Journal of Xenobiotics

38 pages, 2926 KiB

Open AccessReview

Bioaccumulation and Trophic Transfer of Heavy Metals in Marine Fish: Ecological and Ecosystem-Level Impacts

by Andra Oros

J. Xenobiot. 2025, 15(2), 59; https://doi.org/10.3390/jox15020059 - 18 Apr 2025

Heavy metal contamination in marine ecosystems poses a critical environmental challenge, with significant implications for biodiversity, trophic dynamics, and human health. Marine fish are key bioindicators of heavy metal pollution because of their role in food webs and their capacity for bioaccumulation and [...] Read more.

Heavy metal contamination in marine ecosystems poses a critical environmental challenge, with significant implications for biodiversity, trophic dynamics, and human health. Marine fish are key bioindicators of heavy metal pollution because of their role in food webs and their capacity for bioaccumulation and trophic transfer. This review synthesizes current knowledge on the pathways and mechanisms of heavy metal accumulation in marine fish, focusing on factors that influence the uptake, retention, and tissue distribution. We explore the processes governing trophic transfer and biomagnification, highlighting species-specific accumulation patterns and the risks posed to apex predators, including humans. Additionally, we assess the ecological consequences of heavy metal contamination at population, community, and ecosystem levels, emphasizing its effects on fish reproduction, community structure, and trophic interactions. By integrating recent findings, this review highlights key knowledge gaps and suggests future research directions to improve environmental monitoring and risk assessment. Given the persistence and bioavailability of heavy metals in marine environments, effective pollution control strategies and sustainable fisheries management are imperative to mitigate long-term ecological and public health risks. Full article

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19 pages, 4146 KiB

Open AccessArticle

Bacterial Cytochrome P450 Involvement in the Biodegradation of Fluorinated Pyrethroids

by Mohd Faheem Khan, Jun Liao, Zhenyang Liu and Gaurav Chugh

J. Xenobiot. 2025, 15(2), 58; https://doi.org/10.3390/jox15020058 - 18 Apr 2025

Abstract

Fluorinated pyrethroids, such as cyfluthrin and cyhalothrin, are more effective insecticides due to their enhanced stability and lipophilicity. However, they pose greater risks to non-target organisms. Their persistence in the environment and accumulation in tissues can lead to increased toxicity and ecological concerns. [...] Read more.

Fluorinated pyrethroids, such as cyfluthrin and cyhalothrin, are more effective insecticides due to their enhanced stability and lipophilicity. However, they pose greater risks to non-target organisms. Their persistence in the environment and accumulation in tissues can lead to increased toxicity and ecological concerns. This study investigates the biodegradation of the fluorinated pyrethroids β-cyfluthrin (BCF) and λ-cyhalothrin (LCH) using a newly isolated Bacillus sp. MFK14 from a garden soil microbial consortium. Initial screening using ¹⁹F NMR analysis showed that the microbial consortium degraded both pyrethroids, leading to the isolation of Bacillus sp. MFK14. Subsequent GC-MS analysis revealed various degradation intermediates in both pyrethroids after incubation with Bacillus sp. MFK14. Notably, Bacillus sp. MFK14 completely degraded β-cyfluthrin and λ-cyhalothrin within 48 h at 30 °C. Fluoride ions from β-cyfluthrin and trifluoroacetic acid (TFA) from λ-cyhalothrin were detected as the end-products by ¹⁹F NMR analysis of the aqueous fraction. The pathway of the degradation was proposed for both the pyrethroids indicating shared biodegradation pathways despite different fluorinations. Inhibition studies with 1-ABT suggested the involvement of bacterial cytochrome P450 (CYP) enzymes in their biodegradation. The CYPome of Bacillus sp. MFK14 includes 23 CYP variants that showed significant sequence similarity to known bacterial CYPs, suggesting potential roles in pyrethroid biodegradation and environmental persistence. These findings highlight the potential for bioremediation of fluorinated pesticides, offering an environmentally sustainable approach to mitigate their ecological impact. Full article

(This article belongs to the Special Issue New Challenges in the Monitoring, Risk Assessment and Management of Pesticides and Biocides in the “One Health Era”)

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12 pages, 1670 KiB

Open AccessArticle

Interaction of Heavy Metals (Cadmium and Selenium) in an Experimental Study on Goldfish: Hematobiochemical Changes and Oxidative Stress

by Yasaman Aghaei Hashtjin, Mahdieh Raeeszadeh and Ali Parsa Khanghah

J. Xenobiot. 2025, 15(2), 57; https://doi.org/10.3390/jox15020057 - 16 Apr 2025

Abstract

Background: Heavy metal interactions within aquatic ecosystems significantly affect fish physiology. This study evaluated the protective role of selenium against cadmium-induced hematological, biochemical, and electrophoretic alterations in goldfish. Methods: A total of 120 goldfish individuals were divided into four groups: control, cadmium chloride-treated [...] Read more.

