Toxicological Sciences最新文献

Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-28 DOI: 10.1093/toxsci/kfaf043

Mingxin Shi, Yeongseok Oh, Debra A Mitchell, James A Maclean, Ryan J Mclaughlin, Kanako Hayashi

{"title":"Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.","authors":"Mingxin Shi, Yeongseok Oh, Debra A Mitchell, James A Maclean, Ryan J Mclaughlin, Kanako Hayashi","doi":"10.1093/toxsci/kfaf043","DOIUrl":"10.1093/toxsci/kfaf043","url":null,"abstract":"The use of cannabis during pregnancy and nursing is a growing public health concern, and the multigenerational impacts of perinatal cannabis exposure remain largely unknown. To address this knowledge gap, we sought to examine the long-term consequences of perinatal cannabis use on reproductive function and how it might impact subsequent generations. Pregnant female mice were exposed to control vehicle or cannabis extract [25, 100, or 200 mg/ml Δ9-tetrahydrocannabinol (THC) in the cannabis extract] from gestational day 1 to postnatal day 21 (twice/day), encompassing the duration of pregnancy through weaning. Based on plasma THC concentrations in F0 females, we chose 100 and 200 mg/ml THC in the cannabis extract for subsequent studies. The selected doses and exposure conditions did not disrupt pregnancy or nursing in F0 females. Pregnancy and neonatal outcomes, including gestational length, litter size, and sexual ratio, were not affected by cannabis exposure. However, cannabis-exposed neonatal F1 pups were smaller. Cannabis exposure delayed vaginal opening as a sign of puberty onset and disrupted estrous cyclicity in F1 females. However, its effects were minor in F2 and F3 females. F1-F3 females showed no abnormal ovarian and uterine histology or plasma estradiol-17β levels and could produce normal offspring without pregnancy issues. These results suggest that the developmental stages of the hypothalamus and pituitary are likely perturbed by gestational and nursing cannabis exposure in F1 females. However, they are not sufficient to compromise adult reproductive function. The present results indicate limited transgenerational effects of perinatal cannabis exposure on female reproductive parameters.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Developmental perfluorooctanesulfonic acid (PFOS) exposure impairs exocrine pancreas function in zebrafish (Danio rerio).

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-28 DOI: 10.1093/toxsci/kfaf041

Madeline C Tompach, Charlotte K Gridley, Marjorie Marin, Patrick F Murphy, Junghak Lee, John M Clark, Alicia R Timme-Laragy

{"title":"Developmental perfluorooctanesulfonic acid (PFOS) exposure impairs exocrine pancreas function in zebrafish (Danio rerio).","authors":"Madeline C Tompach, Charlotte K Gridley, Marjorie Marin, Patrick F Murphy, Junghak Lee, John M Clark, Alicia R Timme-Laragy","doi":"10.1093/toxsci/kfaf041","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf041","url":null,"abstract":"Developmental perfluorooctanesulfonic acid (PFOS) exposure in zebrafish reduces digestive gene expression and pancreas length, indicating exocrine insufficiency. This project focuses on the production and function of digestive proteases with PFOS exposure. We test the hypothesis that developmental PFOS exposure impairs exocrine pancreas function in the absence of severe morphological changes. Three larval timepoints were assessed, where the nutrient source varies (yolk feed at 4 days post fertilization (dpf), yolk depleted at 6 dpf and exogenously fed at 9 dpf) to understand how nutrients were being used throughout exocrine pancreas development. Tg(ptf1a: GFP) zebrafish were exposed to 0 (0.01% DMSO), 1, 2 and 4 μM PFOS from 0-4 dpf. At 4 dpf, pancreas length was decreased with1 μM and yolk sac area was reduced with 2 and 4 μM PFOS. By 6 dpf, pancreata of zebrafish exposed to 1 μM PFOS had recovered, and pancreas size was decreased with 4 μM PFOS. Protease activity was reduced with PFOS exposure, accompanied by decreases in digestive protease gene expression and trypsin protein. At 9 dpf, there was no measurable change in pancreas size or protease activity with 1 and 2 μM PFOS, indicating morphological and functional recovery even though PFOS was detected in the larvae. This study demonstrates that PFOS exposure can affect the function of the exocrine pancreas in the absence of a detectable change in organ size. We also highlight the mishandling of yolk nutrients, leading to undernutrition at later larval stages and show catch-up growth in morphology and function.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An Analytical Screening Platform to Differentiate Acute and Prolonged Exposures of PFAS on Invasive Cellular Phenotypes.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-28 DOI: 10.1093/toxsci/kfaf044

