Toxics

16 pages, 1814 KB

Open AccessArticle

Strain and Sex Variability in Liver, Kidney and Lung Levels of DNA Adducts EB-GII and bis-N7G-BD Following Inhalation Exposure to 1,3-Butadiene in Collaborative Cross Mice

by Erik Moran, Samantha Goodman, Fred A. Wright, Richard Evans, Natalia Y. Tretyakova and Ivan Rusyn

Toxics 2025, 13(10), 844; https://doi.org/10.3390/toxics13100844 - 3 Oct 2025

Abstract

1,3-butadiene (BD) is a volatile organic pollutant. Upon inhalation, it is metabolically activated to reactive epoxides which alkylate genomic DNA and form potentially mutagenic monoadducts and DNA–DNA crosslinks including N7-(1-hydroxyl-3-buten-1-yl)guanine (EB-GII) and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD). While metabolic activation resulting in [...] Read more.

1,3-butadiene (BD) is a volatile organic pollutant. Upon inhalation, it is metabolically activated to reactive epoxides which alkylate genomic DNA and form potentially mutagenic monoadducts and DNA–DNA crosslinks including N7-(1-hydroxyl-3-buten-1-yl)guanine (EB-GII) and 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD). While metabolic activation resulting in mutagenicity is a well-established mode of action for 1,3-butadiene, characterization of the extent of inter-individual variability in response to BD exposure is a gap in our knowledge. Previous studies showed that population-wide mouse models can be used to evaluate variability in 1,3-butadiene DNA adducts; therefore, we hypothesized that this approach can be used to also study variability in the formation and loss of BD DNA adducts across tissues and between sexes. To test this hypothesis, female and male mice from five genetically diverse Collaborative Cross (CC) strains were exposed to filtered air or 1,3-butadiene (600 ppm, 6 h/day, 5 days/week for 2 weeks) by inhalation. Some animals were kept for two additional weeks after exposure to study DNA adduct persistence. EB-GII and bis-N7G-BD adducts were quantified in liver, lungs and kidney using established isotope dilution ESI-MS/MS methods. We observed strain- and sex-specific effects on both the accumulation and loss of both DNA adducts, indicating that both factors play important roles in the mutagenicity of 1,3-butadiene. In addition, we quantified the intra-species variability for each adduct and found that for most tissues/adducts, variability values across strains were modest compared to default uncertainty factors. Full article

(This article belongs to the Special Issue Evaluating DNA Damage and Toxicological Effects)

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20 pages, 703 KB

Open AccessArticle

Fast Trace Detection of Chlorpyrifos Vapors Using a Handheld Ion Mobility Spectrometer Operated near Ambient Temperature

by Victor Bocoș-Bințințan, Ancuța-Maria Dodea, Tomáš Rozsypal, Adrian Pătruț, Gheorghe Roșian, Aurel-Vasile Martiniuc, Alin-Gabriel Moraru, Simina Vasc and Maria-Paula Bocoș-Bințințan

Toxics 2025, 13(10), 843; https://doi.org/10.3390/toxics13100843 - 2 Oct 2025

Abstract

Chlorpyrifos CPF (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate), known also as Chlorpyrifos-ethyl, is one of the most utilized organophosphorus pesticides worldwide. Additionally, CPF could be used as a chemical warfare agent surrogate. Although its acute toxicity is not high, it is responsible for both a large [...] Read more.

Chlorpyrifos CPF (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate), known also as Chlorpyrifos-ethyl, is one of the most utilized organophosphorus pesticides worldwide. Additionally, CPF could be used as a chemical warfare agent surrogate. Although its acute toxicity is not high, it is responsible for both a large number of intoxications and chronic, delayed neurological effects. In this work, it is reported for the first time the qualitative and quantitative response produced by CPF vapors, using a pocket-held Time-of-Flight Ion Mobility Spectrometer (ToF IMS) with a non-radioactive ionization source and ammonia doping, model LCD-3.2E (Smiths Detection Ltd.), operated near ambient temperature (below 30 °C). Spectra of CPF in positive ion mode included two distinct product ion peaks; thus, identification of CPF vapors by IMS relies on these peaks—the monomer M·NH₄⁺ with reduced ion mobility K₀ = ca. 1.76 cm²V⁻¹s⁻¹ and the dimer M₂·NH₄⁺ with K₀ = ca. 1.47 cm²V⁻¹s⁻¹ (where M may be assignable to CPF molecule)—and positive reactant ions (Pos RIP) have K₀ = ca. 2.25 cm²V⁻¹s⁻¹. Excellent sensitivity, with a limit of detection LOD of 0.72 ppb_v (10.5 μg m⁻³) and a limit of quantification LOQ of 2.41 ppb_v (35.1 μg m⁻³), has been noticed; linear response was up to 100 ppb_v, while saturation occurs over ca. 1000 ppb_v (14.6 mg m⁻³). Our results demonstrate that this method provides a robust tool for both off-site and on-site detecting and quantifying CPF vapors at trace levels, which has strong implications for either industrial hygiene or forensic investigations concerning the pesticide Chlorpyrifos, as well as for monitoring of environmental contamination by organophosphorus pesticides. Full article

