Current Research in Toxicology最新文献

{"title":"Assessing developmental toxicity and non-CYP mediated biotransformation of two anti-epileptics and their human metabolites in zebrafish embryos and larvae","authors":"Jente Hoyberghs ,&nbsp;Axelle Coppens ,&nbsp;Chloé Bars ,&nbsp;Chris Van Ginneken ,&nbsp;Kenn Foubert ,&nbsp;Steven Van Cruchten","doi":"10.1016/j.crtox.2024.100186","DOIUrl":"10.1016/j.crtox.2024.100186","url":null,"abstract":"<div><p>Zebrafish embryo-based assays are a promising alternative for animal testing to screen new compounds for developmental toxicity. However, recent studies in zebrafish embryos showed an immature intrinsic cytochrome P450 (CYP)-mediated biotransformation capacity, as most CYPs were only active at the end of the organogenesis period. Data on other phase I enzymes involved in the biotransformation of xenobiotics in zebrafish embryos is limited. This information is pivotal for proteratogens needing bioactivation to exert their teratogenic potential. Therefore, this study aimed to investigate whether carbamazepine (CBZ) and levetiracetam (LTC), two anti-epileptic drugs that require bioactivation to exert their teratogenic potential, are biotransformed into non-CYP mediated metabolites in the zebrafish embryo and whether one or more of these metabolites cause developmental toxicity in this species. In the first step, zebrafish embryos were exposed to LTC and CBZ and their non-CYP mediated human metabolites, etiracetam carboxylic acid (ECA) and 9-acridine carboxaldehyde (9ACA), acridine (AI), and acridone (AO), respectively, from 5.25 to 120 hpf and morphologically evaluated. Next, the uptake of all compounds and the formation of the metabolites were assessed using LC-MS methods. As LTC and ECA were, respectively, poorly or not taken up by zebrafish larvae during the exposure experiments, we could not determine if LTC and ECA are teratogenic. However, biotransformation of LTC into ECA was observed at 24 hpf and 120 hpf, which indicates that the special type of B-esterase is already active at 24 hpf. CBZ and its three metabolites were teratogenic, as a significant increase in malformed embryos was observed for all of them. All three metabolites were more potent teratogens than CBZ, with AI being the most potent, followed by 9ACA and AO. The myeloperoxidase (MPO) homologue is already active at 24 hpf, as CBZ was biotransformed into 9ACA and AO in 24 hpf zebrafish embryos, and into 9ACA in 120 hpf larvae. Moreover, 9ACA was also found to be biotransformed into AI and AO, and AI into AO. As such, one or more of these metabolites probably contribute to the teratogenic effects observed in zebrafish larvae after exposure to CBZ.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100186"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000392/pdfft?md5=14a59dc81d0aa75c48d98d92747ceecd&pid=1-s2.0-S2666027X24000392-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141703758","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":"Acute toxicity of binary mixtures for quorum sensing inhibitors and sulfonamides against Aliivibrio fischeri: QSAR investigations and joint toxic actions","authors":"Zhenheng Long ,&nbsp;Jingyi Yao ,&nbsp;Minghong Wu ,&nbsp;Shu-shen Liu ,&nbsp;Liang Tang ,&nbsp;Bo Lei ,&nbsp;Jiajun Wang ,&nbsp;Haoyu Sun","doi":"10.1016/j.crtox.2024.100172","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100172","url":null,"abstract":"<div><p>Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of <em>Aliivibrio fischeri</em> (<em>A. fischeri</em>) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in <em>A. fischeri</em> bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC₅₀) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC_50(QSI):EC_50(SA) = 1:1) and non-equitoxic ratios (EC_50(QSI):EC_50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure–activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (<em>E</em>_bind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100172"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000252/pdfft?md5=4d273a8b47eb940adc329daf679fba1f&pid=1-s2.0-S2666027X24000252-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140951175","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":"Visible particles in parenteral drug products: A review of current safety assessment practice","authors":"Frank Liu ,&nbsp;Richard Hutchinson","doi":"10.1016/j.crtox.2024.100175","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100175","url":null,"abstract":"<div><p>Parenteral drug products (PDPs) are administered extensively to treat various diseases. Product quality plays a critical role in ensuring patient safety and product efficacy. One important quality challenge is the contamination of particles in PDPs. Particle presence in PDPs represents potential safety risk to patients. Differential guidance and practice have been in place for visible (VPs) and subvisible particles (SVPs) in PDPs. For SVPs, the amount limits have been harmonized in multiple Pharmacopeias. The pharmaceutical industry follows the guided limits for regulatory and quality compliance. However, for VPs, no such acceptable limit has been set. This results in not only quality but also safety challenges for manufacturers and drug developers in managing and evaluating VPs. It is important to understand the potential safety risk of VPs so these can be weighed against the benefit of the PDPs. To evaluate their potential risk(s), it is necessary to understand their nature, origin, frequency of their occurrence, safety risk, the risk mitigation measures, and the method to evaluate their safety. The current paper reviews the critical literature on these aspects and provides insight into considerations when performing safety assessment and managing the risk(s) for VPs in PDPs.