J. Xenobiot., Volume 14, Issue 2 (June 2024) – 10 articles

Glioblastomas (GBMs) are aggressive and invasive cancers of the brain, associated with high rates of tumour recurrence and poor patient outcomes despite initial treatment. Targeting cell migration is therefore of interest in highly invasive cancers such as GBMs, to prevent tumour dissemination and regrowth. One current aim of GBM research focuses on assessing the anti-migratory properties of novel or repurposed inhibitors, including plant-based drugs which display anti-cancer properties. We investigated the potential anti-migratory activity of plant-based products with known cytotoxic effects in cancers, using a range of two-dimensional (2D) and three-dimensional (3D) migration and invasion assays as well as immunofluorescence microscopy to determine the specific anti-migratory and phenotypic effects of three plant-derived compounds, Turmeric, Indigo and Magnolia bark, on established glioma cell lines. Migrastatic activity was observed in all three drugs, with Turmeric exerting the most inhibitory effect on GBM cell migration into scratches and from the spheroid edge at all the timepoints investigated (p < 0.001). We also observed novel cytoskeletal phenotypes affecting actin and the focal adhesion dynamics. As our in vitro results determined that Turmeric, Indigo and Magnolia are promising migrastatic drugs, we suggest additional experimentation at the whole organism level to further validate these novel findings. Full article

Glyphosate, a widely used herbicide, is linked to a plethora of deleterious effects in both clinical and preclinical studies. Nevertheless, the effects of its main metabolite, aminomethylphosphonic acid (AMPA), whose half-life in soil is even longer than that of glyphosate, have been little explored. On this basis, as a first approach, in this work, we report that intraperitoneal (i.p.) administration of AMPA or glyphosate (at 10, 56, and 100 mg/kg) decreased, to a similar extent, plasma cholinesterase (ChE) activity in acutely exposed rats. Moreover, we designed an experimental protocol to analyze and compare the effects of AMPA and glyphosate on human plasma ChE activity; this protocol consisted of adding these compounds to human plasma to subsequently test the effects of this plasma on the contraction to acetylcholine (ACh) in the frog rectus abdominis muscle (an indirect estimate of ChE activity). Accordingly, this muscular contraction to ACh was evaluated before and after pre-incubation of ACh with (i) plasma alone, (ii) plasma with AMPA, and (iii) plasma with glyphosate. Our results indicate that AMPA, like glyphosate, decreased ChE activity in the plasma of rats (when given i.p.) and humans (when added in vitro), suggesting that both xenobiotics may exert similar toxicological effects. Full article

Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome b₅ (cyt b₅)’s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1’s involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI). Full article

Disinfection during tertiary municipal wastewater treatment is a necessary step to control the spread of pathogens; unfortunately, it also gives rise to numerous disinfection byproducts (DBPs), only a few of which are regulated because of the analytical challenges associated with the vast number of potential DBPs. This study utilized polydimethylsiloxane (PDMS) passive samplers, comprehensive two-dimensional gas chromatography (GC×GC) coupled with time-of-flight mass spectrometry (TOFMS), and non-negative matrix factorization (NMF) spectral deconvolution for suspect screening of DBPs in treated wastewater. PDMS samplers were deployed upstream and downstream of the chlorination unit in a municipal wastewater treatment plant located in Abu Dhabi, and their extracts were analyzed using GC×GC-TOFMS. A workflow incorporating a multi-tiered, eight-filter screening process was developed, which successfully enabled the reliable isolation of 22 candidate DBPs from thousands of peaks. The NMF spectral deconvolution improved the match factor score of unknown mass spectra to the reference mass spectra available in the NIST library by 17% and facilitated the identification of seven additional DBPs. The close match of the first-dimension retention index data and the GC×GC elution patterns of DBPs, both predicted using the Abraham solvation model, with their respective experimental counterparts—with the measured data available in the NIST WebBook and the GC×GC elution patterns being those observed for the candidate peaks—significantly enhanced the accuracy of peak assignment. Isotopic pattern analysis revealed a close correspondence for 11 DBPs with clearly visible isotopologues in reference spectra, thereby further strengthening the confidence in the peak assignment of these DBPs. Brominated analogues were prevalent among the detected DBPs, possibly due to seawater intrusion. The fate, behavior, persistence, and toxicity of tentatively identified DBPs were assessed using EPI Suite™ and the CompTox Chemicals Dashboard. This revealed their significant toxicity to aquatic organisms, including developmental, mutagenic, and endocrine-disrupting effects in certain DBPs. Some DBPs also showed activity in various CompTox bioassays, implicating them in adverse molecular pathways. Additionally, 11 DBPs demonstrated high environmental persistence and resistance to biodegradation. This combined approach offers a powerful tool for future research and environmental monitoring, enabling accurate identification and assessment of DBPs and their potential risks. Full article