(This article belongs to the Section Agrochemicals and Food Toxicology)

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14 pages, 1358 KB

Open AccessArticle

Toxic Metals in Road Dust from Urban Industrial Complexes: Seasonal Distribution, Bioaccessibility and Integrated Health Risk Assessment Using Triangular Fuzzy Number

by Yazhu Wang, Jinyuan Guo, Zhiguang Qu and Fei Li

Toxics 2025, 13(10), 842; https://doi.org/10.3390/toxics13100842 - 2 Oct 2025

Abstract

Urban industrial complexes have been expanding worldwide, reducing the spatial separation between agricultural, residential, and industrial zones, particularly in developing nations. Urban road dust contamination, a sensitive indicator of urban environmental quality, primarily originates in urbanization and industrialization. Its detrimental impacts on human [...] Read more.

Urban industrial complexes have been expanding worldwide, reducing the spatial separation between agricultural, residential, and industrial zones, particularly in developing nations. Urban road dust contamination, a sensitive indicator of urban environmental quality, primarily originates in urbanization and industrialization. Its detrimental impacts on human health arise not only from particulate matter itself but also from toxic and harmful substances embedded within dust particles. Toxic metals in road dust can pose health risks through inhalation, ingestion and contact. To investigate the seasonal patterns, bioaccessibility levels and the potential human health risks linked to toxic metals (Cadmium (Cd), Nickel (Ni), Arsenic (As), Lead (Pb), Zinc (Zn), Copper (Cu), and Chromium (Cr)), 34 dust samples were collected from key roads in proximity to representative industrial facilities in Wuhan’s Qingshan District. The study found that the concentrations of Cd, Pb, and Cu in road dust were within the limits set by the national standard (GB 15618-2018), while Ni and As were not. Seasonally, Ni, As, Pb, Zn, and Cr exhibited higher concentrations during the summer than in other seasons, whereas Cd levels were lowest in spring and highest in autumn, the opposite of Cu. According to the Simplified Bioaccessibility Extraction Test (SBET), the average bioaccessibility rates of toxic metals were Cd > Zn > Cu > Ni > Cr > As > Pb. An improved health risk assessment model was developed, integrating metal enrichment, bioaccessibility, and parameter uncertainty. Results indicated that Cd, Ni, Zn, Cu, As, and Cr posed no significant non-carcinogenic risk. However, for children, the carcinogenic risks of Cd and As were relatively high, identifying them as priority control metals. Therefore, it is recommended to periodically monitor As and Cd and regulate their potential emission sources, especially in winter and spring. Full article

(This article belongs to the Section Air Pollution and Health)

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3 pages, 181 KB

Open AccessEditorial

Closing Editorial: Mercury Cycling and Health Effects

by José Vicente Elias Bernardi, Wanderley Rodrigues Bastos, Jurandir Rodrigues de Souza and Carlos José Sousa Passos

Toxics 2025, 13(10), 841; https://doi.org/10.3390/toxics13100841 - 2 Oct 2025

Abstract

Mercury (Hg) is a persistent global contaminant that cycles among the atmosphere, rivers, oceans, soils, and biota [...] Full article

(This article belongs to the Special Issue Mercury Cycling and Health Effects)

21 pages, 3532 KB

Open AccessArticle

Pollution Status, Ecological Risks, and Potential Sources of Metals in the Middle and Lower Reaches of the Lianjiang River Basin, Guangdong Province, China

by Yongzhong Lai, Le Li, Xianbing Huang, Guoyong Lu, Fengqin Pan and Wenhua Liu

Toxics 2025, 13(10), 840; https://doi.org/10.3390/toxics13100840 - 1 Oct 2025

Abstract

Human activities have led to severe aquatic pollution and significant concerns about the ecological health of the Lianjiang River Basin (LRB). These concerns resulted in the implementation of comprehensive policies and treatments to improve the sediment and water quality. Herein, we explore the [...] Read more.

Human activities have led to severe aquatic pollution and significant concerns about the ecological health of the Lianjiang River Basin (LRB). These concerns resulted in the implementation of comprehensive policies and treatments to improve the sediment and water quality. Herein, we explore the concentrations, sources, and degree of metal contamination in filtered water (FW), suspended solids (SSs), and surficial channel sediments (SCSs) in streams of the LRB. Calculated enrichment factors, an ecological risk index, and a principal component analysis were employed to understand the degree of elemental contamination, ecological risks, and their potential sources. Elements (e.g., Hg, Cd, Sn, Sb, Cu, and Mo) were mainly detected in FW, SSs, and SCSs in the Bergang, Hucheng, Xiashan, and Zhonggang rivers, and the mainstream of the LR. Four potential anthropogenic sources were identified, including electronic waste recycling (e.g., Cu, Sb, Pb, and Ni), mixed pollution (e.g., Se, Zn, Mn, and Mo), metal processing (e.g., Hg, Cr, Sn, and Cd), and battery manufacturing and recycling (e.g., Co, Ni, and Mn). Overall, Sn, Sb, Hg, Cu, and Cd were enriched by 37.5–79.2% and 34.8–91.3% at the SS and SCS sites, respectively. Mercury, Cd, Sn, Sb, Cu, and Mo posed the most risk both in the SSs and SCSs. Overall, the SS and SCS samples from the LRB remain severely contaminated with metals after recent environmental remediation. The implementation of pollution source control, sewage interception, and dredging operations should be further enhanced. Full article

