Pub Date : 2026-03-20DOI: 10.1016/j.toxlet.2026.111883
Ulla Autio, Heidi Sahlman, Miia Tiihonen, Heikki Laitinen, Marjo Huovinen
With a global prevalence of 1.7%, smoking during pregnancy commonly still occurs in many countries. Tobacco smoke contains several harmful and carcinogenic compounds which can cross the placental barrier and cause adverse effects on maternal and fetal health. Developing brains are particularly sensitive to the harmful effects of chemical exposures. The aim of this systematic literature review was to investigate the association between maternal smoking during pregnancy and childhood brain tumors in children aged 0-15 years. A systematic search was conducted using PubMed, Web of Science, CINAHL, and Scopus databases. Of the initial 192 articles, 18 were included in the final analysis, which comprised of three cohort studies and 15 case-control studies. Studies were evaluated for study quality using The National Health, Lung and Blood Institute Study Quality Assessment Tools website and the quality of the studies was mostly good. This systematic literature review found no consistent evidence of an association between maternal tobacco smoking during pregnancy and childhood brain tumors. Of the 18 studies, four reported an association between maternal smoking during pregnancy and childhood brain tumors (CBT), ependymoma, or astrocytoma. If there was an association between CBT and maternal tobacco smoking, it was seen more commonly in young children, ranging from 0 to 4 years. Further studies are needed to establish a more comprehensive understanding.
怀孕期间吸烟的全球患病率为1.7%，在许多国家仍然普遍存在。烟草烟雾中含有几种有害和致癌的化合物，它们可以穿过胎盘屏障，对母亲和胎儿的健康造成不利影响。发育中的大脑对化学物质的有害影响特别敏感。本系统文献综述的目的是调查孕期母亲吸烟与0-15岁儿童儿童期脑肿瘤之间的关系。使用PubMed、Web of Science、CINAHL和Scopus数据库进行系统检索。在最初的192篇文章中，有18篇纳入了最终分析，其中包括3项队列研究和15项病例对照研究。使用国家健康、肺和血液研究所研究质量评估工具网站对研究质量进行评估，研究质量大多良好。这项系统的文献综述没有发现怀孕期间母亲吸烟与儿童脑肿瘤之间存在关联的一致证据。在这18项研究中，有4项报告了怀孕期间母亲吸烟与儿童脑瘤（CBT）、室管膜瘤或星形细胞瘤之间的关系。如果CBT和母亲吸烟之间存在关联，那么在0-4岁的幼儿中更为常见。需要进一步的研究来建立更全面的认识。
{"title":"Is maternal smoking during pregnancy associated with childhood brain tumors? A systematic literature review.","authors":"Ulla Autio, Heidi Sahlman, Miia Tiihonen, Heikki Laitinen, Marjo Huovinen","doi":"10.1016/j.toxlet.2026.111883","DOIUrl":"10.1016/j.toxlet.2026.111883","url":null,"abstract":"<p><p>With a global prevalence of 1.7%, smoking during pregnancy commonly still occurs in many countries. Tobacco smoke contains several harmful and carcinogenic compounds which can cross the placental barrier and cause adverse effects on maternal and fetal health. Developing brains are particularly sensitive to the harmful effects of chemical exposures. The aim of this systematic literature review was to investigate the association between maternal smoking during pregnancy and childhood brain tumors in children aged 0-15 years. A systematic search was conducted using PubMed, Web of Science, CINAHL, and Scopus databases. Of the initial 192 articles, 18 were included in the final analysis, which comprised of three cohort studies and 15 case-control studies. Studies were evaluated for study quality using The National Health, Lung and Blood Institute Study Quality Assessment Tools website and the quality of the studies was mostly good. This systematic literature review found no consistent evidence of an association between maternal tobacco smoking during pregnancy and childhood brain tumors. Of the 18 studies, four reported an association between maternal smoking during pregnancy and childhood brain tumors (CBT), ependymoma, or astrocytoma. If there was an association between CBT and maternal tobacco smoking, it was seen more commonly in young children, ranging from 0 to 4 years. Further studies are needed to establish a more comprehensive understanding.</p>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":" ","pages":"111883"},"PeriodicalIF":2.9,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147494468","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}
Background: Mixtures of estradiol (E2) and benzo[a]pyrene (BaP) occur in surface waters. Seasonal sampling at Longxing Village (Jilin, China) showed total PAHs 1.07-3.14 mg L⁻¹ (BaP 3.0 ×10⁻²-1.3 ×10⁻¹ mg L⁻¹) and estrogenic compounds 42.4-81.8 ng L⁻¹ .We investigated mechanistic indicators and testable hypotheses capturing their joint neurotoxic effects.
