Frontiers in toxicology最新文献

We observed that gestational plus lactational exposure to glyphosate (Gly), as active ingredient, or a glyphosate-based herbicide (GBH) lead to preimplantation losses in F1 female Wistar rats. Here, we investigated whether GBH and/or Gly exposure could impair Hoxa10 gene transcription by inducing epigenetic changes during the receptive stage in rats, as a possible herbicide mechanism implicated in implantation failures. F0 dams were treated with Gly or a GBH through a food dose of 2 mg Gly/kg bw/day from gestational day (GD) 9 up to lactational day 21. F1 female rats were bred, and uterine tissues were analyzed on GD5 (preimplantation period). Transcripts levels of Hoxa10, DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b), histone deacetylases (Hdac-1 and Hdac-3) and histone methyltransferase (EZH2) were assessed by quantitative polymerase chain reaction (qPCR). Four CpG islands containing sites targeted by BstUI methylation-sensitive restriction enzyme and predicted transcription factors (TFs) were identified in Hoxa10 gene. qPCR-based methods were used to evaluate DNA methylation and histone post-translational modifications (hPTMs) in four regulatory regions (RRs) along the gene by performing methylation-sensitive restriction enzymes and chromatin immunoprecipitation assays, respectively. GBH and Gly downregulated Hoxa10 mRNA. GBH and Gly increased DNA methylation levels and Gly also induced higher levels than GBH in all the RRs analyzed. Both GBH and Gly enriched histone H3 and H4 acetylation in most of the RRs. While GBH caused higher H3 acetylation, Gly caused higher H4 acetylation in all RRs. Finally, GBH and Gly enhanced histone H3 lysine 27 trimethylation (H3K27me3) marker at 3 out of 4 RRs studied which was correlated with increased EZH2 levels. In conclusion, exposure to GBH and Gly during both gestational plus lactational phases induces epigenetic modifications in regulatory regions of uterine Hoxa10 gene. We show for the first time that Gly and a GBH cause comparable gene expression and epigenetic changes. Our results might contribute to delineate the mechanisms involved in the implantation failures previously reported. Finally, we propose that epigenetic information might be a valuable tool for risk assessment in the near future, although more research is needed to establish a cause-effect relationship.

Background: fluoride is a beneficial ion that has been used in various fields, from industrial products to therapeutics. However, due to its narrow therapeutic index, fluoride sometimes acts as a toxic agent at relatively higher concentrations in the human body. Based on the interest in genetic stability, its cytotoxic effects have been investigated mainly in nucleated, adherent cells, such as fibroblasts. However, the sensitivity of blood cells, especially anucleate platelets, to fluoride is poorly understood. To fill this gap in the literature, we investigated the effects of relatively low levels of fluoride on platelet energy metabolism, function, and viability.

Methods: Platelet-rich plasma (PRP) was prepared from 15 non-smoking healthy male adults (age: 28-63) and treated with NaF (0.5 or 1.0 mM) in microtubes for up to 3 days. Platelet function was evaluated based on aggregation and adhesion activities. Platelet energy metabolism was evaluated based on intracellular ATP levels, extracellular lactate levels, and respiration activities. The mitochondrial membrane potential (Em) and localization of reactive oxygen species (ROS) were visualized using cytochemical methods. Platelet viability was evaluated by cell counting and tetrazolium reduction.

Result: NaF (1 mM) significantly reduced platelet viability and inhibited functions. Behind these phenomena, NaF substantially decreased mitochondrial Em and increased ROS production along with significant decreases in oxygen consumption and ATP levels. Simultaneously, NaF increased the lactate levels. Although not statistically significant, similar effects were observed at 0.5 mM NaF.

Conclusion: At relatively low levels, NaF has the potential to attenuate platelet function probably primarily through the inhibition of mitochondrial energy generation. Cytotoxicity may be directly related to ROS production. These findings suggest that when used topically, for example, for caries prevention in the oral cavity, NaF could interfere with wound healing and tissue regeneration by endogenous and exogenously added platelets in the form of PRP.