The benzophenone (BP) family, including oxybenzone (BP-3), a prevalent sunscreen ingredient and environmental contaminant, has raised concerns since the year 2005. This study investigated oxybenzone toxicity in zebrafish (Danio rerio) eleutheroembryos and brine shrimp (Artemia salina) nauplii, focusing on the LC₅₀ and developmental impacts. Zebrafish embryos (0.100–1.50 mg/L BP-3, 96 h) and A. salina (0.100–5.00 mg/L BP-3, 48 h) were tested with ultrasound-assisted emulsified liquid-phase microextraction (UA-ELPME) used for zebrafish tissue analysis. HPLC-DAD determined BP-3 concentrations (highest: 0.74 ± 0.13 mg/L). Although no significant zebrafish embryo mortality or hatching changes occurred, developmental effects were evident. Lethal concentrations were determined (A. salina LC₅₀ at 24 h = 3.19 ± 2.02 mg/L; D. rerio embryos LC₅₀ at 24 h = 4.19 ± 3.60 mg/L), with malformations indicating potential teratogenic effects. A. salina displayed intestinal tract alterations and D. rerio embryos exhibited pericardial edema and spinal deformities. These findings highlight oxybenzone’s environmental risks, posing threats to species and ecosystem health. Full article

This study utilizes the National Health and Nutrition Examination Survey (NHANES) 2017–2018 data to explore the relationship between exposure to perfluoroalkyl substances (specifically perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), metals lead (Pb), mercury (Hg), and cadmium (Cd), allostatic load, and hepatic disease markers, including the fatty liver index a measure of the likelihood of non-alcoholic fatty liver disease, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin. The paper identified significant associations and interaction effects by employing descriptive statistics, Spearman’s correlation analysis, linear regression, and Bayesian kernel machine regression (BKMR). Descriptive statistics highlight sex-specific differences in contaminant levels. Spearman’s analysis underscores strong correlations among metals and per- and polyfluoroalkyl substances (PFAS). Linear regression reveals significant impacts of specific contaminants on AST, ALT, ALP, and bilirubin levels, adjusting for age and alcohol consumption. BKMR results further elucidate the complex, potentially synergistic relationships between these environmental exposures and the likelihood of non-alcoholic fatty liver disease, offering nuanced insights into their combined effects on liver health. The findings emphasize the intricate dynamics of environmental exposures on hepatic function, advocating for targeted public health interventions. Full article