(This article belongs to the Section Ecotoxicology)

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22 pages, 3702 KB

Open AccessArticle

QTAIM Based Computational Assessment of Cleavage Prone Bonds in Highly Hazardous Pesticides

by Andrés Aracena, Sebastián Elgueta, Sebastián Pizarro and César Zúñiga

Toxics 2025, 13(10), 839; https://doi.org/10.3390/toxics13100839 - 1 Oct 2025

Abstract

Highly Hazardous Pesticides (HHPs) pose severe risks to human health and the environment, making it essential to understand their molecular stability and degradation pathways. In this study, the Quantum Theory of Atoms in Molecules (QTAIM) was applied to four representative organophosphate pesticides, allowing [...] Read more.

Highly Hazardous Pesticides (HHPs) pose severe risks to human health and the environment, making it essential to understand their molecular stability and degradation pathways. In this study, the Quantum Theory of Atoms in Molecules (QTAIM) was applied to four representative organophosphate pesticides, allowing the identification of electronically weak bonds as intrinsic sites of lability. These findings are consistent with reported hydrolytic, oxidative, enzymatic, and microbial degradation routes. Importantly, QTAIM descriptors proved largely insensitive to solvation, confirming their intrinsic character within the molecular electronic structure. To complement QTAIM, conceptual DFT (Density Functional Theory) reactivity indices were analyzed, revealing that solvent effects induce more noticeable variations in global and local descriptors than in topological parameters. In addition, a Topological Analysis of the Fukui Function (TAFF) was performed, which mapped nucleophilic, electrophilic, and radical susceptibilities directly onto QTAIM basins. The TAFF analysis confirmed that bonds identified as weak by QTAIM (notably P–O, P–S, and P–N linkages) also coincide with the most reactive sites, thereby reinforcing their mechanistic role in degradation pathways. This integrated framework highlights the robustness of QTAIM, the sensitivity of global and local reactivity descriptors to solvation revealed by conceptual DFT, and the complementary insights provided by TAFF, contributing to risk assessment, remediation strategies, and the rational design of safer pesticides. Full article

(This article belongs to the Special Issue Computational Toxicology: Exposure and Assessment)

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11 pages, 536 KB

Open AccessFeature PaperArticle

Association of Exposure to Phthalate Metabolites with Antenatal Depression in US Pregnant Women

by Pallavi Dubey, Chinthana Thangavel, Abdelrahman Yousif, Sophie Kim and Sireesha Reddy

Toxics 2025, 13(10), 838; https://doi.org/10.3390/toxics13100838 - 30 Sep 2025

Abstract

Antenatal depression affects 10–20% of pregnant women, with notable adverse outcomes for the neonates. Limited studies have indicated a potential link between exposure to phthalate metabolites and depression. The association between phthalate metabolites and depression in pregnant women is unknown. We sought to [...] Read more.

Antenatal depression affects 10–20% of pregnant women, with notable adverse outcomes for the neonates. Limited studies have indicated a potential link between exposure to phthalate metabolites and depression. The association between phthalate metabolites and depression in pregnant women is unknown. We sought to evaluate the association of exposure to phthalate metabolites with depression severity score in US pregnant women. This cross-sectional study used data collected by the National Health and Nutrition Examination Survey during 2005–2018 on pregnant adults who completed urinary profiles that examined 12 common phthalate metabolites. Linear and quantile sum regressions were used to evaluate the association between depressive symptoms (measured by the Patient Health Questionnaire, PHQ-9) and concentrations of phthalate metabolites. A total of 208 women were included in the analysis. These women’s mean (SD) age was 27.42 (5.78) years. We found that all the phthalates were associated with PHQ-9 scores except for mono (carboxyoctyl) and mono-isononyl phthalate. Similar results were observed with the association of high levels of phthalates with mild, moderate, and severe depression (PHQ-9 >4 vs. ≤4). All the phthalate metabolites remained significantly associated with depression scores in the adjusted analysis. Among all considered phthalate metabolites, a combination of MCNP, MBP, MiBP, MnBP, and MEHP contributed to the strongest association with higher depression scores. The relative importance was similar for MCNP (weight = 0.32) and MBP (weight = 0.31), followed by MiBP (weight = 0.12), MnBP (weight = 0.08), MEHP (0.07), and MEP (weight = 0.04) for depression scores. Our findings suggest that pregnant women with high exposure to phthalates are more likely to have higher depressive symptom scores. Full article

(This article belongs to the Special Issue Endocrine-Disrupting Chemicals and Reproductive Toxicology)

5 pages, 212 KB

Open AccessEditorial

Heavy Metal Contamination and Its Effects on Ecosystems and Human Health: Challenges and Solutions

by Daochen Zhu

Toxics 2025, 13(10), 837; https://doi.org/10.3390/toxics13100837 - 30 Sep 2025

Abstract

Heavy metals and other potentially toxic elements (PTEs) constitute a durable class of contaminants [...] Full article

