy S. Lambright ,&nbsp;Nicola Evans ,&nbsp;Jermaine Ford ,&nbsp;Justin M. Conley","doi":"10.1016/j.crtox.2024.100180","DOIUrl":"10.1016/j.crtox.2024.100180","url":null,"abstract":"<div><p>Administration of phthalates <em>in utero</em> disrupts gene expression and hormone levels in the fetal rat testis, which are key events in an Adverse Outcome Pathway (AOP) for the Phthalate Syndrome. These measures can be used to predict the postnatal adverse effects of phthalate esters (PEs) on male rat sexual differentiation. Here, pregnant rats were exposed to dibutyl (DBP)- and diisononyl (DINP) phthalate on gestational days 14 to 18 individually and as a mixture (DBP,250 mg/kg/d; DINP, 750 mg/kg/d; and DBP 250 mg/kg/d plus DINP 750 mg/kg/d). We found that each PE reduced testosterone production (T Prod) and related gene transcripts by about 50 % and that they acted in a dose additive manner, reducing T Prod and gene expression by 75 % as a mixture. Based upon effects on T Prod, DINP was 0.33 times as potent as DBP and thus the DBP + DINP mixture was predicted to be equivalent to 500 mg DBP/kg/d.</p><p>Logistic regression models of T Prod predicted that the adverse effects of the DBP + DINP mixture group versus the DBP and DINP individual treatments would reduce anogenital distance (AGD) by 27 % versus 10 %, increase hypospadias in 18 % versus &lt; 1 %, induce epididymal agenesis in 46 % versus 10 %, and increase areolae/nipples in 4.8 % versus &lt; 0.1 % of the, respectively. These predictions were highly consistent with effects from previously published dose response studies on the male reproductive effects of DBP. In summary, these results support the use of this New Approach Method to predict the detrimental effects of PEs and PE mixtures, replacing or reducing the need to run long-term, resource and animal use intensive extended one-generation reproduction studies for this class of chemicals.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100180"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000331/pdfft?md5=0c74927333f72ddbcf93a0ec39b540c1&pid=1-s2.0-S2666027X24000331-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141415617","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}