Background: Heavy metal interactions within aquatic ecosystems significantly affect fish physiology. This study evaluated the protective role of selenium against cadmium-induced hematological, biochemical, and electrophoretic alterations in goldfish. Methods: A total of 120 goldfish individuals were divided into four groups: control, cadmium chloride-treated (2.8 mg/L), sodium selenite-treated (2 mg/L), and a combined cadmium and selenium-treated group. After 14 days, blood samples were collected and analyzed for hematological parameters, biochemical markers, and serum protein electrophoresis. Results: Cadmium exposure led to significant reductions in red blood cell (RBC) and white blood cell (WBC) counts, hemoglobin (Hb), and hematocrit (HCT) (p < 0.001). Selenium supplementation alleviated these declines and improved overall hematological function. Additionally, cadmium exposure decreased albumin and total protein levels while elevating aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, indicating liver damage. Selenium co-treatment reduced cadmium accumulation and mitigated liver toxicity. Elevated urea and creatinine levels in cadmium-exposed fish were also significantly lowered in the combined treatment group (p < 0.0001). Furthermore, selenium supplementation enhanced antioxidant defense mechanisms by increasing catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activity while reducing malondialdehyde (MDA) levels, effectively counteracting cadmium-induced oxidative stress. Conclusion: Sodium selenite at a dose of 2 mg/L effectively mitigated the toxic effects of cadmium chloride on hematological, biochemical, and oxidative stress markers in goldfish, demonstrating its protective potential against heavy metal toxicity. Full article

(This article belongs to the Special Issue Environmental Toxicology and Animal Health: 2nd Edition)

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19 pages, 2603 KiB

Open AccessArticle

Resistance and Biodegradation of Triclosan and Propylparaben by Isolated Bacteria from Greywater

by Daniella Itzhari, Joseph Nzeh and Zeev Ronen

J. Xenobiot. 2025, 15(2), 56; https://doi.org/10.3390/jox15020056 - 15 Apr 2025

Abstract

We investigated the relationship between antibiotic-resistance genes and the antimicrobial agents, triclosan (TCS) and propylparaben (PPB). The greywater microbiome was repeatedly exposed to triclosan and propylparaben and the effect was analyzed using a combination of PCR, Etest, Biolog, 16S rRNA sequencing, and liquid [...] Read more.

We investigated the relationship between antibiotic-resistance genes and the antimicrobial agents, triclosan (TCS) and propylparaben (PPB). The greywater microbiome was repeatedly exposed to triclosan and propylparaben and the effect was analyzed using a combination of PCR, Etest, Biolog, 16S rRNA sequencing, and liquid chromatography. The taxonomic identification points to very similar or even identical isolates, however, the phenotypic analysis suggests that their metabolic potential is different, likely due to genomic variation or differences in the expression of the substrate utilization pathways. For both triclosan and propylparaben, the antibiotic resistance levels among isolates remain consistent regardless of the exposure duration. This suggests that antibiotic-resistance genes are acquired rapidly and that their presence is not directly proportional to the level of micropollutant exposure. In a biodegradation test, TCS was reduced by 50% after 7 h, while PPB decreased only after 75 h. For TCS, the minimal inhibition concentration (MIC) ranged from 64 to above 256 mg/mL. Conversely, for PPB the MIC for the tested strains ranged between 512 and 800 mg/mL. This study highlights the complex interaction between household xenobiotics, greywater microorganisms, and the emergence of antibiotic resistance. Full article

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35 pages, 1668 KiB

Open AccessReview

Stability Dynamics of Plant-Based Extracellular Vesicles Drug Delivery

by Satyavati Rawat, Sanchit Arora, Madhukiran R. Dhondale, Mansi Khadilkar, Sanjeev Kumar and Ashish Kumar Agrawal

J. Xenobiot. 2025, 15(2), 55; https://doi.org/10.3390/jox15020055 - 13 Apr 2025

Abstract

Plant-based extracellular vesicles (PBEVs) have been recognized for their wide range of applications in drug delivery however, the extent of their medicinal applicability depends on how well they are preserved and stored. Assessing their physicochemical properties, such as size, particle concentration, shape, and [...] Read more.

Plant-based extracellular vesicles (PBEVs) have been recognized for their wide range of applications in drug delivery however, the extent of their medicinal applicability depends on how well they are preserved and stored. Assessing their physicochemical properties, such as size, particle concentration, shape, and the activity of their cargo, forms the foundation for determining their stability during storage. Moreover, the evaluation of PBEVs is essential to ensure both safety and efficacy, which are critical for advancing their clinical development. Maintaining the biological activity of EVs during storage is a challenging task, similar to the preservation of cells and other cell-derived products like proteins. However, despite limited studies, it is expected that storing drug-loaded EVs may present fewer challenges compared to cell-based therapies, although some limitations are inevitable. This article provides a comprehensive overview of current knowledge on PBEVs preservation and storage methods, particularly focusing on their role as drug carriers. PBEVs hold promise as potential candidates for oral drug administration due to their effective intestinal absorption and ability to withstand both basic and acidic environments. However, maintaining their preservation and stability during storage is critical. Moreover, this review centers on the isolation, characterization, and storage of PBEVs, exploring the potential advantages they offer. Furthermore, it highlights key areas that require further research to overcome existing challenges and enhance the development of effective preservation and storage methods for therapeutic EVs. Full article

