Current Research in Toxicology最新文献

{"title":"Mono-(2-ethylhexyl) phthalate induces trophoblast hypoxia and mitochondrial dysfunction through HIF-1α-miR-210-3p axis in HTR-8/SVneo cell line","authors":"Sunitha Meruvu,&nbsp;Zehuan Ding,&nbsp;Mahua Choudhury","doi":"10.1016/j.crtox.2024.100188","DOIUrl":"10.1016/j.crtox.2024.100188","url":null,"abstract":"<div><p>The exposure to the ubiquitous phthalate metabolite mono-(2-ethylhexyl) phthalate (MEHP) is connected to dysregulated trophoblast function and placenta health; however, the underlying mechanisms preluding this scenario remain to be elucidated. In this study, we explored the hypoxemic effects of MEHP on a human placental first-trimester trophoblast cell line (HTR-8/Svneo). MEHP-treated trophoblast cells displayed significantly increased levels of oxidative stress and hypoxia-inducible factor-1 alpha (HIF-1α) attributed by the induction of hypoxia. Further, HIF-1α exhibited higher DNA binding activity and upregulated gene expression of its downstream target vascular endothelial growth factor A (VEGFA). The hypoxia-induced microRNA miR-210-3p was also significantly increased upon MEHP treatment followed by disrupted mitochondrial ATP generation and membrane potential. This was identified to possibly be facilitated by lowered mitochondrial DNA copy number and inhibited expression of electron transport chain subunits, such as mitochondrial complex-IV. These results suggest potential adverse effects of MEHP exposure in a trophoblast cell line mediated by HIF-1α and the epigenetic modulator miR-210-3p. Chronic placental hypoxia and oxidative stress have long been implicated in the pathogenesis of pregnancy complications such as preeclampsia. As we’ve revealed genetic and epigenetic factors underscoring a potential mechanism induced by MEHP, this brings to light another significant implication of phthalate exposure on maternal and fetal health.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100188"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000410/pdfft?md5=9232c7cf93c3879dc45fd371b48a8926&pid=1-s2.0-S2666027X24000410-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141841856","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":"The dynamic face of cadmium-induced Carcinogenesis: Mechanisms, emerging trends, and future directions","authors":"Mohamed Ali Hussein ,&nbsp;Abishek Kamalakkannan ,&nbsp;Kamyab Valinezhad ,&nbsp;Jhishnuraj Kannan ,&nbsp;Nikhila Paleati ,&nbsp;Rama Saad ,&nbsp;André Kajdacsy-Balla ,&nbsp;Gnanasekar Munirathinam","doi":"10.1016/j.crtox.2024.100166","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100166","url":null,"abstract":"<div><p>Cadmium (Cd) is a malleable element with odorless, tasteless characteristics that occurs naturally in the earth’s crust, underground water, and soil. The most common reasons for the anthropological release of Cd to the environment include industrial metal mining, smelting, battery manufacturing, fertilizer production, and cigarette smoking. Cadmium-containing products may enter the environment as soluble salts, vapor, or particle forms that accumulate in food, soil, water, and air. Several epidemiological studies have highlighted the association between Cd exposure and adverse health outcomes, especially renal toxicity, and the impact of Cd exposure on the development and progression of carcinogenesis. Also highlighted is the evidence for early-life and even maternal exposure to Cd leading to devastating health outcomes, especially the risk of cancer development in adulthood. Several mechanisms have been proposed to explain how Cd mediates carcinogenic transformation, including epigenetic alteration, DNA methylation, histone posttranslational modification, dysregulated non-coding RNA, DNA damage in the form of DNA mutation, strand breaks, and chromosomal abnormalities with double-strand break representing the most common DNA form of damage. Cd induces an indirect genotoxic effect by reducing p53′s DNA binding activity, eventually impairing DNA repair, inducing downregulation in the expression of DNA repair genes, which might result in carcinogenic transformation, enhancing lipid peroxidation or evasion of antioxidant interference such as catalase, superoxide dismutase, and glutathione. Moreover, Cd mediates apoptosis evasion, autophagy activation, and survival mechanisms. In this review, we decipher the role of Cd mediating carcinogenic transformation in different models and highlight the interaction between various mechanisms. We also discuss diagnostic markers, therapeutic interventions, and future perspectives.