(This article belongs to the Special Issue Heavy Metal Contamination and Its Effects on Ecosystems and Human Health: Challenges and Solutions)

17 pages, 2282 KB

Open AccessSystematic Review

Association of Bisphenol Exposure and Serum Hypothalamic–Pituitary–Thyroid Axis Hormone Levels in Adults and Pregnant Women: A Systematic Review and Meta-Analysis

by Mazhar Sultan, Xuan Ma, Qiurun Yu, Francis Manyori Bigambo, Yufeng Tang, Natasha Chitakwa, Farah Kafauit, Qinrou Chen, Quanquan Guan and Yankai Xia

Toxics 2025, 13(10), 836; https://doi.org/10.3390/toxics13100836 - 30 Sep 2025

Abstract

Background: Bisphenols (BPs) are present in medical instruments, plastic containers, and personal care products (PCPs). Bisphenol A has been replaced by its alternatives, bisphenol S, F, AF, and B. Due to the awareness of their toxicity, mixed exposure to these alternatives at the [...] Read more.

Background: Bisphenols (BPs) are present in medical instruments, plastic containers, and personal care products (PCPs). Bisphenol A has been replaced by its alternatives, bisphenol S, F, AF, and B. Due to the awareness of their toxicity, mixed exposure to these alternatives at the regional level has been given less attention; there is a need to study this area of research. This meta-analysis examined the exposure of urinary bisphenol A and its metabolites to blood Hypothalamic–Pituitary–Thyroid axis hormones (HPT axis hormones) in pregnant women and adult males and females. We searched Embase, PubMed, Web of Science, Cochrane Library, and CINAHL until 8 January 2025, yielding 4588 articles using the PECO framework. Quality assessment was done using AHRQ: Agency for Healthcare Research and Quality for cross-sectional and NOS: Newcastle Ottawa Scale for cohort studies, with combined exposure evaluated using random and fixed-effect models. The I² test assessed heterogeneity. We included eighteen studies for the final analysis. Fixed-effect model estimates revealed that BPA is negatively associated with thyroid-stimulating hormone (TSH) in female and male adults (β = −0.02; 95% CI = −0.04 to −0.01); (β = −0.08; 95% CI = −0.14 to −0.02). In Females, BPA was positively associated with free thyroxine, FT4 (β = 0.001, 95% CI, 0.001 to 0.001). In the male group, BPA was negatively associated with FT4 (β = −0.001, 95% CI, −0.001 to −0.001). As per pregnant women, there was no association found between exposure to bisphenols and total Thyroxine (TT4), FT4, and TSH in both trimesters (β = 0.010, 95% CI = −0.030 to 0.050); (β = 0.001, 95% CI = −0.010 to 0.010); (β = −0.001, 95% CI = −0.010 to 0.001), respectively, for early pregnancy. Bisphenols can significantly influence HPT axis hormones in adult males, females, and pregnant women. Gender-based studies were observed, concluding that adult females are more affected by bisphenol exposures than adult males. The subgroup analysis based on the regions did not reveal any associations. Full article

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16 pages, 1621 KB

Open AccessArticle

Combined Repeated-Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test of Calcium Nitrate Tetrahydrate in Sprague Dawley Rats

by Ji-Woo Eom, Han-il Kang, Jae-Hyun Lee, Si-Hwan Song, Jeong-hyun Hong, Seungjin Bae, Chun-Ja Nam and Kyung-Min Lim

Toxics 2025, 13(10), 835; https://doi.org/10.3390/toxics13100835 - 30 Sep 2025

Abstract

Calcium nitrate tetrahydrate, used in fertilizers, wastewater treatment, and concrete admixtures, has limited toxicity data despite extensive industrial use. This study evaluated its repeated-dose and reproductive/developmental toxicity in Sprague Dawley rats following OECD TG 422, which combines TG 407 and 421 to extend [...] Read more.

Calcium nitrate tetrahydrate, used in fertilizers, wastewater treatment, and concrete admixtures, has limited toxicity data despite extensive industrial use. This study evaluated its repeated-dose and reproductive/developmental toxicity in Sprague Dawley rats following OECD TG 422, which combines TG 407 and 421 to extend dosing than TG 407 and reduce animal use compared with separate studies. Rats were administered 0, 100, 300, or 1000 mg/kg/day. Males were treated for 49 days and females from 2 weeks pre-mating to postpartum day 13; the recovery group was observed for an additional 2 weeks. Endpoints included clinical signs, body weight, food consumption, hematology, serum biochemistry, organ weights, histopathology, reproductive performance, and F1 development. No systemic toxicity was observed in F0 males. Minimal prostate atrophy occurred in high-dose males but was considered non-adverse due to limited severity. One high-dose female died on PPD 1, and high-dose F1 litters showed decreased litter size, increased post-implantation loss, and a reduced live-born index. Based on these results, NOAELs were cautiously assigned 1000 mg/kg/day for repeated-dose and male reproductive toxicity and 300 mg/kg/day for female reproductive and developmental toxicity. TG 422 efficiently characterized hazards while reducing animal use, though its limited duration and scope indicate the need for complementary studies. Full article