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100175"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000288/pdfft?md5=efc636ba939c818d5db77f3189465eb5&pid=1-s2.0-S2666027X24000288-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141308253","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":"An in vitro toxicological assessment of two electronic cigarettes: E-liquid to aerosolisation","authors":"E. Bishop,&nbsp;F. Miazzi,&nbsp;S. Bozhilova,&nbsp;N. East,&nbsp;R. Evans,&nbsp;D. Smart,&nbsp;M. Gaca,&nbsp;D. Breheny,&nbsp;D. Thorne","doi":"10.1016/j.crtox.2024.100150","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100150","url":null,"abstract":"<div><p>Interest in the toxicological assessment of iterations of e-cigarette devices, e-liquid formulations and flavour use is increasing. Here, we describe a multiple test matrix and <em>in<!--> <!-->vitro</em> approach to assess the biological impact of differing e-cigarette activation mechanism (button vs. puff-activated) and heating technology (cotton vs. ceramic wick). The e-liquids selected for each device contained the same nicotine concentration and flavourings. We tested both e-liquid and aqueous extract of e-liquid aerosol using a high throughput cytotoxicity and genotoxicity screen. We also conducted whole aerosol assessment both in a reconstituted human airway lung tissue (MucilAir) with associated endpoint assessment (cytotoxicity, TEER, cilia beat frequency and active area) and an Ames whole aerosol assay with up to 900 consecutive undiluted puffs. Following this testing it is shown that the biological impact of these devices is similar, taking into consideration the limitations and capturing efficiencies of the different testing matrices. We have contextualised these responses against previous published reference cigarette data to establish the comparative reduction in response consistent with reduced risk potential of the e-cigarette products tested in this study as compared to conventional cigarettes.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100150"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000033/pdfft?md5=4e092ed55a75181fa32f780895b7e5fe&pid=1-s2.0-S2666027X24000033-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139480197","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":"Identification of estrogen receptor agonists among hydroxylated polychlorinated biphenyls using classification-based quantitative structure–activity relationship models","authors":"Lukman K. Akinola ,&nbsp;Adamu Uzairu ,&nbsp;Gideon A. Shallangwa ,&nbsp;Stephen E. Abechi ,&nbsp;Abdullahi B. Umar","doi":"10.1016/j.crtox.2024.100158","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100158","url":null,"abstract":"<div><p>Identification of estrogen receptor (ER) agonists among environmental toxicants is essential for assessing the potential impact of toxicants on human health. Using 2D autocorrelation descriptors as predictor variables, two binary logistic regression models were developed to identify active ER agonists among hydroxylated polychlorinated biphenyls (OH-PCBs). The classifications made by the two models on the training set compounds resulted in accuracy, sensitivity and specificity of 95.9 %, 93.9 % and 97.6 % for ERα dataset and 91.9 %, 90.9 % and 92.7 % for ERβ dataset. The areas under the ROC curves, constructed with the training set data, were found to be 0.985 and 0.987 for the two models. Predictions made by models I and II correctly classified 84.0 % and 88.0 % of the test set compounds and 89.8 % and 85.8% of the cross-validation set compounds respectively. The two classification-based QSAR models proposed in this paper are considered robust and reliable for rapid identification of ERα and ERβ agonists among OH-PCB congeners.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100158"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000112/pdfft?md5=aaea4139aa15cb5789aef7803b3c55c3&pid=1-s2.0-S2666027X24000112-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139985348","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":"Cigarette smoking inhibits myoblast regeneration by promoting proteasomal degradation of NPAT protein and hindering cell cycle progression","authors":"Jianfeng Wang ,&nbsp;Jinling Liu ,&nbsp;Jingjing Shao ,&nbsp;Hongyu Chen ,&nbsp;Luyun Cui ,&nbsp;Pei Zhang ,&nbsp;Yinan Yao ,&nbsp;Jianying Zhou ,&nbsp;Zhang Bao","doi":"10.1016/j.crtox.2024.100161","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100161","url":null,"abstract":"<div><p>Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100161"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000148/pdfft?md5=62b76c5eac046a7203d59ddece106329&pid=1-s2.0-S2666027X24000148-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140062871","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":"Perfluorooctanesulfonic acid (PFOS) disrupts