Methods: A PC12 neuronal-differentiation model was exposed to BaP, E2 and NGF. Phenotypic assays (proliferation/viability, ROS, neurite outgrowth) were integrated with time-series transcriptomics (GO/KEGG), qPCR, and molecular docking of E2/BaP to protein tyrosine phosphatase receptor type O (PTPRO).
Significant findings: BaP accelerated proliferation and increased ROS, accompanied by transcriptomic enrichment of chemokine/GPCR-PI3K-Akt survival and anti-apoptotic signaling. Under BaP background, NGF-containing conditions were associated with a shift toward TrkA-MAPK-linked programs and up-regulation of neuronal differentiation/axonogenesis genes, consistent with the observed neurite outgrowth. Docking suggested plausible binding poses of E2 and BaP within a ligandable pocket on PTPRO and associated residue-level interaction features. Consistently, NGF up-regulated PTPRO, BaP attenuated this induction, and E2 + NGF partially restored expression, consistent with an E2F1-PTPRO-linked module. Overall, NGF partially offset BaP-associated toxicity, and PTPRO was nominated as a mechanistic candidate node associated with exposure to axonal growth. Together, these results provide mechanistic plausibility and prioritize E2F1/PTPRO- and ROS-linked pathways as mixture-associated indicators for follow-up validation in water-quality-relevant contexts.
{"title":"Surface-water estradiol-benzo[a]pyrene mixtures: Transcriptomics in a PC12 neuronal differentiation model nominate an E2F1-PTPRO axis as a candidate mechanistic biomarker.","authors":"Caiyun Sun, Peng Wang, Yu Xia, Mengyuan An, Shuang Liu, Chuanbing Wu, Wansheng Zhang, Wenwen Li, Yuhan Zhou, Junkai Hao, Liang Xu","doi":"10.1016/j.toxlet.2026.111882","DOIUrl":"10.1016/j.toxlet.2026.111882","url":null,"abstract":"<p><strong>Background: </strong>Mixtures of estradiol (E2) and benzo[a]pyrene (BaP) occur in surface waters. Seasonal sampling at Longxing Village (Jilin, China) showed total PAHs 1.07-3.14 mg L⁻¹ (BaP 3.0 ×10⁻²-1.3 ×10⁻¹ mg L⁻¹) and estrogenic compounds 42.4-81.8 ng L⁻¹ .We investigated mechanistic indicators and testable hypotheses capturing their joint neurotoxic effects.</p><p><strong>Methods: </strong>A PC12 neuronal-differentiation model was exposed to BaP, E2 and NGF. Phenotypic assays (proliferation/viability, ROS, neurite outgrowth) were integrated with time-series transcriptomics (GO/KEGG), qPCR, and molecular docking of E2/BaP to protein tyrosine phosphatase receptor type O (PTPRO).</p><p><strong>Significant findings: </strong>BaP accelerated proliferation and increased ROS, accompanied by transcriptomic enrichment of chemokine/GPCR-PI3K-Akt survival and anti-apoptotic signaling. Under BaP background, NGF-containing conditions were associated with a shift toward TrkA-MAPK-linked programs and up-regulation of neuronal differentiation/axonogenesis genes, consistent with the observed neurite outgrowth. Docking suggested plausible binding poses of E2 and BaP within a ligandable pocket on PTPRO and associated residue-level interaction features. Consistently, NGF up-regulated PTPRO, BaP attenuated this induction, and E2 + NGF partially restored expression, consistent with an E2F1-PTPRO-linked module. Overall, NGF partially offset BaP-associated toxicity, and PTPRO was nominated as a mechanistic candidate node associated with exposure to axonal growth. Together, these results provide mechanistic plausibility and prioritize E2F1/PTPRO- and ROS-linked pathways as mixture-associated indicators for follow-up validation in water-quality-relevant contexts.</p>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":" ","pages":"111882"},"PeriodicalIF":2.9,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147463494","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}
Pub Date : 2026-03-01Epub Date: 2026-01-28DOI: 10.1016/j.toxlet.2026.111844
Maike Felipe Santos Barbetta , Giovanni Stoppa Baviera , Leandro Oka-Duarte , Icaro Salgado Perovani , Anderson Rodrigo Moraes de Oliveira
Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evaluated the enantioselective inhibition by racemic DF and its enantiomers over the major cytochrome P450 (CYP) isoforms present in human liver microsomes. The inhibition screening showed that (+)-DF preferentially inhibited CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5, whereas (−)-DF was more active against CYP2C19 and CYP3A4/5. IC50 and kinetic studies confirmed moderate inhibition without time-dependent effect. DF competitively inhibited CYP2C9 with a Ki value of 2.13 µmol L−1. Finally, R1 factor estimations indicated that in vivo inhibition is unlikely even at exposure levels up to 100-fold above the acceptable daily intake. These results highlight the enantioselective inhibitory potential of a pesticide metabolite and its relevance for pesticide–drug interactions and human toxicity.