Ryan A Lidgett, Abel A Miranda Buzetta, J Ian Baker, Pearl Dang, Amy L Oldenburg, Matthew R Lockett

{"title":"An Analytical Screening Platform to Differentiate Acute and Prolonged Exposures of PFAS on Invasive Cellular Phenotypes.","authors":"Ryan A Lidgett, Abel A Miranda Buzetta, J Ian Baker, Pearl Dang, Amy L Oldenburg, Matthew R Lockett","doi":"10.1093/toxsci/kfaf044","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf044","url":null,"abstract":"Per- and polyfluoroalkyl substances (PFAS) are \"forever chemicals\" and pervasive environmental contaminants associated with cancer. Epidemiological studies found that an increased incidence of hormone-sensitive breast cancer is correlated with PFAS exposure. Cell-based assays provide a well-controlled experimental platform to quantify cellular responses as a function of exposure. Given the nearly 15,000 known PFAS on the Environmental Protection Agency's toxicity database (DSSTox), in vitro models are the only feasible approach to screen this large molecular library. One of the Hallmarks of Cancer is increased migration and invasion, two processes that are the gateway to metastasis. Using a paper-based invasion assay developed in our lab, we compared the invasion of the MCF7 and M231 cell lines after acute and prolonged exposures to two legacy PFAS compounds individually and in equimolar mixtures: PFOA and PFOS. An acute exposure matches many invasion assays, evaluating cellular movement over a 24-h period in the presence of the molecule of interest. The prolonged exposures in this work exposed five consecutive cell passages to the PFAS. We hypothesized that prolonged PFAS exposures would select for invasive sub-populations. These prolonged exposures increased MCF7 and M231 cells compared to acute exposures of the same PFAS concentration (10 µM). The prolonged exposures to PFOA and PFOS at environmentally relevant concentrations (10 nM) did not increase invasion. Our results highlight the need to assess different exposure durations in vitro and that the paper-based invasion assay is a reasonable screening tool.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dose-response modeling of effects in mice after exposure to a polyfluoroalkyl substance (Nafion byproduct 2). 建立小鼠接触多氟烷基物质（Nafion 副产品 2）后的剂量-反应模型。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-28 DOI: 10.1093/toxsci/kfaf042

J Christopher Corton, Jeffrey S Gift, Scott S Auerbach, Jie Liu, Kaberi P Das, Hongzu Ren, Johnsie R Lang, Neil Chernoff, Christopher Lau, Donna Hill

{"title":"Dose-response modeling of effects in mice after exposure to a polyfluoroalkyl substance (Nafion byproduct 2).","authors":"J Christopher Corton, Jeffrey S Gift, Scott S Auerbach, Jie Liu, Kaberi P Das, Hongzu Ren, Johnsie R Lang, Neil Chernoff, Christopher Lau, Donna Hill","doi":"10.1093/toxsci/kfaf042","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf042","url":null,"abstract":"The polyfluorinated alkyl substance (PFAS) Nafion BP2 (1,1,2,2-tetrafluoro-2-[1,1,1,2,3,3-hexafluoro-3-(1,1,2,2-tetrafluoroethoxy)propan-2-yl]oxyethane-1-sulfonic acid) has been detected in surface and ground water, as well as in the blood of people living near PFAS manufacturing facilities. Given that very little is known about the potential toxicity of Nafion BP2 and safe exposure levels have not yet been determined, we performed a benchmark dose analysis of phenotypic and genomic effects in mice. Male and female Balb-c mice were exposed daily to Nafion BP2 at multiple doses for 7 days by oral gavage. Full-genome transcript profiling showed that Nafion BP2 in both sexes activates a number of transcription factors linked to liver toxicity, including constitutive androstane receptor (CAR), pregnane X receptor, and NRF2, but unlike other long-chain PFAS, there was no activation of peroxisome proliferator-activated receptor α. Nafion BP2 caused hepatic steatosis in both sexes. Benchmark dose (BMD) estimates for 15 non-genomic effects were 0.25 mg/kg/day and above. BMDs for transcriptional effects were 0.04 mg/kg/day and above. The most sensitive gene sets in both males and females were related to effects on xenobiotic metabolism and the cell cycle, which are plausibly related at a mechanistic level to activation of CAR. The xenobiotic metabolism and cell cycle findings were largely consistent when dose values based on internal dose were employed in the analysis. These values, along with the identification of molecular targets linked to hazards, may facilitate the determination of human health guidance for Nafion BP2.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SETBP1-R54P mutation promotes malignant transformation of cadmium-induced 16HBE cells by down-regulating circ_0007095 expression.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-27 DOI: 10.1093/toxsci/kfaf040