(This article belongs to the Section Drug Therapeutics)

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18 pages, 806 KiB

Open AccessReview

Manganese Neurotoxicity: A Comprehensive Review of Pathophysiology and Inherited and Acquired Disorders

by Giuseppe Magro, Vincenzo Laterza, Federico Tosto and Angelo Torrente

J. Xenobiot. 2025, 15(2), 54; https://doi.org/10.3390/jox15020054 - 4 Apr 2025

Abstract

Manganese (Mn) is an essential trace element and a cofactor for several key enzymes, such as mitochondrial superoxide dismutase. Consequently, it plays an important defense role against reactive oxygen species. Despite this, Mn chronic overexposure can result in a neurological disorder referred to [...] Read more.

Manganese (Mn) is an essential trace element and a cofactor for several key enzymes, such as mitochondrial superoxide dismutase. Consequently, it plays an important defense role against reactive oxygen species. Despite this, Mn chronic overexposure can result in a neurological disorder referred to as manganism, which shares some similarities with Parkinson’s disease. Mn levels seem regulated by many transporters responsible for its uptake and efflux. These transporters play an established role in many inherited disorders of Mn metabolism and neurotoxicity. Some inherited Mn metabolism disorders, caused by mutations of SLC30A10 and SLC39A14, assume crucial importance since earlier treatment results in a better prognosis. Physicians should be familiar with the clinical presentation of these disorders as the underlying cause of dystonia/parkinsonism and look for other accompanying features, such as liver disease and polycythemia, which are typically associated with SLC30A10 mutations. This review aims to highlight the currently known Mn transporters, Mn-related neurotoxicity, and its consequences, and it provides an overview of inherited and acquired disorders of Mn metabolism. Currently available treatments are also discussed, focusing on the most frequently encountered presentations. Full article

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13 pages, 240 KiB

Open AccessArticle

Comparative Analysis of Inflammatory and Heavy Metal Biomarkers in Exclusive E-Cigarette Users, Combustible Tobacco Users, and Non-Users Aged 18–30: A Cross-Sectional NHANES Analysis

by Luke Manietta, William Drake and Wasantha Jayawardene

J. Xenobiot. 2025, 15(2), 53; https://doi.org/10.3390/jox15020053 - 1 Apr 2025

Abstract

While cigarette smoking has declined, e-cigarette use among young adults has increased in the USA. This cross-sectional study compared complete blood counts, C-reactive protein, and select blood metals (lead, cadmium, mercury, selenium, manganese) among exclusive combustible tobacco users, exclusive e-cigarette users, and non-users [...] Read more.

While cigarette smoking has declined, e-cigarette use among young adults has increased in the USA. This cross-sectional study compared complete blood counts, C-reactive protein, and select blood metals (lead, cadmium, mercury, selenium, manganese) among exclusive combustible tobacco users, exclusive e-cigarette users, and non-users using NHANES data from 2013–2023 in the USA. The goal of this study was to compare biomarker data from e-cigarette users and combustible tobacco users to that of non-users. Among 756 participants aged 18–30, 229 reported no tobacco use, 74 used only e-cigarettes, and 453 smoked only combustible tobacco. Survey-weighted analyses adjusted for age, sex, race/ethnicity, and body mass index revealed that exclusive combustible use was associated with significantly elevated white blood cell counts, hemoglobin, hematocrit, mean corpuscular volume, lymphocytes, monocytes, neutrophils, and higher blood lead and cadmium. E-cigarette-only use showed fewer deviations overall but included higher mean corpuscular hemoglobin concentration and lower cadmium, selenium, and methyl mercury relative to non-users. Neither group differed significantly in red blood cell count or C-reactive protein, and inorganic/ethyl mercury and manganese levels were largely unchanged. These findings underscore pronounced hematologic and metal-related alterations in combustible tobacco users and fewer, but not negligible, changes among e-cigarette users. Further research is needed to determine the long-term health implications of exclusive e-cigarette use, including potential impacts on antioxidant micronutrient levels. Full article

18 pages, 16680 KiB

Open AccessArticle

A Novel Protocol for Culturing Polarized Proximal Tubular Epithelial Cells from Kidney Biopsies: Enhancing Platforms for Drug Excretion and Nephrotoxicity Studies

by Tadej Petreski, Lidija Gradišnik, Luka Varda, Polona Kovačič, Jurij Dolenšek, Andraž Stožer, Sebastjan Bevc and Uroš Maver

J. Xenobiot. 2025, 15(2), 52; https://doi.org/10.3390/jox15020052 - 1 Apr 2025

Abstract

The kidneys are integral to homeostasis but are susceptible to nephrotoxic compounds. Proximal tubular epithelial cells (PTECs) mediate drug metabolism and transport and are widely used in preclinical studies. However, commercial PTECs are limited in availability and physiological relevance. This study aimed to [...] Read more.