{"title":"Enantioselective CYP inhibition by diclofop, the active metabolite of diclofop-methyl: Mechanism and relevance for human exposure","authors":"Maike Felipe Santos Barbetta , Giovanni Stoppa Baviera , Leandro Oka-Duarte , Icaro Salgado Perovani , Anderson Rodrigo Moraes de Oliveira","doi":"10.1016/j.toxlet.2026.111844","DOIUrl":"10.1016/j.toxlet.2026.111844","url":null,"abstract":"<div><div>Diclofop (DF) is the main chiral metabolite of diclofop-methyl (DFM), a widely used herbicide for grass weed control. While DFM toxicity is documented, little is known about DF, despite its persistence. This study evaluated the enantioselective inhibition by racemic DF and its enantiomers over the major cytochrome P450 (CYP) isoforms present in human liver microsomes. The inhibition screening showed that (+)-DF preferentially inhibited CYP1A2, CYP2C9, CYP2E1, and CYP3A4/5, whereas (−)-DF was more active against CYP2C19 and CYP3A4/5. IC<sub>50</sub> and kinetic studies confirmed moderate inhibition without time-dependent effect. DF competitively inhibited CYP2C9 with a K<sub>i</sub> value of 2.13 µmol L<sup>−1</sup>. Finally, R<sub>1</sub> factor estimations indicated that <em>in vivo</em> inhibition is unlikely even at exposure levels up to 100-fold above the acceptable daily intake. These results highlight the enantioselective inhibitory potential of a pesticide metabolite and its relevance for pesticide–drug interactions and human toxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111844"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146094273","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}
Pub Date : 2026-03-01Epub Date: 2026-02-02DOI: 10.1016/j.toxlet.2026.111851
Deepa Sharma , Tarang Kumar Shah , Reshma Sinha
The triclosan (TCS) has been widely used as an antimicrobial and antibacterial agent in personal care products, medical, acrylic, veterinary, and household items. Owing to its capacity to interfere with hormone-regulated pathways, it has been evidenced as a potential endocrine-disrupting chemical. This review summarizes the existing data on the mechanistic basis of TCS-induced endocrine disruption, emphasizing its impacts on steroidogenesis, receptor-based signalling, thyroid hormone regulation, crosstalk with metabolic hormones, and transformation product hazards. Consolidating molecular and cellular studies, this review highlights TCS-altered major endocrine functions and identifies areas of concern requiring further investigation for risk assessment and regulatory decisions.