Wei Chen, Yufei Liu, Meizhen Li, Ye Wang, Kai Shang, Rongxiang Li, Qiuyi Lin, Yushan Chen, Huixian Zeng, Yihui Ling, Xiaodi Qin, Qiuhan Hua, Yindai Zhang, Tianshu Lin, Yun Zhou, Yiguo Jiang

{"title":"SETBP1-R54P mutation promotes malignant transformation of cadmium-induced 16HBE cells by down-regulating circ_0007095 expression.","authors":"Wei Chen, Yufei Liu, Meizhen Li, Ye Wang, Kai Shang, Rongxiang Li, Qiuyi Lin, Yushan Chen, Huixian Zeng, Yihui Ling, Xiaodi Qin, Qiuhan Hua, Yindai Zhang, Tianshu Lin, Yun Zhou, Yiguo Jiang","doi":"10.1093/toxsci/kfaf040","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf040","url":null,"abstract":"Some cancers are strongly associated with exposure to environmental carcinogens, and genetic and epigenetic alterations are crucial in carcinogenesis. However, the interaction between genetic mutations and epigenetic regulation in cancer development has not been sufficiently examined. Here, we investigated the roles of gene mutations and altered circRNA expression in the malignant transformation of human bronchial epithelial cells after continuous exposure to CdCl2 (10 μM). The circular RNA circ_0007095 was down-regulated, and the SETBP1-R54P single nucleotide variant (SNV) accumulated during Cd carcinogenesis. The decreased circ_0007095 expression enhanced CdCl2-induced cancer cell proliferation, migration and tumor formation, and the accumulation of SETBP1-R54P also promoted CdCl2-induced carcinogenesis. Mechanistic studies showed that SETBP1-R54P mutation promoted circ_0007095 degradation by activating the KLF4-PFKP axis in the RNA degradation pathway. SETBP1-R54P mutation promoted the malignant transformation of Cd-induced 16HBE cells by regulating circ_0007095 expression. Our findings emphasize the importance of the interaction between genetic variation and epigenetic regulation during environmental chemical carcinogenesis, and advance understanding of cancer etiology.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cadmium exposure and osteoporosis: Epidemiological evidence and mechanisms.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-24 DOI: 10.1093/toxsci/kfaf031

Cai Tang, Xingmin Lv, Lingling Zou, Yi Rong, Lu Zhang, Maoting Xu, Sheng Li, Guiquan Chen

{"title":"Cadmium exposure and osteoporosis: Epidemiological evidence and mechanisms.","authors":"Cai Tang, Xingmin Lv, Lingling Zou, Yi Rong, Lu Zhang, Maoting Xu, Sheng Li, Guiquan Chen","doi":"10.1093/toxsci/kfaf031","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf031","url":null,"abstract":"Cadmium (Cd) is a toxic heavy metal with a long biological half-life, exerting adverse effects on most tissues and organs in the human body. Inhalation, ingestion, and skin contact are the main ways of exposure to Cd. Bone is one of the target organs of Cd. The aging of the population has been considered as the reason for the high incidence rate of osteoporosis, but recent studies have emphasized that the risk of osteoporosis is related to cadmium exposure. With the widespread use of cadmium containing materials in industrial and agricultural activities, the risk of cadmium exposure is worrying. This review covers the epidemiological, in vivo, and in vitro studies on cadmium exposure and osteoporosis. Epidemiological evidence has emphasized a positive association between cadmium exposure and the occurrence rates of osteoporosis and fractures. Experimental studies have demonstrated that Cd induces osteoporosis through both direct and indirect pathways. The indirect pathway encompasses inducing renal dysfunction to impair calcium and phosphorus metabolism, while the direct pathway consists of directly influencing bone cells. This review aims to emphasize that cadmium exposure may be an overlooked risk factor for osteoporosis and to elucidate the direct and indirect molecular mechanisms by which Cd induces osteoporosis. Understanding the pathogenesis of cadmium-induced osteoporosis is crucial for the development of preventive and therapeutic strategies.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Adolescent exposure to Δ9-tetrahydrocannabinol (THC) impairs testicular function in young adult male mice.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-24 DOI: 10.1093/toxsci/kfaf035

Jinhwan Lim, Caitlin Quach, Julie Nguyen, Andrew Rizk, Samantha Getze, Kwang-Mook Jung, Stephen V Mahler, Daniele Piomelli, Ulrike Luderer