The kidneys are integral to homeostasis but are susceptible to nephrotoxic compounds. Proximal tubular epithelial cells (PTECs) mediate drug metabolism and transport and are widely used in preclinical studies. However, commercial PTECs are limited in availability and physiological relevance. This study aimed to develop a novel, reliable protocol for isolating and culturing PTECs from human kidney biopsies. Primary PTECs were isolated from kidney biopsies of two patients (MFUM-RPTEC-1 and MFUM-RPTEC-2). Their morphology, population doubling time, transepithelial electrical resistance (TEER), and phenotypic markers were evaluated. Polarization and transporter expression were analyzed using cells cultured on Transwell inserts. Colonies formed within 24–48 h, with confluence reached by 8–10 days and dome (hemicyst) formation by day 13. TEER values peaked at 190 Ω/cm² after 7–14 days, confirming tight junction formation. Immunostaining identified characteristic markers (e.g., SGLT2, OAT1/3, OCT2, P-gp, MRP4, MATE1, N-cadherin, ZO-1, CK-18). Cells cultured on Transwell plates exhibited native polarization, expressing transporters crucial for drug excretion on apical and basolateral surfaces. We present two robust protocols for isolating and characterizing PTECs, offering a scalable method to obtain functional, polarized cells from scarce biopsy material. The isolated PTECs, therefore, present a valuable platform for preclinical studies, especially for drug excretion testing through the expressed transporters. Drug competition for these transporters during tubular secretion is also a common cause of nephrotoxicity. Full article

(This article belongs to the Section Drug Therapeutics)

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29 pages, 1680 KiB

Open AccessReview

The Role of Xenobiotic Caffeine on Cardiovascular Health: Promises and Challenges

by Roberto Campagna and Arianna Vignini

J. Xenobiot. 2025, 15(2), 51; https://doi.org/10.3390/jox15020051 - 31 Mar 2025

Abstract

Cardiovascular diseases (CVDs) represent a leading cause of premature mortality and disability worldwide, with their incidence expected to rise, potentially reaching 24 million deaths per year by 2030. These multifactorial diseases, including hypertension, coronary artery disease, arrhythmia, and heart failure, are often linked [...] Read more.

Cardiovascular diseases (CVDs) represent a leading cause of premature mortality and disability worldwide, with their incidence expected to rise, potentially reaching 24 million deaths per year by 2030. These multifactorial diseases, including hypertension, coronary artery disease, arrhythmia, and heart failure, are often linked to metabolic disturbances such as diabetes, oxidative stress, endothelial dysfunction, and inflammation. Natural compounds, such as caffeine, have been explored for their potential therapeutic effects on CVDs. Caffeine, found in coffee, tea, cocoa, and various energy drinks, is a widely consumed psychoactive compound with noted analgesic and anti-inflammatory properties. Despite its long history of use, caffeine’s impact on cardiovascular health remains controversial, with both beneficial and harmful effects reported. This review examines the current literature on the effects of caffeine on cardiovascular diseases (CVDs), with an emphasis on preclinical and clinical studies, its pharmacokinetic properties, and the molecular mechanisms it modulates. There is evidence that moderate caffeine intake can be beneficial for some CVDs, such as hypertension, while for other CVDs, such as dyslipidemia, the evidence collected so far suggests that caffeine intake could be detrimental since it increases total cholesterol levels. But variability in dosage, intake patterns, and individual factors (such as genetics and diet) complicates the reliability of results. Additionally, challenges related to dose standardization and the absence of consistent clinical trial designs hinder the full utilization of caffeine in CVD treatment. Nonetheless, caffeine appears to be safe for individuals without significant cardiovascular conditions. Future research should aim for well-designed studies with precise patient cohorts and standardized methodologies to better assess caffeine’s role in CVD management. Full article

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14 pages, 272 KiB

Open AccessArticle

Serum and Cerebrospinal Fluid Malondialdehyde Levels in Patients with Mild Cognitive Impairment

by Stavroula Ioannidou, Argyrios Ginoudis, Kali Makedou, Magda Tsolaki and Evgenia Lymperaki

J. Xenobiot. 2025, 15(2), 50; https://doi.org/10.3390/jox15020050 - 30 Mar 2025

Abstract

Mild cognitive impairment (MCI) is recognized as an intermediate stage between normal aging and dementia. Oxidative stress is implicated in the pathophysiology of neurodegenerative diseases, playing a crucial role. This study aimed to investigate the differences in malondialdehyde (MDA) levels in the serum [...] Read more.