{"title":"Triclosan’s interference with endocrine signalling: A mechanistic investigation","authors":"Deepa Sharma , Tarang Kumar Shah , Reshma Sinha","doi":"10.1016/j.toxlet.2026.111851","DOIUrl":"10.1016/j.toxlet.2026.111851","url":null,"abstract":"<div><div>The triclosan (TCS) has been widely used as an antimicrobial and antibacterial agent in personal care products, medical, acrylic, veterinary, and household items. Owing to its capacity to interfere with hormone-regulated pathways, it has been evidenced as a potential endocrine-disrupting chemical. This review summarizes the existing data on the mechanistic basis of TCS-induced endocrine disruption, emphasizing its impacts on steroidogenesis, receptor-based signalling, thyroid hormone regulation, crosstalk with metabolic hormones, and transformation product hazards. Consolidating molecular and cellular studies, this review highlights TCS-altered major endocrine functions and identifies areas of concern requiring further investigation for risk assessment and regulatory decisions.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111851"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120220","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}
Pub Date : 2026-03-01Epub Date: 2026-01-30DOI: 10.1016/j.toxlet.2026.111850
Uttara Das , Neetu Shukla , Deeksha Ojha , Garima Sagar , Somendu Kumar Roy , Sanghamitra Bandyopadhyay
Bisphenol S (BPS) and bisphenol F (BPF) have gained attention as endocrine disruptors that affect brain functions, with their specific impact on the cerebellum being less thoroughly explored. Estrogen receptors (ERs) are crucial in maintaining neuronal health in the cerebellum, which participates in motor coordination. Additionally, bone morphogenetic proteins (BMPs) participate in various neuronal processes and are influenced by ER signaling. This study investigated how environmentally relevant doses of BPS and BPF (0.4–40 μg/kg) affect cerebellar functions in adult female rats, with a particular emphasis on ER and BMP signaling. Our assessments of motor coordination, conducted using rota-rod and grip strength tests, indicated that exposure to BPS/BPF significantly compromised balance and muscle strength. Investigation of cerebellar tissue revealed decreased levels of estrogen receptors ERα and ERβ, along with reduced BMP2 at both mRNA and protein levels. BMP2 signaling was also diminished, marked by lower BMPR2 and downstream components like p-Smad. Notably, ER agonists PPT and DPN restored BMP2 levels, while BMP2 administration enhanced ERα and ERβ levels, highlighting a reciprocal relationship between these signaling pathways. Moreover, treatments with PPT, DPN, and BMP2 led to improvements in neuronal survival, NeuN levels, and overall motor coordination performance. In conclusion, BPS and BPF disrupt cerebellar functions and neuronal health by interfering with the interplay between ER and BMP2 signaling, suggesting that targeting these pathways may help mitigate the adverse effects of these chemicals.
{"title":"Bisphenol S and F disrupt cerebellar functions and neuronal health: The role of estrogen receptor and BMP2 signaling","authors":"Uttara Das , Neetu Shukla , Deeksha Ojha , Garima Sagar , Somendu Kumar Roy , Sanghamitra Bandyopadhyay","doi":"10.1016/j.toxlet.2026.111850","DOIUrl":"10.1016/j.toxlet.2026.111850","url":null,"abstract":"<div><div>Bisphenol S (BPS) and bisphenol F (BPF) have gained attention as endocrine disruptors that affect brain functions, with their specific impact on the cerebellum being less thoroughly explored. Estrogen receptors (ERs) are crucial in maintaining neuronal health in the cerebellum, which participates in motor coordination. Additionally, bone morphogenetic proteins (BMPs) participate in various neuronal processes and are influenced by ER signaling. This study investigated how environmentally relevant doses of BPS and BPF (0.4–40 μg/kg) affect cerebellar functions in adult female rats, with a particular emphasis on ER and BMP signaling. Our assessments of motor coordination, conducted using rota-rod and grip strength tests, indicated that exposure to BPS/BPF significantly compromised balance and muscle strength. Investigation of cerebellar tissue revealed decreased levels of estrogen receptors ERα and ERβ, along with reduced BMP2 at both mRNA and protein levels. BMP2 signaling was also diminished, marked by lower BMPR2 and downstream components like p-Smad. Notably, ER agonists PPT and DPN restored BMP2 levels, while BMP2 administration enhanced ERα and ERβ levels, highlighting a reciprocal relationship between these signaling pathways. Moreover, treatments with PPT, DPN, and BMP2 led to improvements in neuronal survival, NeuN levels, and overall motor coordination performance. In conclusion, BPS and BPF disrupt cerebellar functions and neuronal health by interfering with the interplay between ER and BMP2 signaling, suggesting that targeting these pathways may help mitigate the adverse effects of these chemicals.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111850"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100773","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}
Pub Date : 2026-03-01Epub Date: 2026-02-10DOI: 10.1016/j.toxlet.2026.111855
Asrat Fekadu Demsie
Soil samples collected from irrigated farmlands around Lake Ziway were thoroughly analyzed for 35 different pesticides, yielding significant insights into contamination profiles and the non-dietary health risks associated with these substances in the region. The analysis utilized gas chromatography-mass spectrometry (GC-MS) techniques. To assess non-dietary health risks, the study employed metrics such as the hazard index (HI) and Incremental Lifetime Cancer Risk (ILCR), considering various exposure pathways, including ingestion, dermal contact, and inhalation for both children and adults. The results revealed a concerning level of pesticide contamination in the agricultural soils of the area. Propargite was identified as the most prevalent contaminant, with a concentration of 62.463 ± 21.963 µg/kg, followed by p,p’-DDE at 46.85 ± 10.052 µg/kg. Other pesticides were detected at significantly lower levels. Risk estimates based on HI values indicated a non-carcinogenic risk for children and adults at 1.08E-02 and 1.35E-03, respectively, suggesting that the non-carcinogenic risk remains within acceptable limits (HI <1). The ILCR for children across all exposure levels, as well as for adults in terms of ingestion was found to be range from 1.59E-08–3.38E-16, suggesting that there is no significant cancer risk to humans through these pathways. However, the ILCRs associated with dermal contact for adults indicate a potential cancer risk, with estimates ranging from 10−4 to 10−6. Furthermore, model estimates indicate that adults face a greater cancer risk of non-dietary pesticide exposure compared to children. These findings highlight the urgent need for enhanced monitoring programs that address both currently used and banned pesticides.