{"title":"Adolescent exposure to Δ9-tetrahydrocannabinol (THC) impairs testicular function in young adult male mice.","authors":"Jinhwan Lim, Caitlin Quach, Julie Nguyen, Andrew Rizk, Samantha Getze, Kwang-Mook Jung, Stephen V Mahler, Daniele Piomelli, Ulrike Luderer","doi":"10.1093/toxsci/kfaf035","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf035","url":null,"abstract":"Cannabis use typically starts in early to mid-adolescence. Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, targets cannabinoid receptors (CBRs) to exert its pharmacological effects. Expression of CBRs has been observed in human and rodent testes, but their potential role in the control of reproductive function remains unclear. We aimed to elucidate how THC exposure during adolescence or young adulthood affects the reproductive health of males. C57BL/6N male mice were given THC (5 mg/kg) or vehicle, once daily by intraperitoneal (ip) injection from postnatal day (PND) 30 to PND 43 (adolescent exposure) or PND 70 to PND 83 (adult exposure), and testes were harvested at PND 70 and PND 110, respectively. Results showed that CBRs (CB1R and CB2R) and enzymes that biosynthesize or inactivate the endocannabinoid anandamide (AEA) -N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) or fatty acid amide hydrolase (FAAH), respectively-are expressed in the mouse testis. THC exposure in adolescence decreased sperm numbers and increased seminiferous tubule degeneration in young adult testes, while adult exposure did not affect spermatogenesis and seminiferous tubule morphology. Both adolescent and adult THC exposure resulted in decreased plasma testosterone levels; however, only mice with adolescent THC exposure showed impaired steroidogenesis with dysregulated expression of steroidogenic acute regulatory protein (StAR) and steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1). Our results support that adolescent THC exposure may cause testicular toxicity through direct and aberrant activation of CBRs in the testis. These studies show that the adolescent testis is more sensitive than the adult testis to THC-induced disruption of spermatogenesis.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Kupffer cell expression of macrophage receptor with collagenous structure (MARCO) modulates macrophage gene induction and limits acute liver injury.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-21 DOI: 10.1093/toxsci/kfaf037

Lauren G Poole, Zimu Wei, Anthony Schulte, Holly M Cline, Matthew P Bernard, John P Buchweitz, Mitchell R McGill, James P Luyendyk

{"title":"Kupffer cell expression of macrophage receptor with collagenous structure (MARCO) modulates macrophage gene induction and limits acute liver injury.","authors":"Lauren G Poole, Zimu Wei, Anthony Schulte, Holly M Cline, Matthew P Bernard, John P Buchweitz, Mitchell R McGill, James P Luyendyk","doi":"10.1093/toxsci/kfaf037","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf037","url":null,"abstract":"Macrophages displaying a pro-repair and anti-inflammatory polarization have been implicated in resolution of acute liver injury. Macrophage receptor with collagenous structure (MARCO) expression marks tolerogenic hepatic macrophages and is expressed by pro-resolution macrophages in the injured liver. We tested the hypothesis that MARCO promotes repair of the acetaminophen (APAP)-injured liver. Robust and sustained induction of MARCO mRNA and protein expression was evident in livers of mice challenged with a hepatotoxic dose of APAP (ie, 300 mg/kg), whereas hepatic MARCO induction failed in mice with APAP-induced liver failure (ie, 600 mg/kg). Serum proteomics identified a significant increase in serum MARCO levels in surviving acute liver failure (ALF) patients, but not in ALF patients who died. MARCO expression was high in F480+ liver macrophages, and MARCO deficiency reduced macrophage expression of pro-resolution markers such as Gpnmb and Mertk during the repair phase (ie, 48 hours). The results suggested a delay in necrosis resolution along with a trend towards increased mortality in APAP-challenged MARCO-/- mice. Notably, a robust increase in peak hepatic injury (ie, 6-24 hours post-APAP challenge) was evident in MARCO-/- mice, which could not be ascribed to differences in NAPQI/APAP-adduct generation nor changes in hepatic neutrophil/macrophage numbers. Interestingly, a reduction in hepatic CD11c+ cells, shown previously to limit APAP-induced liver injury, was evident 24 hours after APAP challenge in MARCO-/- mice. The results indicate that MARCO deficiency worsens APAP-induced acute liver injury in mice and provide experimental and initial translational evidence linking MARCO induction to positive outcomes in acute liver injury.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Mixture Parameterized Biologically Based Dosimetry Model to Predict Body Burdens of PAHs in Developmental Zebrafish Toxicity Assays.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-21 DOI: 10.1093/toxsci/kfaf039