(This article belongs to the Special Issue Reproductive and Developmental Toxicity of Environmental Factors)

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20 pages, 3750 KB

Open AccessArticle

Heavy Metal Pollution and Health-Ecological Risk Assessment in Agricultural Soils: A Case Study from the Yellow River Bend Industrial Parks

by Zang Liu, Li Mo, Jiahui Liang, Huading Shi, Jingjing Yao and Xiaoxiu Lun

Toxics 2025, 13(10), 834; https://doi.org/10.3390/toxics13100834 - 30 Sep 2025

Abstract

Agricultural soils near industrial parks in the Yellow River bend region face severe heavy metal pollution, posing a significant to human health. This study integrated field sampling with laboratory analysis and applied geostatistical analysis, positive matrix factorization (PMF) modeling, and health risk assessment [...] Read more.

Agricultural soils near industrial parks in the Yellow River bend region face severe heavy metal pollution, posing a significant to human health. This study integrated field sampling with laboratory analysis and applied geostatistical analysis, positive matrix factorization (PMF) modeling, and health risk assessment models to systematically investigate the pollution levels, spatial distribution, sources, and ecological health risks of heavy metals in the area. The main findings are as follows: (1) The average concentrations of the eight heavy metals (Hg, Cr, Cu, Pb, Zn, As, Cd, and Ni) in the study area were 0.04, 48.3, 54.3, 45.7, 70.0, 22.9, 0.4, and 35.7 mg·kg⁻¹, respectively. The concentrations exceeded local background values by factors ranging from 1.32 to 11.2. Exceedances of soil screening and control values were particularly pronounced for Cd and As. Based on the geoaccumulation index, over 75% of the sampling sites for Cr, Pb, Zn, and Cd were classified as moderately to heavily polluted. Potential ecological risk assessment highlighted Cd as the significant ecological risk factor, indicating considerable heavy metal pollution in the region. (2) Kriging interpolation demonstrated elevated concentrations in the western (mid-upper) and eastern (mid-lower) subregions. Pearson correlation analysis suggested common sources for Cu-Pb-As-Cd and Cr-Zn-Ni. (3) PMF source apportionment identified four primary sources: traffic emissions (38.19%), natural and agricultural mixed sources (34.55%), metal smelting (17.61%), and atmospheric deposition (10.10%). (4) Health risk assessment indicated that the non-carcinogenic risk for both adults and children was within acceptable limits (adults: 0.065; children: 0.12). Carcinogenic risks were also acceptable (adults: 5.67 × 10⁻⁵; children: 6.70 × 10⁻⁵). In conclusion, priority should be given to the control of traffic emissions and agriculturally derived sources in the management of soil heavy metal contamination in this region, while the considerable contribution of smelting activities warrants heightened attention. This study provides a scientific basis for the prevention, control, and targeted remediation of regional soil heavy metal pollution. Full article

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17 pages, 2025 KB

Open AccessArticle

Cerebellar Mechanisms Underlying Autism-like Cognitive Deficits in Mouse Offspring with Prenatal Valproic Acid Exposure

by Juan Wang, Xu-Lan Zhou, Zi-Han Ma, Li Liu, Qian Zhou, Jia-Wei Wen, Jia-Hui Wen, Hui Su, Yu-Han Zhang and Xiao-Chun Xia

Toxics 2025, 13(10), 833; https://doi.org/10.3390/toxics13100833 - 30 Sep 2025

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social communication and repetitive behaviors, involving various brain regions. Emerging evidence highlights the critical role of the cerebellum in the pathophysiology of autism; however, the underlying molecular mechanisms remain poorly [...] Read more.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social communication and repetitive behaviors, involving various brain regions. Emerging evidence highlights the critical role of the cerebellum in the pathophysiology of autism; however, the underlying molecular mechanisms remain poorly understood. This study aimed to establish a prenatal valproic acid (VPA)-induced mouse model of ASD and explore the potential molecular mechanisms underlying cerebellar ASD-like phenotypes through DIA-based proteomics and bioinformatics analyses. Significant cognitive impairment and anxiety-like behaviors were detected using an open field test and novel object test following VPA exposure, respectively. Additionally, reduced numbers of Purkinje cells with irregular arrangement were observed in the cerebellum. Furthermore, cerebellar proteomics analyses revealed that they identified 193 differentially expressed proteins (DEPs) involved in multiple pathways, including axon guidance, glutamatergic synapse, long-term potentiation, and calcium signaling, among others. Notably, dysfunction of glutamate receptor signaling and disruptions in axon-guidance signaling appear to be major molecular mechanisms underlying cerebellar impairment. Together, these findings suggest that Grin2b may serve as a critical molecule linking synaptic neurotransmission and neurodevelopmental disorders. Thus, Grin2b may represent a potential therapeutic target for addressing cognitive impairment in ASD. Full article

(This article belongs to the Section Neurotoxicity)

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10 pages, 1348 KB

Open AccessArticle

The Aryl Hydrocarbon Receptor Mediates the Neurodevelopmental Toxicity of Perfluorooctane Sulfonamide in Zebrafish Larvae

by Pinyi Chen, Kang Wang, Jie Zhang, Yan Jiang and Tao Chen

Toxics 2025, 13(10), 832; https://doi.org/10.3390/toxics13100832 - 30 Sep 2025

Abstract

Perfluorooctane sulfonamide (PFOSA), the direct precursor to perfluorooctane sulfonate (PFOS), is widely present in the environment. Research has indicated that PFOSA is cardiotoxic and hepatotoxic, but its impact on neurodevelopment remains unclear. In the current study, we observed that exposure of PFOSA caused [...] Read more.