{"title":"Assessment of non-dietary human health risk based on concentration of multiresidue pesticides in soil of irrigated farmland around Lake Ziway, Ethiopia","authors":"Asrat Fekadu Demsie","doi":"10.1016/j.toxlet.2026.111855","DOIUrl":"10.1016/j.toxlet.2026.111855","url":null,"abstract":"<div><div>Soil samples collected from irrigated farmlands around Lake Ziway were thoroughly analyzed for 35 different pesticides, yielding significant insights into contamination profiles and the non-dietary health risks associated with these substances in the region. The analysis utilized gas chromatography-mass spectrometry (GC-MS) techniques. To assess non-dietary health risks, the study employed metrics such as the hazard index (HI) and Incremental Lifetime Cancer Risk (ILCR), considering various exposure pathways, including ingestion, dermal contact, and inhalation for both children and adults. The results revealed a concerning level of pesticide contamination in the agricultural soils of the area. Propargite was identified as the most prevalent contaminant, with a concentration of 62.463 ± 21.963 µg/kg, followed by p,p’-DDE at 46.85 ± 10.052 µg/kg. Other pesticides were detected at significantly lower levels. Risk estimates based on HI values indicated a non-carcinogenic risk for children and adults at 1.08E-02 and 1.35E-03, respectively, suggesting that the non-carcinogenic risk remains within acceptable limits (HI <1). The ILCR for children across all exposure levels, as well as for adults in terms of ingestion was found to be range from 1.59E-08–3.38E-16, suggesting that there is no significant cancer risk to humans through these pathways. However, the ILCRs associated with dermal contact for adults indicate a potential cancer risk, with estimates ranging from 10<sup>−4</sup> to 10<sup>−6</sup>. Furthermore, model estimates indicate that adults face a greater cancer risk of non-dietary pesticide exposure compared to children. These findings highlight the urgent need for enhanced monitoring programs that address both currently used and banned pesticides.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111855"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146174583","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}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.toxlet.2026.111843
Yao Zhang , Kehan Wang , Jingzhu Lu , Ruicheng Wang , Chun Pan , Tan Ma , Fuyuan Ma
Dibutyl benzene-1,2-dicarboxylate (DBP), a ubiquitous plasticizer, readily crosses the placenta, posing a risk to male offspring development. Previous studies have found that maternal DBP exposure leads to multiple organ development disorders in male offspring, but the effect on skeletal development in male offspring mice is unclear. In this study, pregnant mice were orally administered corn oil from day 12 of pregnancy or given different doses of DBP by gavage. Our results showed that prenatal DBP exposure induced dose-dependent deterioration in the male offspring's femoral bone microarchitecture, as revealed by micro-CT. In vitro, we found that the primary metabolite MBP disrupted the osteogenic-adipogenic balance in bone marrow mesenchymal stem cells (BMSCs) by suppressing osteogenic differentiation while promoting adipogenic differentiation. Mechanistically, MBP treatment induced a premature senescent phenotype in BMSCs, as evidenced by heightened senescence-associated β-galactosidase (SA-β-Gal) activity, upregulation of senescence markers (γH2AX, p16, p21), and increased secretion of senescence-associated inflammatory factors. Critically, treatment with rapamycin prevented MBP-induced senescence and restored the osteogenic-adipogenic balance in BMSCs. This study identifies BMSCs senescence as a pivotal mechanism underlying DBP-induced skeletal retardation, providing novel insights into the environmental bone toxicity of phthalate exposure.