Mild cognitive impairment (MCI) is recognized as an intermediate stage between normal aging and dementia. Oxidative stress is implicated in the pathophysiology of neurodegenerative diseases, playing a crucial role. This study aimed to investigate the differences in malondialdehyde (MDA) levels in the serum and cerebrospinal fluid (CSF) of patients with MCI compared to FDA-approved biomarkers, based on age, sex, and education level. Participants aged 55–90 years old were categorized into three groups based on FDA-approved biomarkers, especially the CSF Aβ42/Aβ40 ratio and clinical screening assessments: 30 MCI (A+) patients with abnormal CSF Aβ42/Aβ40 ratios (Group A), 30 MCI (A−) patients with normal CSF Aβ42/Aβ40 ratios (Group B), and 30 healthy (A−) participants with normal CSF Aβ42/Aβ40 ratios (Group C). The measurements of CSF FDA-approved biomarkers were performed using an automated immunochemical method (Fujirebio, Inc.), while MDA determination was performed using a competitive inhibition enzyme immunoassay technique (ELK Biotechnology Co., Ltd.). Our results showed that the mean CSF MDA values were significantly lower in group C than in group A (83 ng/mL vs. 130 ng/mL, p = 0.024) and group B (83 ng/mL vs. 142 ng/mL, p = 0.011), respectively. Differences in serum and CSF MDA levels were presented in the study groups based on sex, age, and education level. These findings suggest that lipid peroxidation, as indicated by CSF MDA, could serve as a potential biomarker for the early recognition of MCI. Full article

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16 pages, 1526 KiB

Open AccessArticle

Urinary β₂-Microglobulin Predicts the Risk of Hypertension in Populations Chronically Exposed to Environmental Cadmium

by Soisungwan Satarug

J. Xenobiot. 2025, 15(2), 49; https://doi.org/10.3390/jox15020049 - 28 Mar 2025

Abstract

Chronic exposure to the pollutant cadmium (Cd) is inevitable for most people because it is present in nearly all food types. Concerningly, the risk of developing hypertension has been linked to dietary Cd exposure lower than 58 µg/day for a 70 kg person. [...] Read more.

Chronic exposure to the pollutant cadmium (Cd) is inevitable for most people because it is present in nearly all food types. Concerningly, the risk of developing hypertension has been linked to dietary Cd exposure lower than 58 µg/day for a 70 kg person. The mechanisms involved are, however, unclear. Since the kidneys play an indispensable role in long-term blood pressure regulation, and they are also the main site of Cd accumulation and toxicity, a retrospective analysis was conducted to examine if kidney damage and malfunction, reflected by urinary β₂-microglobulin excretion (E_β2M), and the estimated glomerular filtration rate (eGFR), are related to Cd excretion (E_Cd) and blood pressure variation. Data were obtained from 689 Thai Nationals without diabetes or occupational exposure to Cd, of which 32.4% had hypertension and 7.3% had β₂-microglobulinuria, defined as an increase in the β₂M excretion rate ≥ 300 µg/g creatinine. Respective prevalence odds ratio (POR) and 95% confidence interval (CI) values for β₂-microglobulinuria and hypertension were 10.7 (1.36–83.4), p = 0.024 and 2.79 (1.60–4.87) p < 0.001, comparing the top quartile of E_Cd with the bottom quartile. Only in subjects with eGFR below 90 mL/min/1.73 m² did systolic blood pressure (SBP) and diastolic blood pressure (DBP) both increase linearly with E_β2M (respective β = 0.182 and 0.192 for SBP and DBP) after adjustment for age, body mass index, gender, and smoking. The present study confirms the significant impact of Cd on the risk of having hypertension, following GFR loss induced by Cd. A simple mediation model analysis for cause–effect inference has provided, for the first time, evidence that may link rising SBP and DBP in Cd-exposed people to a novel role of β₂M as a predictor of blood pressure variability. Full article

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27 pages, 639 KiB

Open AccessReview

Developments in Toxicity Testing with Duckweeds

by Paul Ziegler

J. Xenobiot. 2025, 15(2), 48; https://doi.org/10.3390/jox15020048 - 26 Mar 2025

Abstract

Duckweeds are a family of small floating macrophytes (the Lemnaceae) that inhabit quiet freshwaters worldwide. They have long been employed to determine toxicity to higher plants in the aquatic environment, and standardized national and international protocols have been developed for this purpose using [...] Read more.

Duckweeds are a family of small floating macrophytes (the Lemnaceae) that inhabit quiet freshwaters worldwide. They have long been employed to determine toxicity to higher plants in the aquatic environment, and standardized national and international protocols have been developed for this purpose using two representative species. While these protocols, which assess the growth of the leaf-like fronds of the tested duckweed, are indeed suitable and still frequently used for detecting the toxicity of water-borne substances to aquatic higher plant life, they are cumbersome and lengthy, determine endpoints rather than depict toxicity timelines, and provide no information as to the mechanisms involved in the indicated toxicity. Progress has been made in downscaling, shortening and improving the standardized assay procedures, and the use of alternative duckweed species, protocols and endpoints for detecting toxicity has been explored. Biomarkers of toxic effect have long been determined concomitantly with testing for toxicity itself, and their potential for the assessment of toxicity has recently been greatly expanded by transcriptomic, proteomic and metabolomic techniques complemented by FITR spectroscopy, transformation and genotoxicity and timescale toxicity testing. Improved modern biomarker analysis can help to both better understand the mechanisms underlying toxicity and facilitate the identification of unknown toxins. Full article

(This article belongs to the Special Issue Legacy and Emerging Pollutants and Their Effects through the Lens of Environmental Management)

29 pages, 1283 KiB

Open AccessReview

Associations of Environmental Exposure to Arsenic, Manganese, Lead, and Cadmium with Alzheimer’s Disease: A Review of Recent Evidence from Mechanistic Studies

by Giasuddin Ahmed, Md. Shiblur Rahaman, Enrique Perez and Khalid M. Khan

J. Xenobiot. 2025, 15(2), 47; https://doi.org/10.3390/jox15020047 - 24 Mar 2025

Abstract

Numerous epidemiological studies indicate that populations exposed to environmental toxicants such as heavy metals have a higher likelihood of developing Alzheimer’s disease (AD) compared to those unexposed, indicating a potential association between heavy metals exposure and AD. The aim of this review is [...] Read more.