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100166"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000197/pdfft?md5=c08f999a224581b582db3eea858bbc40&pid=1-s2.0-S2666027X24000197-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643964","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":"Evaluation of the diphenyl herbicide, oxyfluorfen, for effects on thyroid hormones in the juvenile rat","authors":"T.E. Stoker ,&nbsp;G.D. DeVane ,&nbsp;A.R. Buckalew ,&nbsp;J.R. Bailey ,&nbsp;J.L. Ford ,&nbsp;A.S. Murr","doi":"10.1016/j.crtox.2023.100146","DOIUrl":"10.1016/j.crtox.2023.100146","url":null,"abstract":"<div><p>Recently, oxyfluorfen, a pre- and post-emergent diphenyl ether herbicide, was identified in our laboratory as an inhibitor of iodide uptake by the sodium iodide symporter (NIS), the first key step in the synthesis of thyroid hormones (THs). This inhibition was observed <em>in vitro</em>, using both a human NIS engineered cell line (hNIS-HEK293T-EPA) and a rat thyroid follicular cell line (FRTL-5). Oxyfluorfen was found to be a potent inhibitor of NIS activity with an EC50 of approximately 2 µM in both cell lines with no observed cytotoxicity at any concentration tested up to 100 μM. The current research tested the hypothesis that oxyfluorfen alters circulating concentrations of THs. This hypothesis was first tested in a pilot study with both juvenile male and female rats exposed to oxyfluorfen for 4 days at 0, 125, 250 and 500 mg/kg/day. Once we identified that this short-term 4-day oxyfluorfen exposure suppressed both total serum thyroxine (T4) and triiodothyronine (T3) at all doses, we tested seven lower concentrations of oxyfluorfen (0.8125 to 62.5 mg/kg day) in an 8-day exposure paradigm to more closely evaluate the dose–response. We found that oxyfluorfen suppressed serum T4 with a LOEL of 3.25 mg/kg/day and T3 with a LOEL 62.5 mg/kg/day. Analytical chemistry of the serum showed an accumulation over time following oral exposure to oxyfluorfen in both the 4- and 8-day groups. Analytical chemistry of the thyroid glands in the 8-day study revealed higher accumulation in the thyroid as compared to the serum (2 to 3- fold at 62.5 mg/kg). No changes in thyroid weight or serum TSH were observed following the 8-day exposure. This study is the first to demonstrate an effect of oxyfluorfen on serum thyroid hormones in the rat. Additional studies are needed to further evaluate the effects on thyroid homeostasis with extended exposures and the potential implications of the observed effects.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100146"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000440/pdfft?md5=ac2684b7e8b3b845fb41ef3cd791c35d&pid=1-s2.0-S2666027X23000440-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139019388","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":"In vitro-in silico study on the influence of dose, fraction bioactivated and endpoint used on the relative potency value of pyrrolizidine alkaloid N-oxides compared to parent pyrrolizidine alkaloids","authors":"Yasser Alhejji ,&nbsp;Frances Widjaja ,&nbsp;Shenghan Tian ,&nbsp;Thomas Hoekstra ,&nbsp;Sebastiaan Wesseling ,&nbsp;Ivonne M.C.M. Rietjens","doi":"10.1016/j.crtox.2024.100160","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100160","url":null,"abstract":"<div><p>Pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) are phytotoxins found in food, feed and the environment. Yet, limited data exist from which the relative potency of a PA-N-oxide relative to its corresponding PA (REP_{PANO to PA}) can be defined. This study aims to investigate the influence of dose, fraction bioactivated and endpoint on the REP_{PANO to PA} of a series of pyrrolizidine N-oxides using in vitro-in silico