{"title":"Maternal dibutyl benzene-1,2-dicarboxylate exposure accelerates bone marrow mesenchymal stem cells senescence to induce skeletal retardation in male offspring mice","authors":"Yao Zhang , Kehan Wang , Jingzhu Lu , Ruicheng Wang , Chun Pan , Tan Ma , Fuyuan Ma","doi":"10.1016/j.toxlet.2026.111843","DOIUrl":"10.1016/j.toxlet.2026.111843","url":null,"abstract":"<div><div>Dibutyl benzene-1,2-dicarboxylate (DBP), a ubiquitous plasticizer, readily crosses the placenta, posing a risk to male offspring development. Previous studies have found that maternal DBP exposure leads to multiple organ development disorders in male offspring, but the effect on skeletal development in male offspring mice is unclear. In this study, pregnant mice were orally administered corn oil from day 12 of pregnancy or given different doses of DBP by gavage. Our results showed that prenatal DBP exposure induced dose-dependent deterioration in the male offspring's femoral bone microarchitecture, as revealed by micro-CT. <em>In vitro</em>, we found that the primary metabolite MBP disrupted the osteogenic-adipogenic balance in bone marrow mesenchymal stem cells (BMSCs) by suppressing osteogenic differentiation while promoting adipogenic differentiation. Mechanistically, MBP treatment induced a premature senescent phenotype in BMSCs, as evidenced by heightened senescence-associated β-galactosidase (SA-β-Gal) activity, upregulation of senescence markers (γH2AX, p16, p21), and increased secretion of senescence-associated inflammatory factors. Critically, treatment with rapamycin prevented MBP-induced senescence and restored the osteogenic-adipogenic balance in BMSCs. This study identifies BMSCs senescence as a pivotal mechanism underlying DBP-induced skeletal retardation, providing novel insights into the environmental bone toxicity of phthalate exposure.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111843"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081064","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}
The development of robust human in vitro models is crucial for advancing neurotoxicology and reducing animal testing. Human-induced pluripotent stem cell (hiPSC)-derived neuronal models hold great promise, but still show limitations in recapitulating certain neurodevelopmental processes. Currently, rodent primary cultures remain the gold standard for studying complex processes such as synaptogenesis. A key mechanism in glutamatergic synapse maturation is the GluN2B/GluN2A switch, which promotes the recruitment of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, increasing the structural and functional complexity of the synaptic spines. This study characterizes the development of the glutamatergic machinery in hiPSC-derived neurons, focusing on the expression and maturation of N-methyl-D-aspartate (NMDA) and AMPA receptors. The increase of neuronal markers and the reduction of progenitor markers confirmed the differentiation efficiency. However, discrepancies emerged between transcriptional and protein profiles of key receptor subunits. GluN2A mRNA levels increased over time, while protein levels remained similar to those of neural progenitor cells (NPCs). Conversely, the GluN3A transcript increased at 30 and 60 days in vitro (DIV), while protein abundance decreased. Similar transcript–protein mismatches were observed for some AMPA receptor subunits. These results suggest that this model does not reach full glutamatergic maturity within the tested timeframe. Therefore, optimizing differentiation conditions (such as extending culture duration or adding maturation cues) may be necessary to better reproduce receptor dynamics. Finally, this study highlights the need to integrate protein-level analyses with transcriptional data to improve the reliability of hiPSC-derived neuronal models for neurotoxicity and NMDA receptor–mediated excitotoxicity studies.