Numerous epidemiological studies indicate that populations exposed to environmental toxicants such as heavy metals have a higher likelihood of developing Alzheimer’s disease (AD) compared to those unexposed, indicating a potential association between heavy metals exposure and AD. The aim of this review is to summarize contemporary mechanistic research exploring the associations of four important metals, arsenic (As), manganese (Mn), lead (Pb), and cadmium (Cd), with AD and possible pathways, processes, and molecular mechanisms on the basis of data from the most recent mechanistic studies. Primary research publications published during the last decade were identified via a search of the PubMed Database. A thorough literature search and final screening yielded 45 original research articles for this review. Of the 45 research articles, 6 pertain to As, 9 to Mn, 21 to Pb, and 9 to Cd exposures and AD pathobiology. Environmental exposure to these heavy metals induces a wide range of pathological processes that intersect with well-known mechanisms leading to AD, such as oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, autophagy dysfunction, and tau hyperphosphorylation. While exposure to single metals shares some affected pathways, certain effects are unique to specific metals. For instance, Pb disrupts the blood–brain barrier (BBB) and mitochondrial functions and alters AD-related genes epigenetically. Cd triggers neuronal senescence via p53/p21/Rb. As disrupts nitric oxide (NO) signaling, cortical, and synaptic function. Mn causes glutamate excitotoxicity and dopamine neuron damage. Our review provides a deeper understanding of biological mechanisms showing how metals contribute to AD. Information regarding the potential metal-induced toxicity relevant to AD may help us develop effective therapeutic AD intervention, treatment, and prevention. Full article

(This article belongs to the Special Issue Integrative Studies on Environmental Toxicity, Bioaccumulation and Remediation Strategies for Hazardous Substances)

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39 pages, 4044 KiB

Open AccessReview

The Soil–Plant Continuity of Rare Earth Elements: Insights into an Enigmatic Class of Xenobiotics and Their Interactions with Plant Structures and Processes

by Angela Martina, Lorenzo Ferroni and Elena Marrocchino

J. Xenobiot. 2025, 15(2), 46; https://doi.org/10.3390/jox15020046 - 20 Mar 2025

Abstract

Rare earth elements (REEs) are increasingly present in the environment owing to their extensive use in modern industries, yet their interactions with plants remain poorly understood. This review explores the soil–plant continuum of REEs, focusing on their geochemical behavior in soil, the mechanisms [...] Read more.

Rare earth elements (REEs) are increasingly present in the environment owing to their extensive use in modern industries, yet their interactions with plants remain poorly understood. This review explores the soil–plant continuum of REEs, focusing on their geochemical behavior in soil, the mechanisms of plant uptake, and fractionation processes. While REEs are not essential for plant metabolism, they interact with plant structures and interfere with the normal functioning of biological macromolecules. Accordingly, the influence of REEs on the fundamental physiological functions of plants is reviewed, including calcium-mediated signalling and plant morphogenesis. Special attention is paid to the interaction of REEs with photosynthetic machinery and, particularly, the thylakoid membrane. By examining both the beneficial effects at low concentrations and toxicity at higher levels, this review provides some mechanistic insights into the hormetic action of REEs. It is recommended that future research should address knowledge gaps related to the bioavailability of REEs to plants, as well as the short- and long-range transport mechanisms responsible for REE fractionation. A better understanding of REE–plant interactions will be critical in regard to assessing their ecological impact and the potential risks in terms of agricultural and natural ecosystems, to ensure that the benefits of using REEs are not at the expense of environmental integrity or human health. Full article

(This article belongs to the Section Ecotoxicology)

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20 pages, 9004 KiB

Open AccessArticle

Erioflorin and Erioflorin Acetate Induce Cell Death in Advanced Prostate Cancer Through ROS Increase and NF-κB Inhibition

by Cecilia Villegas, Iván González-Chavarría, Viviana Burgos, Jaime R. Cabrera-Pardo, Bernd Schmidt and Cristian Paz

J. Xenobiot. 2025, 15(2), 45; https://doi.org/10.3390/jox15020045 - 18 Mar 2025

Abstract

Germacranes are a type of sesquiterpene lactones with anti-inflammatory and cytotoxic properties against cancer cell lines. In this in vitro study, erioflorin and erioflorin acetate were isolated and purified from the leaves of Podanthus mitiqui Lindl (Mitique or Mitriu), a shrub endemic to [...] Read more.