data and physiologically based kinetic (PBK) modeling. The first endpoint used to calculate the REP_{PANO to PA} was the ratio of the area under the concentration–time curve of PA resulting from an oral dose of PA-N-oxide divided by that from an equimolar dose of PA (Method 1). The second endpoint was the ratio of the amount of pyrrole-protein adducts formed under these conditions (Method 2). REP_{PANO to PA} values appeared to decrease with increasing dose, with the decrease for Method 2 already starting at lower dose level than for Method 1. At dose levels as low as estimated daily human intakes, REP_{PANO to PA} values amounted to 0.92, 0.81, 0.78, and 0.68 for retrorsine N-oxide, seneciphylline N-oxide, riddelliine N-oxide and senecivernine N-oxide, respectively, and became independent of the dose or fraction bioactivated, because no GSH depletion, saturation of PA clearance or PA-N-oxide reduction occurs. Overall, the results demonstrate the strength of using PBK modeling in defining REP_{PANO to PA} values, thereby substantiating the use of the same approach for other PA-N-oxides for which in vivo data are lacking.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100160"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000136/pdfft?md5=558a8507f5b1e3044fad14e8be8c39a4&pid=1-s2.0-S2666027X24000136-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140052433","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":"Lactational exposure of human infants to metal(loid)s in Sub-Saharan Africa and Mediterranean Europe: A systematic review and meta-analysis","authors":"Amarachi Paschaline Onyena ,&nbsp;Onyinyechi Bede-Ojimadu ,&nbsp;Taagbara Jolly Abaate ,&nbsp;Dokuboba Amachree ,&nbsp;Chiara Frazzoli ,&nbsp;Opeyemi M. Folorunso ,&nbsp;Beatrice Bocca ,&nbsp;Orish E. Orisakwe","doi":"10.1016/j.crtox.2024.100201","DOIUrl":"10.1016/j.crtox.2024.100201","url":null,"abstract":"<div><div>Breast milk, a fundamental component of infant nutrition, may serve as a reservoir for various metal(loid)s, which could pose significant health risks to infants of mothers exposed to toxic metals. Human exposure levels to metal(loid)s vary across regions, influenced by differences in diet, lifestyle, and environmental factors. This systematic review compares metal(loid) concentrations in breast milk from Sub-Saharan Africa (SSA) and Mediterranean Europe (Med. Europe), identifying key determinants of exposure. PubMed, Scopus, and Google Scholar were searched for articles reporting metal concentrations in human breast milk samples from SSA and Med. Europe. Weighted mean concentrations were estimated and compared between the two regions. Twenty-five studies from SSA and seventeen from Med. Europe were included in the review. Mean concentrations of cadmium (12.38 ± 1.21 µg/L vs 0.22 ± 0.51 µg/L; p &lt; 0.0001), lead (14.96 ± 8.10 µg/L vs 1.16 ± 4.00 µg/L; p &lt; 0.0001), and mercury (2.01 ± 1.37 µg/L vs 0.95 ± 4.32 µg/L; p = 0.008) were higher in breast milk samples from SSA than Med. Europe. Conversely, breast milk samples from SSA had lower concentrations of selenium (7.38 ± 2.67 µg/L vs 13.09 ± 16.89 µg/L; p &lt; 0.0001) and iron (138.78 ± 106.33 µg/L vs 371.97 ± 446.74 µg/L; p &lt; 0.0001) than those from Med. Europe. Key determinants of metal(loid)s levels in breast milk included maternal smoking, dietary patterns, and environmental exposure. There is an urgent need for effective interventions and policies to reduce metals exposure, particularly in SSA, to safeguard maternal and infant health.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100201"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142698305","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":"Bridging the gap between toxicity and carcinogenicity of mineral fibres by connecting the fibre parameters to the key characteristics of carcinogens: A comprehensive model inspiring asbestos-induced cancer prevention strategies","authors":"Alessandro F. Gualtieri ,&nbsp;Erika Ferrari ,&nbsp;Luca Rigamonti ,&nbsp;Barbara Ruozi ,&nbsp;Serena Mirata ,&nbsp;Vanessa Almonti ,&nbsp;Mario Passalacqua ,&nbsp;Stefania Vernazza ,&nbsp;Silvia Di Valerio ,&nbsp;Giovanni Tossetta ,&nbsp;Salvatore Vaiasicca ,&nbsp;Antonio D. Procopio ,&nbsp;Francesca Fazioli ,&nbsp;Daniela Marzioni ,&nbsp;Armanda Pugnaloni ,&nbsp;Sonia Scarfì","doi":"10.1016/j.crtox.2024.100202","DOIUrl":"10.1016/j.crtox.2024.100202","url":null,"abstract":"<div><h3>Background</h3><div>Today, many research groups in the world are struggling to fully understand the mechanisms leading to the carcinogenesis of hazardous mineral fibres, like asbestos, in view of devising effective cancer prevention strategies and therapies. Along this research line, our work attempts the completion of a model aimed at evaluating how, and to what extent, physical-crystal-chemical and morphological parameters of mineral fibres prompt adverse effects <em>in vivo</em> leading to carcinogenesis.</div></div><div><h3>Methods</h3><div><em>In vitro</em> toxicology tests that deliver information on the 10 key characteristics of carcinogens adopted by the International Association for Research on Cancer (IARC) have been systematically collected for a commercial chrysotile, standard UICC crocidolite and wollastonite. The analysis of the <em>in vitro</em> data allowed us to assess the major fibre parameters responsible for alterations in the key characteristics of carcinogens for each investigated fibre and the intensity of their effect.</div></div><div><h3>Results</h3><div>Crystal habit and density of the fibres affect exposure but are not major parameters contributing to the KCs. For chrysotile, besides length, we found that fibre parameters that greatly contribute to the KCs are the surface area and the dissolution rate with the related velocity of release of metals (namely iron). For crocidolite, they are the fibre length, iron content and related parameters like the ferrous iron content, iron nuclearity, transition metals content and zeta potential.</div></div><div><h3>Conclusions</h3><div>The results of our study can be a starting point for developing personalized cancer screening and prevention strategies as long as the nature of the fibre of the exposed patient is known. We can speculate on a future personalized prevention therapy targeting the fibres with surface-engineered nanocarriers with active complexes that are selective for the surface charge of the fibres. For chrysotile, a complex with deferasirox that can chelate Fe²⁺ and deferoxamine that preferentially chelates Fe³⁺ is proposed with the anchorage to the silica chrysotile surface driven by aspartic acid. For crocidolite, deferiprone chelating both Fe³⁺ and Fe²⁺ combined with lysine to attract the silica crocidolite surface is proposed.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100202"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142698303","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":"Sesquiterpene-evoked phytochemical toxicity in PC12 neuronal cells reveals a variable degree of oxidative stress and alpha-tocopherol and glutathione-dependent protection","authors":"John Staton Laws III,&nbsp;Scott D. Smid","doi":"10.1016/j.crtox.2023.100144","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100144","url":null,"abstract":"<div><p>Phytochemicals are often promoted generally as antioxidants and demonstrate variable levels of reactive oxygen species (ROS) sequestration in vitro, which attributes to their neuroprotective bioactivity. Sesquiterpenes from cannabis and essential oils may demonstrate bifunctional properties towards cellular oxidative stress, possessing pro-oxidant activities by generating ROS or scavenging ROS directly. Sesquiterpenes can also oxidize forming sesquiterpene oxides, however the relative contribution they make to the bioactivity or cytotoxicity of complex botanical extracts more generally is unclear, while selected cannabis-prevalent terpenes such as β-caryophyllene may also activate cannabinoid receptors as part of their biological activity. In the present study, we investigated selected sesquiterpenes β-caryophyllene and humulene and their oxidized forms (β-caryophyllene oxide and zerumbone, respectively) against established antioxidants (ascorbic acid, α-tocopherol, and glutathione) and in the presence of cannabinoid receptor 1 and cannabinoid receptor 