Perfluorooctane sulfonamide (PFOSA), the direct precursor to perfluorooctane sulfonate (PFOS), is widely present in the environment. Research has indicated that PFOSA is cardiotoxic and hepatotoxic, but its impact on neurodevelopment remains unclear. In the current study, we observed that exposure of PFOSA caused neurodevelopmental toxicity in zebrafish embryos in a dose-dependent manner, as evidenced by impaired motor abilities and decreased swimming distance. We then demonstrated that PFOSA exposure downregulated the mRNA expression of neurodevelopment-related genes including a1-tubulin, elavl3, ache and dat. Moreover, PFOSA exposure resulted in dose-dependent oxidative stress, which triggers apoptosis in the brains of zebrafish larvae. We further showed that inhibition of the aryl hydrocarbon receptor (AhR) alleviated the oxidative stress and apoptosis induced by PFOSA, thereby counteracting the neurodevelopmental abnormalities in zebrafish larvae. In conclusion, these findings indicate PFOSA causes neurodevelopmental disorders by inducing oxidative stress and apoptosis through the AhR pathway. Full article

(This article belongs to the Section Reproductive and Developmental Toxicity)

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22 pages, 3831 KB

Open AccessSystematic Review

Time- and Dose-Dependent Cardiovascular Effects of Nicotine-Containing Electronic Cigarettes in Young Adults: A Systematic Review and Meta-Analysis

by Carmen Ranchal-Lavela, David Casanova-Rodríguez, Antonio Ranchal-Sanchez, María José De La Torre-Aguilar and Jose Manuel Jurado-Castro

Toxics 2025, 13(10), 831; https://doi.org/10.3390/toxics13100831 - 30 Sep 2025

Abstract

Objective: To synthesize the current evidence on the cardiovascular effects of electronic cigarettes (ECs) in young adults (18–30 years), distinguishing between acute and chronic exposure, and comparing their effects to conventional tobacco (CT) use. Methods: A systematic review and meta-analysis (PROSPERO: CRD420251072847) was [...] Read more.

Objective: To synthesize the current evidence on the cardiovascular effects of electronic cigarettes (ECs) in young adults (18–30 years), distinguishing between acute and chronic exposure, and comparing their effects to conventional tobacco (CT) use. Methods: A systematic review and meta-analysis (PROSPERO: CRD420251072847) was conducted following PRISMA guidelines. A total of 21 studies (12 RCTs, 8 case–control, 1 cohort) involving 17241 participants were included. Results: Acute EC use, particularly with nicotine, significantly increased systolic blood pressure (SBP: MD = 3.14 mmHg, 95% CI: 0.76 to 5.52), diastolic blood pressure (DBP: MD = 2.05 mmHg, 95% CI: 0.85 to 3.25), and heart rate (HR: MD = 4.23 bpm, 95% CI: 2.10 to 6.37), with effects most pronounced at 0 min post-exposure and dissipating within 1 h. Chronic EC use was associated with reduced endothelium-dependent vasodilation and early atherosclerotic changes. Nicotine-free ECs induced fewer cardiovascular alterations. Comparisons with CT revealed less severe cardiovascular damage with ECs, though still significant when compared to non-smokers. Conclusion: Nicotine-containing EC use in young individuals is associated with modest, predominantly acute and dose-dependent, cardiovascular effects, including transient increases in BP and HR. While initially less harmful than CT, the evidence is largely from cross-sectional studies and acute use, so ECs cannot be considered safe and their use warrants caution in youth. Full article

(This article belongs to the Special Issue Effects of Air Pollutants on Cardiorespiratory Health)

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18 pages, 8441 KB

Open AccessFeature PaperArticle

Effects of the Novel Triazole Fungicide Ipfentrifluconazole on Different Endpoints in Zebrafish Larvae

by Mingfei Xu, Yilin Huang, Mingrong Qian, Yuanxiang Jin and Hu Zhang

Toxics 2025, 13(10), 830; https://doi.org/10.3390/toxics13100830 - 29 Sep 2025

Abstract

The potential hazards of triazole fungicides to non-target organisms necessitate environmental risk assessment. This study, therefore, focused on characterizing the differential toxicity of the enantiomers of Ipfentrifluconazole (IFZ), a new triazole fungicide, in zebrafish larvae using a multi-endpoint approach. Acute toxicity tests determined [...] Read more.