Hypertensive disorders in pregnancy (HDP) are the most prevalent diseases during pregnancy. In addition to the already identified risk factors, exposure to environmental contaminants has been also considered a new one. Phthalates, which are classified as priority environmental pollutants due to their ubiquitousness and endocrine disrupting properties, have been implicated in HDP in some epidemiological studies. Nevertheless, phthalates’ vascular impacts still need to be clarified. Thus, we aimed to understand the connection between phthalates exposure and the occurrence of gestational hypertension, as well as the pathway involved in the pathological vascular effects. We investigated diethyl phthalate’s (DEP) effect on the vascular reactivity of the human umbilical arteries (HUAs) from normotensive and hypertensive pregnant women. Both DEP’s nongenomic (within minutes effect) and genomic (24 h exposure to DEP) actions were evaluated, as well as the contribution of cyclic guanosine monophosphate and Ca²⁺ channel pathways. The results show that short-term exposure to DEP interferes with serotonin and histamine receptors, while after prolonged exposure, DEP seems to share the same vasorelaxant mechanism as estrogens, through the NO/sGC/cGMP/PKG signaling pathway, and to interfere with the L-type Ca²⁺ channels. Thus, the vascular effect induced by DEP is similar to that observed in HUA from hypertensive pregnancies, demonstrating that the development of HDP may be a consequence of DEP exposure. Full article

Graphene-based nanomaterials are exceptionally attractive for a wide range of applications, raising the likelihood of the release of graphene-containing nanoparticles into aquatic environments. The growing use of these carbon nanomaterials in different industries highlights the crucial need to investigate their environmental impact and evaluate potential risks to living organisms. The current investigation evaluated the nanotoxicity of graphene (nanoflakes) and graphene oxide (GO) nanoparticles on the cardiorespiratory responses (heart rate, gill ventilation frequency), as well as the swimming and nesting behavioral parameters of early stage larvae and juvenile salmonids. Both short-term (96 h) and long-term (23 days) exposure experiments were conducted using two common species: brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss). The findings demonstrated notable alterations in fish nesting behavior, swimming performance, and cardiorespiratory functions, indicating the potential toxicity of nanoparticles. This impact was observed at both physiological and whole-organismal levels in salmonids at early stages. Future investigations should explore different types of nanocarbons and their potential enduring effects on fish population structure, considering not only individual survival but also broader aspects of development, including feeding, reproductive, and other social dynamics. Full article

With the increasing integration of nanomaterials into daily life, the potential ecotoxicological impacts of nanoparticles (NPs) have attracted increased attention from the scientific community. This study assessed the ecotoxicity of ZnS quantum dots (QDs) doped with varying molar concentrations of Mn²⁺ on Chlorella vulgaris. The ZnS:Mn QDs were synthesized using the polyol method. The size of the ZnS:Mn QDs ranged from approximately 1.1 nm to 2 nm, while the aggregation size in Seine River water was 341 nm at pH 6 and 8. The presence of ZnS:Mn (10%) NPs exhibited profound toxicity to Chlorella vulgaris, with immediate reductions in viability (survival cells) from 71%, 60% to 51%, 52% in BG11 and Seine River water, respectively, at a concentration of 100 mg L⁻¹ of ZnS:Mn (10%) NPs. Additionally, the ATP content in Chlorella vulgaris significantly decreased in Seine River water (by 20%) after 3 h of exposure to ZnS:Mn (10%) NPs. Concurrently, SOD activity significantly increased in Seine River water, indicating that the ZnS:Mn (10%) NPs induced ROS production and triggered an oxidative stress response in microalgae cells. Full article

Bisphenol S (BPS), one of the substitutes for bisphenol A (BPA), is widely used in various commodities. The BPS concentrations in surface water have gradually increased in recent years, making it a predominant bisphenol analogue in the aquatic environment and raising concerns about its health and ecological effects on aquatic organisms. For this study, we conducted a 96 h acute toxicity test and a 15-day developmental exposure test to assess the adverse effects of BPS exposure in Chinese medaka (Oryzias sinensis), a new local aquatic animal model. The results indicate that the acute exposure of Chinese medaka embryos to BPS led to relatively low toxicity. However, developmental exposure to BPS was found to cause developmental abnormalities, such as decreased hatching rate and body length, at 15 dpf. A transcriptome analysis showed that exposure to different concentrations of bisphenol S often induced different reactions. In summary, environmental concentrations of BPS can have adverse effects on the hatching and physical development of Chinese medaka, and further attention needs to be paid to the potential toxicity of environmental BPS. Full article