{"title":"Transcript-protein discrepancy of glutamatergic receptor subunits in human iPSC-derived neurons: Implications for neurotoxicity testing","authors":"Melania Maria Serafini , Miriam Midali , Giacomo Grumelli , Alessandro Cutarelli , Marina Marinovich , Luciano Conti , Barbara Viviani","doi":"10.1016/j.toxlet.2026.111834","DOIUrl":"10.1016/j.toxlet.2026.111834","url":null,"abstract":"<div><div>The development of robust human in vitro models is crucial for advancing neurotoxicology and reducing animal testing. Human-induced pluripotent stem cell (hiPSC)-derived neuronal models hold great promise, but still show limitations in recapitulating certain neurodevelopmental processes. Currently, rodent primary cultures remain the gold standard for studying complex processes such as synaptogenesis. A key mechanism in glutamatergic synapse maturation is the GluN2B/GluN2A switch, which promotes the recruitment of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, increasing the structural and functional complexity of the synaptic spines. This study characterizes the development of the glutamatergic machinery in hiPSC-derived neurons, focusing on the expression and maturation of N-methyl-<span>D</span>-aspartate (NMDA) and AMPA receptors. The increase of neuronal markers and the reduction of progenitor markers confirmed the differentiation efficiency. However, discrepancies emerged between transcriptional and protein profiles of key receptor subunits. GluN2A mRNA levels increased over time, while protein levels remained similar to those of neural progenitor cells (NPCs). Conversely, the GluN3A transcript increased at 30 and 60 days in vitro (DIV), while protein abundance decreased. Similar transcript–protein mismatches were observed for some AMPA receptor subunits. These results suggest that this model does not reach full glutamatergic maturity within the tested timeframe. Therefore, optimizing differentiation conditions (such as extending culture duration or adding maturation cues) may be necessary to better reproduce receptor dynamics. Finally, this study highlights the need to integrate protein-level analyses with transcriptional data to improve the reliability of hiPSC-derived neuronal models for neurotoxicity and NMDA receptor–mediated excitotoxicity studies.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111834"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146067245","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}
Pub Date : 2026-03-01Epub Date: 2026-01-28DOI: 10.1016/j.toxlet.2026.111845
Amanda Rebonatto Oltramari , Alice Santos Da Silva , Marina Machado Cabrera , Geisson Marcos Nardi , Fátima Regina Mena Barreto Silva , Gabriel Adan Araújo Leite
Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, recent studies indicate potential reproductive toxicity associated with statin use in animal and human studies. This study aimed to evaluate the reproductive parameters and fertility in adult female Swiss mice exposed to relevant doses of rosuvastatin. Female mice were divided into three experimental groups: control (0.9 % saline solution), 1.5 mg/kg of rosuvastatin, and 5.5 mg/kg of rosuvastatin. The treatments were administered via gavage from postnatal day (PND) 80 to PND 110, and the reproductive and developmental parameters, as well as the general health status of the animals, were assessed. There was a reduction in total serum cholesterol and triglyceride levels, a reduced total number of antral follicles, and an increased ovarian follicular atresia, as confirmed by increased cleaved caspase-9 and caspase-3 immunostaining in the granulosa cells of antral follicles, in the rosuvastatin-treated females. However, no adverse effects were observed in body mass gain and the hepatic markers of non-pregnant females. The treatment with rosuvastatin preceding gestation reduced pregnancy rate and increased post-implantation losses, resorptions, and fetal mortality, especially at the lower dose. In summary, the exposure to rosuvastatin during adulthood may compromise follicular dynamics and reduce female reproductive performance. These outcomes reinforce the need for caution in the use of statins by women of reproductive age.
{"title":"Rosuvastatin exposure during adulthood increases ovarian follicular atresia and reduces reproductive performance in female mice","authors":"Amanda Rebonatto Oltramari , Alice Santos Da Silva , Marina Machado Cabrera , Geisson Marcos Nardi , Fátima Regina Mena Barreto Silva , Gabriel Adan Araújo Leite","doi":"10.1016/j.toxlet.2026.111845","DOIUrl":"10.1016/j.toxlet.2026.111845","url":null,"abstract":"<div><div>Statins are widely used to manage lipid disorders and reduce cardiovascular risk in humans. Rosuvastatin, one of the most effective statins, decreases cholesterol biosynthesis and exerts pleiotropic effects. However, recent studies indicate potential reproductive toxicity associated with statin use in animal and human studies. This study aimed to evaluate the reproductive parameters and fertility in adult female Swiss mice exposed to relevant doses of rosuvastatin. Female mice were divided into three experimental groups: control (0.9 % saline solution), 1.5 mg/kg of rosuvastatin, and 5.5 mg/kg of rosuvastatin. The treatments were administered via gavage from postnatal day (PND) 80 to PND 110, and the reproductive and developmental parameters, as well as the general health status of the animals, were assessed. There was a reduction in total serum cholesterol and triglyceride levels, a reduced total number of antral follicles, and an increased ovarian follicular atresia, as confirmed by increased cleaved caspase-9 and caspase-3 immunostaining in the granulosa cells of antral follicles, in the rosuvastatin-treated females. However, no adverse effects were observed in body mass gain and the hepatic markers of non-pregnant females. The treatment with rosuvastatin preceding gestation reduced pregnancy rate and increased post-implantation losses, resorptions, and fetal mortality, especially at the lower dose. In summary, the exposure to rosuvastatin during adulthood may compromise follicular dynamics and reduce female reproductive performance. These outcomes reinforce the need for caution in the use of statins by women of reproductive age.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111845"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081126","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}
Pub Date : 2026-03-01Epub Date: 2026-02-02DOI: 10.1016/j.toxlet.2026.111848
Shuang Qin , Longhui Xie , Jianwei Lan , Yang Yang , Wuliang Diao , Yinkuan Ning
Background
Epidemiological evidence has established associations between heavy metal exposure and increased risks of various cancers. However, causality remains difficult to establish in conventional observational studies due to residual confounding and reverse causation. Mendelian randomization (MR) could overcome these limitations by using genetic variants as instrumental variables to strengthen causal inference. This study employs a two-sample MR approach to investigate the potential causal effects of serum heavy metal concentrations on multiple cancer types.