The potential hazards of triazole fungicides to non-target organisms necessitate environmental risk assessment. This study, therefore, focused on characterizing the differential toxicity of the enantiomers of Ipfentrifluconazole (IFZ), a new triazole fungicide, in zebrafish larvae using a multi-endpoint approach. Acute toxicity tests determined the LC₅₀ values of 1.709 mg/L for rac-IFZ, 1.531 mg/L for (+)-IFZ, and 1.809 mg/L for (−)-IFZ, indicating a higher toxicity of the (+)-enantiomer. To avoid overt mortality while revealing organ-level effects, we chose a concentration of approximately 20% of the LC50 of (+)-IFZ, which is 340 μg/L, as the exposure concentration. Exposure to IFZ induced developmental defects, including swim bladder malformation, cardiac blood pooling, and metabolic disturbances during the early developmental stage of zebrafish. Additionally, cardiac and hepatic development and function were disrupted in zebrafish larvae following IFZ exposure. Biochemical and transcriptomic analyses revealed distinct toxic mechanisms: (+)-IFZ primarily disrupted lipid metabolism through alterations in PPAR signaling pathway and fatty acid degradation, while (−)-IFZ significantly impaired cardiac function by affecting adrenergic signaling in cardiomyocytes and cardiac muscle contraction. Rac-IFZ mainly influenced drug metabolism, particularly cytochrome P450-related pathways. These findings demonstrated the toxic effects of IFZ, emphasizing the need for evaluating environmental and health risks of chiral pesticides. The study provides valuable insights into the molecular mechanisms underlying IFZ toxicity. Full article

(This article belongs to the Section Ecotoxicology)

17 pages, 1743 KB

Open AccessFeature PaperArticle

Inhibition of Muscle-Specific Protein Kinase (MuSK) Releases Organophosphate-Aged Acetylcholinesterase (AChE) from C2C12 Cells

by Monica Moncada-Restrepo, Sarah Eysoldt, Jeronimo Medina, Valentina Di Guida and Jeremy W. Chambers

Toxics 2025, 13(10), 829; https://doi.org/10.3390/toxics13100829 - 29 Sep 2025

Abstract

Mechanistically, OPs inhibit acetylcholinesterase (AChE), an enzyme that terminates cholinergic transmission, triggering a sustained activation of acetylcholine receptors. A component of the treatment for OP intoxication is oximes as AChE reactivators. However, oximes may not be efficacious and could worsen OP effects. Further, [...] Read more.

Mechanistically, OPs inhibit acetylcholinesterase (AChE), an enzyme that terminates cholinergic transmission, triggering a sustained activation of acetylcholine receptors. A component of the treatment for OP intoxication is oximes as AChE reactivators. However, oximes may not be efficacious and could worsen OP effects. Further, dealkylation of the AChE-OP adducts prevents oxime reactivation. Therefore, other approaches are needed to rescue AChE activity. We propose that replacing aged extracellular AChE with active intracellular enzymes may be an effective approach. Thus, molecular screening was used to identify small molecules that could displace aged AChE. C2C12 myoblasts were treated with 20 μM of diisopropylfluorophosphate (DFP) for one hour, followed by a drug panel. AChE activity and surface abundance were measured after 6 h. From the chemical screen, a promising hit, Pz-1 (a tyrosine kinase inhibitor), was identified, which decreased surface AChE on DFP-exposed C2C12 myoblasts in a dose-dependent manner without impacting viability. Additionally, AChE presence and activity were recovered after washing and supplementing the media with 100 nM of acetylcholine. Biochemically, Pz-1 inhibits muscle-specific protein kinase (MuSK), a kinase that interacts with AChE. These results suggest that altering MuSK activity may disrupt protein–protein interactions, destabilizing AChE, which may lead to the discovery of new countermeasures for OP exposures. Full article

(This article belongs to the Section Neurotoxicity)

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14 pages, 20431 KB

Open AccessArticle

Construction of a Novel 3D Urinary Bladder Mucosa Model and Its Application in Toxicity Assessment of Arsenicals

by Runjie Guo, Min Gi, Tohru Kiyono, Arpamas Vachiraarunwong, Shugo Suzuki, Masaki Fujioka, Guiyu Qiu, Kwanchanok Praseatsook, Yurina Kawamura, Anna Kakehashi, Ikue Noura, Xiaoli Xie and Hideki Wanibuchi

Toxics 2025, 13(10), 828; https://doi.org/10.3390/toxics13100828 - 29 Sep 2025

Abstract

The urinary bladder is a primary target organ for environmental toxicants such as arsenic. The objects of this study were two-fold. First, we constructed a novel 3D urinary bladder mucosa model (3D-UBMM) composed of an overlying epithelium and a supporting subepithelial layer. Primary [...] Read more.