Christian I Rude, Jordan N Smith, Ricky P Scott, Katherine J Schultz, Kim A Anderson, Robyn L Tanguay

{"title":"A Mixture Parameterized Biologically Based Dosimetry Model to Predict Body Burdens of PAHs in Developmental Zebrafish Toxicity Assays.","authors":"Christian I Rude, Jordan N Smith, Ricky P Scott, Katherine J Schultz, Kim A Anderson, Robyn L Tanguay","doi":"10.1093/toxsci/kfaf039","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf039","url":null,"abstract":"Polycyclic aromatic hydrocarbons (PAHs) are a group of environmental toxicants found ubiquitously as complex mixtures in human impacted environments. Developmental zebrafish exposures have been used widely to study PAH toxicity, but most studies report nominal exposure concentrations. Nominal exposure concentrations can be unreliable dose metrics due to differences in toxicant bioavailability resulting from disparate exposure methodologies and chemical properties. Toxicokinetic modeling can predict toxicant tissue doses to facilitate comparison between exposures of different chemicals, methodologies, and biological models. We parameterize a biologically based dosimetry model for developmental zebrafish toxicity assays for 9 PAHs. The model was optimized with measurements from media, tissue, and plastic plate walls throughout a static developmental exposure to a mixture of ten PAHs of high abundance within the Portland Harbor Superfund Site. Plate binding, volatilization, zebrafish permeability, and tissue-media partitioning coefficients vary widely between PAHs. Model predictions accounted for 83% and 54% of 48 hpf body burdens within a factor of 2 resulting from exposures to mixtures and individual PAHs respectively. Accounting for solubility significantly improves model performance. Competition for active sites in metabolizing enzymes may change biotransformation kinetics between individual PAH and mixture exposures. Area under the curve estimations of concentrations in zebrafish resulted in altered hazard rankings from nominal exposure concentrations. Future work will be oriented to generalizing the model to other PAHs. This PAH dosimetry model improves the interpretability of developmental zebrafish toxicity assays by providing time resolved body burdens from nominal exposure concentrations.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gallic acid relieved bortezomib-induced peripheral neurotoxicity by restoring Schwann cell lysosomal activity.

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-03-20 DOI: 10.1093/toxsci/kfaf032

Xiaoliang Liu, Ke Wang, Xingxian Zhang, Jiayu Qi, Danyan Zhu, Zechao Wang, Zhi He, Jianbiao Yao, Xiangnan Zhang, Jiaying Wu

{"title":"Gallic acid relieved bortezomib-induced peripheral neurotoxicity by restoring Schwann cell lysosomal activity.","authors":"Xiaoliang Liu, Ke Wang, Xingxian Zhang, Jiayu Qi, Danyan Zhu, Zechao Wang, Zhi He, Jianbiao Yao, Xiangnan Zhang, Jiaying Wu","doi":"10.1093/toxsci/kfaf032","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf032","url":null,"abstract":"Bortezomib (BTZ) serves as a first-line medication for multiple myeloma (MM) therapy. Unfortunately, despite its prominent efficacy in MM therapy, BTZ-induced peripheral neuropathy (BIPN) presents a significant challenge for patients lacks an established therapeutic solution. Previous research has demonstrated the involvement of lysosomal dysfunction in Schwann cells as a key in the pathological process of BIPN, suggesting that agents enhancing lysosomal activity could hold promise as a treatment for BIPN. Gallic acid (GA) is a natural compound known to preserve lysosomal integrity. However, it remains unidentified whether GA is effective in ameliorating BIPN. The administration of GA in mice demonstrated a significant reversal of BTZ-induced mechanical hypersensitivity, reduction in tail nerve conduction velocity, and demyelination of sciatic nerve. GA counteracted BTZ-induced lysosomal dysfunction as evidenced by DQ-Red-BSA staining in RSC96 Schwann cells. BTZ-induced lysosomal proteins loss and autophagic flux blockage were also hindered by GA. Further analysis revealed that BTZ resulted in the increased phosphorylation of transcription factor EB (TFEB) and reduced nuclear translocation of TFEB in RSC96 cells, and these effects that were reversed upon GA treatment. Importantly, GA did not compromise the cytotoxic effects of BTZ on RPMI 8226 cells, indicating little interference with the pharmacological effects of BTZ. In summary, this study provides compelling evidence that GA can ameliorate BIPN in mice. GA activated TFEB signaling, promoted the lysosomal activity and thus restore autophagy flux in Schwann cells exposed to BTZ. These findings underscore the potential of GA as a promising therapeutic intervention for BIPN.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0