Germacranes are a type of sesquiterpene lactones with anti-inflammatory and cytotoxic properties against cancer cell lines. In this in vitro study, erioflorin and erioflorin acetate were isolated and purified from the leaves of Podanthus mitiqui Lindl (Mitique or Mitriu), a shrub endemic to Chile and traditionally used in Mapuche medicine to treat urinary and digestive disorders. Their effects on advanced prostate cancer cell lines (DU-145 and 22Rv1) were evaluated. Cytotoxicity was assessed using real-time cell death and clonogenic assays. Apoptosis was determined by measuring reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), and apoptotic cell percentage through flow cytometry. Gene expression of BAX and BCL-2 was analyzed via RT-qPCR, while NF-κB activation was studied in DU-145 cells and human monocytic NF-κB reporter assays using LPS stimulation and alkaline phosphatase activity quantification. Erioflorin acetate exhibited the highest cytotoxicity, with IC₅₀ values of 35.1 µM (22Rv1) and 27.3 µM (DU-145), compared to erioflorin, which had IC₅₀ values of 50.3 µM and 56.5 µM, respectively. Both compounds increased ROS levels, reduced ΔΨm, and induced apoptosis. RT-qPCR analysis revealed that erioflorin elevated the BAX/BCL-2 ratio, and both compounds inhibited NF-κB activation by preventing IκBα phosphorylation. In conclusion, the findings demonstrate that erioflorin and erioflorin acetate exert significant in vitro cytotoxic and cytostatic effects on prostate cancer cells, supporting their potential as natural candidates for prostate cancer therapy. Full article

(This article belongs to the Section Natural Products/Herbal Medicines)

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53 pages, 12782 KiB

Open AccessReview

Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation

by Pradeepraj Durairaj and Zixiang Leonardo Liu

J. Xenobiot. 2025, 15(2), 44; https://doi.org/10.3390/jox15020044 - 14 Mar 2025

Abstract

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier in neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and the progression of neurodegenerative diseases. The brain’s complex architecture, composed of interconnected cell types and receptors, drives unique neuronal signaling [...] Read more.

Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier in neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and the progression of neurodegenerative diseases. The brain’s complex architecture, composed of interconnected cell types and receptors, drives unique neuronal signaling pathways, modulates enzyme functions, and leads to distinct CYP gene expression and regulation patterns compared to the liver. Despite their relatively low levels of expression, brain CYPs exert significant influence on drug responses, neurotoxin susceptibility, behavior, and neurological disease risk. These enzymes are essential for maintaining brain homeostasis, mediating cholesterol turnover, and synthesizing and metabolizing neurochemicals, neurosteroids, and neurotransmitters. Moreover, they are key participants in oxidative stress responses, neuroprotection, and the regulation of inflammation. In addition to their roles in metabolizing psychotropic drugs, substances of abuse, and endogenous compounds, brain CYPs impact drug efficacy, safety, and resistance, underscoring their importance beyond traditional drug metabolism. Their involvement in critical physiological processes also links them to neuroprotection, with significant implications for the onset and progression of neurodegenerative diseases. Understanding the roles of cerebral CYP enzymes is vital for advancing neuroprotective strategies, personalizing treatments for brain disorders, and developing CNS-targeting therapeutics. This review explores the emerging roles of CYP enzymes, particularly those within the CYP1–3 and CYP46 families, highlighting their functional diversity and the pathological consequences of their dysregulation on neurological health. It also examines the potential of cerebral CYP-based biomarkers to improve the diagnosis and treatment of neurodegenerative disorders, offering new avenues for therapeutic innovation. Full article

(This article belongs to the Topic Phase I and Phase II Xenobiotic-Metabolizing Enzymes: Structure, Function, and Regulation)

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14 pages, 4463 KiB

Open AccessArticle

Green Carbon Dots from Pinecones and Pine Bark for Amoxicillin and Tetracycline Detection: A Circular Economy Approach

by Saheed O. Sanni, Ajibola A. Bayode, Hendrik G. Brink, Nils H. Haneklaus, Lin Fu, Jianping Shang and Hua-Jun Shawn Fan

J. Xenobiot. 2025, 15(2), 43; https://doi.org/10.3390/jox15020043 - 11 Mar 2025

Abstract

Over the years, the abuse of antibiotics has increased, leading to their presence in the environment. Therefore, a sustainable method for detecting these substances is crucial. Researchers have explored biomass-based carbon dots (CDs) to detect various contaminants, due to their low cost, environmental [...] Read more.