The urinary bladder is a primary target organ for environmental toxicants such as arsenic. The objects of this study were two-fold. First, we constructed a novel 3D urinary bladder mucosa model (3D-UBMM) composed of an overlying epithelium and a supporting subepithelial layer. Primary human bladder urothelial and fibroblast cells were immortalized by introducing the human CDK4^R24C and TERT genes. The construction of the 3D-UBMM involved incorporating immortalized fibroblast cells into a collagen raft, while immortalized urothelial cells were cultured at the air-liquid interface. This 3D-UBMM closely resembles the human bladder epithelium in terms of morphology and marker protein expression, including uroplakin 1b, P63, and cytokeratin 5. Second, using the 3D-UBMM we investigated the cytotoxicity of sodium arsenite (iAs^III) and dimethylarsenic acid (DMA^V). Exposure to iAs^III and DMA^V resulted in increased urothelial necrosis, increased γ-H2AX-positive cells, and reduced P63-positive cells, all in a dose–response manner. These findings affirm that this novel 3D-UBMM resembles the human bladder epithelium and offers a practical in vitro model for evaluating bladder toxicants and carcinogens, identifying mechanisms of carcinogenesis, and supporting hazard identification and risk assessment. Full article

(This article belongs to the Section Novel Methods in Toxicology Research)

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15 pages, 3484 KB

Open AccessArticle

Differences in Toxicity Induced by Varying Degrees of Polymerization of Tristyrylphenol Ethoxylates in Male Mice

by Chunmei Li, Fen Jin, Fengzhong Wang and Bei Fan

Toxics 2025, 13(10), 827; https://doi.org/10.3390/toxics13100827 - 28 Sep 2025

Abstract

Nonylphenol ethoxylates (NPEOs) are widely utilized in pesticide formulations and industrial products but are known for their endocrine-disrupting properties. Consequently, substitutes such as tristyrylphenol ethoxylates (TSPEOs) have been introduced as inert ingredients in pesticide formulations. Here, we showed that TSPEOs exhibited subacute toxicity [...] Read more.

Nonylphenol ethoxylates (NPEOs) are widely utilized in pesticide formulations and industrial products but are known for their endocrine-disrupting properties. Consequently, substitutes such as tristyrylphenol ethoxylates (TSPEOs) have been introduced as inert ingredients in pesticide formulations. Here, we showed that TSPEOs exhibited subacute toxicity in male mice. For the first time, we studied the differences in subacute toxicity (28-day exposure) and the potential toxic effects of TSPEOs with varying polymerization degrees, specifically agricultural emulsifier (AE) #602 and AE #604, in male mice. We demonstrate that AE #602 can induce liver injury, as evidenced by hepatocyte swelling and vacuolar degeneration across all treated groups, along with significant hepatocellular necrosis in the high-dose group. These pathological changes were associated with alterations in oxidative stress biomarkers, including a significant decrease in malondialdehyde levels (0.57 times in the high-dose group, p < 0.05) and increased activities of glutathione peroxidase (up to 1.27 times, p < 0.05) and glutathione, suggesting a potential adaptive compensatory response. Both TSPEOs were found to cause gastric injury according to the results of organ indices and histopathological analyses. AE #604, with lower polymerization degree, caused more severe gastric injury than AE #602. Our findings indicate that NPEO substitutes should be tested for hepatotoxicity and gastrotoxicity and highlight the need for further research into the toxicity differences induced by varying degrees of polymerization of TSPEOs on human health. Full article

(This article belongs to the Section Agrochemicals and Food Toxicology)

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19 pages, 1782 KB

Open AccessArticle

Unexpected High Blood Lead Levels in a Remote Indigenous Community in the Northeastern Peruvian Amazon

by Pedro Mayor, Guillem Rius-Taberner, Gabriela M. Ulloa and Martí Orta-Martínez

Toxics 2025, 13(10), 826; https://doi.org/10.3390/toxics13100826 - 27 Sep 2025

Abstract

Recent studies suggest that Pb-based ammunition could be an important route of Pb exposure for Indigenous Peoples in tropical rainforests. We analyzed blood lead levels (BLL) and isotopic signatures in 111 humans, 97 wild animals, 81 fish, and potential environmental Pb sources in [...] Read more.

Recent studies suggest that Pb-based ammunition could be an important route of Pb exposure for Indigenous Peoples in tropical rainforests. We analyzed blood lead levels (BLL) and isotopic signatures in 111 humans, 97 wild animals, 81 fish, and potential environmental Pb sources in an Indigenous community in the remote and well-preserved Peruvian Amazon with no history of industrial activity. Median BLL was 11.74 μg dL⁻¹, with BLL ≥ 5 µg dL⁻¹ in 95.8% children <12-yo and 94.5% adults. Pb concentrations in wild animals were 7.00 ± 22.40 mg kg⁻¹ DW in liver, 0.06 ± 0.09 mg kg⁻¹ DW in fish muscle tissues, 17.1 ± 10.8 mg kg⁻¹ in soils and 3.4–3.8 mg L⁻¹ in the main river, although 0.43-0.53 mg L⁻¹ were the Pb levels in decanted water used for drinking and cooking. The similarity of isotopic signatures (^207/206Pb and ^208/206Pb) shows that the main Pb sources for humans are river waters (97.6%) and Pb-based ammunition (78.7%). Fish and wildlife act as Pb transporters from water, and wildlife act as Pb transporter from ammunition. Evidence of high human BLL in a remote, non-industrialized Amazonian area demonstrates the urgency of designing regional policies that include health prevention measures, focused on drinking water filtration systems and the use of non-toxic, Pb-free ammunitions. Full article

(This article belongs to the Special Issue Effects of Exposure to Emerging Environmental Pollutants on Human Health)

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