2 antagonists, to gain a better understanding of the molecular and cellular mechanisms of neuroprotection versus neurotoxicity in semi-differentiated rat neuronal phaeochromocytoma (PC12) cells. Our results demonstrate that the sesquiterpenes β-caryophyllene, humulene and zerumbone possess concentration-dependent neurotoxic effects in PC12 cells. Both β-caryophyllene- and humulene-evoked toxicity was unaffected by CB1 or CB2 receptor antagonism, demonstrating this occurred independently of cannabinoid receptors. Both glutathione and α-tocopherol were variably able to alleviate the concentration-dependent loss of PC12 cell viability from exposure to β-caryophyllene, humulene and zerumbone. During 4-hour exposure to sesquiterpenes only modest increases in ROS levels were noted in PC12 cells, with glutathione co-incubation significantly inhibiting intracellular ROS production. However, significant increases in ROS levels in PC12 cells were demonstrated during 24-hour incubation with either antioxidants or sesquiterpenes individually, and with additive toxicity exhibited in combination. Overall, the results highlight a concentration-dependent profile of sesquiterpene neurotoxicity independent of cannabinoid receptors and dissociated from the formation of reactive oxygen species as a marker or correlate to the loss of cell viability.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100144"},"PeriodicalIF":3.3,"publicationDate":"2023-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000427/pdfft?md5=815a2b37a0d18927d6e43c4fbf6bf55e&pid=1-s2.0-S2666027X23000427-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138739197","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":"The upregulation of lamin A/C as a compensatory mechanism during tight junction disruption in renal tubular cells mediated by calcium oxalate crystals","authors":"Sudarat Hadpech,&nbsp;Paleerath Peerapen,&nbsp;Visith Thongboonkerd","doi":"10.1016/j.crtox.2023.100145","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100145","url":null,"abstract":"<div><p>Calcium oxalate monohydrate (COM), the most important crystal causing kidney stone disease, upregulates lamin A/C but downregulates zonula occludens-1 (ZO-1) in renal tubular cells. While roles for F-actin and α-tubulin and their association with ZO-1 are known to regulate COM-mediated tight junction (TJ) disruption, roles of lamin A/C and its interplay with ZO-1 in COM kidney stone model remain unclear and are thus the objectives of this study. Lamin A/C was knocked down in MDCK cells by silencing RNA specific for <em>LMNA</em> (siLMNA). Both wild-type (WT) and siLMNA cells were treated with COM for 48-h compared with the untreated (control) cells. Western blotting and immunofluorescence staining revealed upregulated lamin A/C and downregulated ZO-1 in the COM-treated WT cells. siLMNA successfully reduced lamin A/C expression in both control and COM-treated cells. Nonetheless, siLMNA did not reverse the effect of COM on the decreases in ZO-1 and transepithelial resistance, but further reduced their levels in both control and COM-treated cells. Protein-protein interaction analysis demonstrated that two cytoskeletal proteins (actin and tubulin) served as the linkers to connect lamin A/C with ZO-1 and occludin (both of which are the TJ proteins). Altogether, these data implicate that lamin A/C and ZO-1 are indirectly associated to control TJ function, and ZO-1 expression is regulated by lamin A/C. Moreover, COM-induced upregulation of lamin A/C most likely serves as a compensatory mechanism to cope with the downregulation of ZO-1 during COM-mediated TJ disruption.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100145"},"PeriodicalIF":3.3,"publicationDate":"2023-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000439/pdfft?md5=e8d399b693a850ebd5d17503600d5d14&pid=1-s2.0-S2666027X23000439-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138839707","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":"The pathogenesis of albuminuria in cadmium nephropathy","authors":"Soisungwan Satarug ,&nbsp;David A. Vesey ,&nbsp;Glenda C. Gobe ,&nbsp;Kenneth R. Phelps","doi":"10.1016/j.crtox.2023.100140","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100140","url":null,"abstract":"<div><h3>Background</h3><p>Urinary cadmium excretion (E_Cd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β₂-microglobulinuria (E_β2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E_alb) to E_β2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins.</p></div><div><h3>Methods</h3><p>To depict excretion rates per functional nephron, E_Cd, E_alb, and E_β2M were normalized to creatinine clearance (C_cr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E_alb/C_cr, E_β2M/C_cr, and eGFR to several independent variables. Simple linear regressions of eGFR, E_alb/C_cr, and E_β2M/C_cr on E_Cd/C_cr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E_alb/C_cr and E_β2M/C_cr and decrements in eGFR were quantified through four quartiles of E_Cd/C_cr.</p></div><div><h3>Results</h3><p>As age or E_Cd/C_cr rose, E_alb/C_cr and E_β2M/C_cr also rose, and eGFR fell. In linear regressions, slopes relating E_alb/C_cr and E_β2M/C_cr to E_Cd/C_cr were similar. After adjustment of dependent variables for age, coefficients of determination (R²) for all regressions rose by a multiple, and slopes approached unity. E_alb/C_cr and E_β2M/C_cr were similarly associated with each other. Mean E_alb/C_cr and E_β2M/C_cr rose and mean eGFR fell in stepwise fashion through quartiles of E_Cd/C_cr. Whereas E_β2M/C_cr did not vary with blood pressure, E_alb/C_cr rose in association with hypertension in two of the four quartiles.</p></div><div><h3>Conclusions</h3><p>Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β₂M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100140"},"PeriodicalIF":3.3,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000385/pdfft?md5=fb62735e49213e668766e81df7ba0200&pid=1-s2.0-S2666027X23000385-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138570421","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":"Lestaurtinib induces DNA damage that is related to estrogen receptor activation","authors":"Masato Ooka ,&nbsp;Shu Yang ,&nbsp;Li Zhang ,&nbsp;Kota Kojima ,&nbsp;Ruili Huang ,&nbsp;Kouji Hirota ,&nbsp;Shunichi Takeda ,&nbsp;Menghang Xia","doi":"10.1016/j.crtox.2022.100102","DOIUrl":"10.1016/j.crtox.2022.100102","url":null,"abstract":"<div><p>A number of chemicals in the environment pose a threat to human health. Recent studies indicate estradiol induces DNA damage through the activation of the estrogen receptor alpha (ERα). Given that many environmental chemical compounds act like hormones once they enter the human body, it is possible that they induce DNA damage in the same way as estradiol, which is of great concern to females with the BRCA1 mutation. In this study, we developed an antibody-based high content method measuring γH2AX, a biomarker for DNA damage, to test a subset of 907 chemical compounds in MCF7 cells. The assay was optimized for a 1536 well plate format and had a satisfactory assay performance with Z-factor of 0.67. From the screening, we identified 128 compounds that induce γH2AX expression in the cells. These compounds were further examined for their γH2AX induction in the presence of an ER inhibitor, tamoxifen. After tamoxifen treatment, four compounds induced less γH2AX expression compared to those without tamoxifen treatment, suggesting these compounds induced γH2AX that is related to ERα activation. These four compounds were chosen for further studies to assess their ERα activating capability and <em>c-MYC</em> induction. Only lestaurtinib, a selective tyrosine kinase inhibitor, induced ERα activation, which was confirmed by both ERα beta-lactamase reporter gene assay and molecular docking analysis. Lestaurtinib also increased <em>c-MYC</em> expression, a target gene of ERα signaling, measured by the quantitative PCR method. This data suggests that lestaurtinib acts as a DNA damage inducer that is related to ERα activation.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"4 ","pages":"Article 100102"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5a/a1/main.PMC9816669.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10508174","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}