Methods
Genetic instruments for heavy metal exposure were obtained from genome-wide association study (GWAS) data. The primary causal estimates were derived using the inverse variance weighted (IVW) method, with robustness assessed and pleiotropy addressed through supplementary analyses, including weighted median, MR-Egger regression, and MR-PRESSO. All analyses accounted for multiple testing via Bonferroni correction.
Results
Mendelian randomization analysis revealed that genetically predicted serum nickel conferred an elevated risk of cervical cancer (OR = 1.473, 95 % CI: 1.102–1.969, P = 0.009), while serum manganese exhibited a protective effect against acute lymphoblastic leukemia (OR = 0.399, 95 % CI:0.173–0.922, P = 0.032). Additionally, serum lead was associated with an increased risk of biliary tract cancer (OR = 1.315, 95 % CI: 1.04–1.661, P = 0.022), and serum copper was causally linked to higher overall cancer incidence (OR = 1.052, 95 % CI: 1.004–1.102, P = 0.032).
Conclusion
This study provides solid evidence for causal effects of heavy metal exposure on cancer development. The findings compel further investigation into the biological mechanisms involved and highlight the urgency of developing targeted public health interventions to mitigate these risks.
{"title":"Heavy metal exposure and cancer risk: Findings from a Mendelian randomization study","authors":"Shuang Qin , Longhui Xie , Jianwei Lan , Yang Yang , Wuliang Diao , Yinkuan Ning","doi":"10.1016/j.toxlet.2026.111848","DOIUrl":"10.1016/j.toxlet.2026.111848","url":null,"abstract":"<div><h3>Background</h3><div>Epidemiological evidence has established associations between heavy metal exposure and increased risks of various cancers. However, causality remains difficult to establish in conventional observational studies due to residual confounding and reverse causation. Mendelian randomization (MR) could overcome these limitations by using genetic variants as instrumental variables to strengthen causal inference. This study employs a two-sample MR approach to investigate the potential causal effects of serum heavy metal concentrations on multiple cancer types.</div></div><div><h3>Methods</h3><div>Genetic instruments for heavy metal exposure were obtained from genome-wide association study (GWAS) data. The primary causal estimates were derived using the inverse variance weighted (IVW) method, with robustness assessed and pleiotropy addressed through supplementary analyses, including weighted median, MR-Egger regression, and MR-PRESSO. All analyses accounted for multiple testing via Bonferroni correction.</div></div><div><h3>Results</h3><div>Mendelian randomization analysis revealed that genetically predicted serum nickel conferred an elevated risk of cervical cancer (OR = 1.473, 95 % CI: 1.102–1.969, P = 0.009), while serum manganese exhibited a protective effect against acute lymphoblastic leukemia (OR = 0.399, 95 % CI:0.173–0.922, P = 0.032). Additionally, serum lead was associated with an increased risk of biliary tract cancer (OR = 1.315, 95 % CI: 1.04–1.661, P = 0.022), and serum copper was causally linked to higher overall cancer incidence (OR = 1.052, 95 % CI: 1.004–1.102, P = 0.032).</div></div><div><h3>Conclusion</h3><div>This study provides solid evidence for causal effects of heavy metal exposure on cancer development. The findings compel further investigation into the biological mechanisms involved and highlight the urgency of developing targeted public health interventions to mitigate these risks.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111848"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146120205","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}
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