cadherin-16 in the developing rat thyroid gland","authors":"Nichlas Davidsen,&nbsp;Louise Ramhøj,&nbsp;Anne-Sofie Ravn Ballegaard,&nbsp;Anna Kjerstine Rosenmai,&nbsp;Cecillie Sofie Henriksen,&nbsp;Terje Svingen","doi":"10.1016/j.crtox.2024.100154","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100154","url":null,"abstract":"<div><p>Perfluorooctanesulfonic acid (PFOS) can disrupt the thyroid hormone (TH) system in rodents, potentially affecting perinatal growth and neurodevelopment. Some studies also suggest that gestational exposure to PFOS can lead to lower TH levels throughout life, indicating that PFOS may compromise thyroid gland development. To address this question, we utilized a rat thyroid gland <em>ex vivo</em> culture system to study direct effects of PFOS on the developing thyroid. No significant changes to follicular structure or size were observed with 1 µM or 10 µM PFOS exposure. However, the transcription factor <em>Foxe1</em>, together with <em>Tpo</em> and <em>Lrp2</em>, were upregulated<em>,</em> whereas the key transcription factor <em>Pax8</em> and its downstream target gene <em>Cdh16</em> were significantly downregulated at the transcript level, observed with both RT-qPCR and RNAscope. Notably, <em>Cdh16</em> expression was not uniformly downregulated across <em>Cdh16</em>-postive cells, but instead displayed a patchy expression pattern across the thyroid gland. This is a significant change in expression pattern compared to control thyroids where <em>Cdh16</em> is expressed relatively uniformly<em>.</em> The disrupted expression pattern was also seen at the protein level. This suggests that PFOS exposure can impact follicular growth and structure. Compromised follicle integrity, if irreversible, could help explain reduced TH synthesis postnatally. This view is supported by observed changes to <em>Tpo</em> and <em>Lrp2</em> expression, two factors that play a role in TH synthesis.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100154"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000070/pdfft?md5=d6bb075a4f229d5e54f3b2d446c18f78&pid=1-s2.0-S2666027X24000070-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139710242","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":"Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art","authors":"Michael Aschner ,&nbsp;Airton C. Martins ,&nbsp;Gustavo H. Oliveira-Paula ,&nbsp;Anatoly V. Skalny ,&nbsp;Irina P. Zaitseva ,&nbsp;Aaron B. Bowman ,&nbsp;Anatoly A. Kirichuk ,&nbsp;Abel Santamaria ,&nbsp;Yousef Tizabi ,&nbsp;Alexey A. Tinkov","doi":"10.1016/j.crtox.2024.100170","DOIUrl":"10.1016/j.crtox.2024.100170","url":null,"abstract":"<div><p>The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100170"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000239/pdfft?md5=ef102019acae5357af36df505014d6c1&pid=1-s2.0-S2666027X24000239-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140785269","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":"Toxicokinetics of a developmental toxicity test in zebrafish embryos and larvae: Relationship with drug exposure in humans and other mammals","authors":"Tasuku Nawaji ,&nbsp;Naohiro Mizoguchi ,&nbsp;Ryuta Adachi ,&nbsp;Hiroki Teraoka","doi":"10.1016/j.crtox.2024.100187","DOIUrl":"10.1016/j.crtox.2024.100187","url":null,"abstract":"<div><p>To study the effects of drugs on embryo/fetal development (EFD), developmental and reproductive toxicity studies in zebrafish (<em>Danio rerio</em>) embryos is expected to be an accepted alternative method to animal studies using mammals. However, there is a lack of clarity in the relationship between the concentration of developmental toxicity agents in whole embryos or larvae (Ce) and that in aqueous solution (Cw), and also between the amount of drug exposure required to cause developmental toxicity in zebrafish embryos or larvae and that required in mammals. Here, we measured Ce for developmental toxicity agents every 24 h starting at 24 h post fertilization (hpf). We found a high correlation (<em>R</em>²: 0.87–0.96) between log [Ce/Cw] and the <em>n</em>-octanol–water distribution coefficient at pH 7 (logD) of each drug at all time points up to 120 hpf. We used this relationship to estimate the Ce values of the 21 positive-control reference drugs listed in ICH guidelines on reproductive and developmental toxicity studies (ICH S5). We then calculated the area under the Ce–time curve in zebrafish (zAUC) for each drug from the regression equation between log [Ce/Cw] and logD and compared it with the AUC at the no-observed-adverse-effect level in rats and rabbits and at the effective dose in humans described in ICH S5. The log of the calculated zAUC for the 14 drugs identified as positive in the zebrafish developmental toxicity test was relatively highly positively correlated with the log [AUC] for rats, rabbits, and humans. These findings provide important and positive information on the applicability of the zebrafish embryo developmental toxicity test as an alternative method of EFD testing. (267 words)</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100187"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000409/pdfft?md5=e51bc51b975b612fc02cfa0805c6d807&pid=1-s2.0-S2666027X24000409-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141623724","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}