Over the years, the abuse of antibiotics has increased, leading to their presence in the environment. Therefore, a sustainable method for detecting these substances is crucial. Researchers have explored biomass-based carbon dots (CDs) to detect various contaminants, due to their low cost, environmental friendliness, and support of a circular economy. In our study, we reported the synthesis of CDs using pinecones (PCs) and pinebark (PB) through a sustainable microwave method. We characterized the PCCDs and PBCDs using X-ray diffraction, Raman spectroscopy, Transmission Electron Microscope, and Fourier transform infrared, Ultraviolet-visible, and photoluminescence (PL) spectroscopy. The PCCDs and PBCDs were tested for the detection of amoxicillin (AMX) and tetracycline (TC). The results indicated that the sizes of the PCCDs and PBCDs were 19.2 nm and 18.39 nm, respectively, and confirmed the presence of the 002 plane of the graphitic carbon structure. They exhibited excitation wavelength dependence, good stability, and quantum yields ranging from 6% to 11%. PCCDs and PBCDs demonstrated “turn-off” detection for TC and AMX. The limits of detection (LOD) for TC across a broader concentration range were found to be 0.062 µM for PCCDs and 0.2237 µM for PBCDs. For AMX detection, PBCDs presented an LOD of 0.49 µM. Full article

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15 pages, 803 KiB

Open AccessArticle

Assessing the Application of Physiologically Based Pharmacokinetic Models in Acute Chemical Incidents

by Sydney Boone, Wenjie Sun, Pavani Gonnabathula, Jennifer Wu, Maureen F. Orr, M. Moiz Mumtaz and Patricia Ruiz

J. Xenobiot. 2025, 15(2), 42; https://doi.org/10.3390/jox15020042 - 11 Mar 2025

Abstract

Chemical release incidents in the United States involve hazardous chemicals that can harm nearby communities. A historical tracking of these chemical release incidents from 1991 to 2014 across up to 16 states has been conducted by The Agency for Toxic Substances and Disease [...] Read more.

Chemical release incidents in the United States involve hazardous chemicals that can harm nearby communities. A historical tracking of these chemical release incidents from 1991 to 2014 across up to 16 states has been conducted by The Agency for Toxic Substances and Disease Registry (ATSDR), utilizing the Hazardous Substances Emergency Events Surveillance (HSEES) and the National Toxic Substance Incidents Program (NTSIP) systems. By analyzing surveillance data, patterns of these different chemical releases can be identified to develop and construct a health-protective course of action. Physiologically Based Pharmacokinetic (PBPK) models can simulate chemical exposures during acute chemical incidents. For a retrospective study of an acute chemical release in 2012, we examined the components necessary to integrate PBPK-modeled exposure assessments in ATSDR’s Assessment of Chemical Exposure (ACE) program. We focused on data from a published investigation of vinyl chloride (VC) exposure to assess the utility of PBPK in evaluating exposures among residential populations near the release site. The initial estimate from the real-time air monitoring at the release site revealed that air levels greatly exceeded the Acute Exposure Guideline Levels (AEGL) of 1200 ppm, with PBPK models predicting corresponding VC blood levels of 3.17 mg/L. “Real-time” and “after-action” air modeling estimated VC levels at various distances from the release site over time. PBPK modeling provided insight into possible residential blood levels of VC over several days following the incident. These findings indicate that PBPK modeling could be valuable for reconstructing exposure scenarios associated with acute chemical releases. Full article

(This article belongs to the Topic Environmental Toxicology and Human Health—2nd Edition)

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16 pages, 14338 KiB

Open AccessArticle

Toxic Effects of Bis(4-hydroxyphenyl) Methane (BPF) on the Development and Reproduction of Chironomus tentans

by Chenglin Zhang, Zhen Wang, Huilin Liang, Shuai Sun, Weilong Xing, Bing Zhang, Feng Ge and Lei Wang

J. Xenobiot. 2025, 15(2), 41; https://doi.org/10.3390/jox15020041 - 9 Mar 2025

Abstract

Bis(4-hydroxyphenyl) methane (BPF), as a bisphenolic compound, has toxic effects on organisms such as endocrine disruption and immobilization of growth and development. This study evaluated the effect concentrations of BPF on Chironomus tentans and investigated the impact of BPF exposure at various sub-lethal [...] Read more.

Bis(4-hydroxyphenyl) methane (BPF), as a bisphenolic compound, has toxic effects on organisms such as endocrine disruption and immobilization of growth and development. This study evaluated the effect concentrations of BPF on Chironomus tentans and investigated the impact of BPF exposure at various sub-lethal concentrations on the growth, development, and reproductive capacity of different instars of C. tentans. The results demonstrated that exposure at concentrations of 2.0, 2.5, 3.0, and 4.0 mg·L⁻¹ delayed pupation, inhibited the development of imaginal discs, and caused an initial rise followed by a decline in the expression levels of genes related to larval development (ecr, usp, e74). Additionally, exposure at concentrations of 1.0, 1.5, and 2.0 mg·L⁻¹ led to fluctuations in the expression levels of genes related to adult development and reproduction (ecr, kr-h1, foxo, inr, pdk, akt, and vg) in both female and male adults, with varying degrees of effect. Furthermore, BPF exposure inhibited male fertility, causing significant damage to the gonadal tissues, though it did not affect the final hatching of eggs. These findings indicate that BPF exhibits developmental and reproductive toxicity in C. tentans, with 2.0 mg·L⁻¹ identified as the lowest effective concentration at which BPF affects pupation in midges. Full article

(This article belongs to the Special Issue Environmental Toxicology and Animal Health: 2nd Edition)

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