There is a well-recognized relationship between a person's body burden of essential trace elements such as copper and their neurological function in which both deficiencies and exposures to excessive concentrations are associated with adverse clinical outcomes. Preclinical studies indicate chronic excess copper exposure is associated with altered motor function, dopaminergic neuronal loss, astrocytosis, and microgliosis. Copper also promotes oligomerization and fibrilization of α-synuclein suggesting it may hasten the course of an α-synucleinopathy. Here we report a rare case of early onset Lewy Body Dementia with Parkinsonism in a 53-year-old Caucasian woman exposed to copper contaminated drinking water for more than 10 years. Her hair and that of her daughter had streaks of blue-green discoloration as did the porcelain sinks in their home. Testing confirmed copper contamination of the drinking water. A neurologist diagnosed her with Lewy Body Dementia with Parkinsonism. Skin biopsy for phosphorylated α was consistent with a diagnosis of an α-synucleinopathy. These findings suggest chronic exposure to excessive copper may act as disease modifying factor in Lewy Body Dementia with Parkinsonism. It has previously been recommended that individuals at risk of Alzheimer's disease (AD) avoid excessive intake of copper. Genetic studies indicate that Lewy Body Dementia shares risk factors and pathways with AD. Based on the observations in this patient we recommend that individuals at risk for an α-synucleinopathy based on a positive family history, genetic testing, and/or positive results on a skin biopsy for phosphorylated α-synuclein avoid exposure to excess copper.

Due to the growing safety and environmental concerns associated with biocides, phenolic-soy branched chain fatty acids (phenolic-soy BCFAs) are synthesized as new bio-based antimicrobial agents. Safety evaluation is essential before the wide adoption of these new antimicrobial products. This study was initiated to evaluate the safety of four phenolic-soy BCFAs (with phenol, thymol, carvacrol, or creosote branches). Methyl-branched iso-oleic acid, phenol, and creosote were included in the study as controls. In silico toxicity simulation tools predicted that the phenolic BCFAs had much higher toxicities to aquatic organisms than free phenolics did, while the opposite was predicted for rats. The developmental toxicity of four phenolic-soy BCFAs was assessed using an in vivo chicken embryonic assay. Results showed that creosote-soy BCFA had much lower mortality rates than creosote at the same dosages. Additionally, creosote-soy BCFA and methyl-branched iso-oleic acid induced minimal estrogenic activity in the concentration range of 10 nM - 1 µM. Carvacrol-soy BCFA treatments significantly increased (p < 0.05) oxidative stress levels with higher thiobarbituric acid reactive substances in the livers of chicken embryos. Altogether, the phenolic-soy BCFAs, especially creosote-soy BCFA, reported in this study are potentially promising and safer bio-based antimicrobial products.

Introduction: Sites associated with gadolinium (Gd) deposition in the brain (e.g., the globus pallidus) are known to contain high concentrations of ferric iron. There is considerable debate over the mechanism of Gd deposition in the brain. The role of iron transport mechanisms in Gd deposition has not been determined. Thus, we seek to identify if Gd deposition can be controlled by modifying iron exposure. Methods: Female Sprague-Dawley rats were given diets with controlled iron levels at 2-6 ppm, 6 ppt (20 g/kg Fe carbonyl) or 48 ppm for 3 weeks to induce iron deficiency, overload or normalcy. They were kept on those diets while receiving a cumulative 10 mmol/kg dose of gadodiamide intravenously over 2 weeks, then left to washout gadodiamide for 3 days or 3 weeks before tissues were harvested. Gd concentrations in tissues were analyzed by ICP-MS. Results: There were no significant effect of dietary iron and total Gd concentrations in the organs, but there was a significant effect of iron status on Gd distribution in the brain. For the 3-week washout cohort, there was a non-significant trend of increasing total brain deposition and decreasing dietary iron, and about 4-fold more Gd in the olfactory bulbs of the low iron group compared to the other groups. Significant brain accumulation was observed in the low iron group total brain Gd in the 3-week washout group relative to the 3-day washout group and no accumulation was observed in other tissues. There was a strong negative correlation between femur Gd concentrations and concentrations in other organs when stratifying by dietary iron. Discussion: Gd brain deposition from linear Gd-based contrast agents (GBCAs) are dependent upon iron status, likely through variable transferrin saturation. This iron dependence appears to be associated with redistribution of peripheral deposited Gd (e.g., in the bone) into the brain.

Neurotoxicants are substances that can lead to adverse structural or functional effects on the nervous system. These can be chemical, biological, or physical agents that can cross the blood brain barrier to damage neurons or interfere with complex interactions between the nervous system and other organs. With concerns regarding social policy, public health, and medicine, there is a need to ensure rigorous testing for neurotoxicity. While the most common neurotoxicity tests involve using animal models, a shift towards stem cell-based platforms can potentially provide a more biologically accurate alternative in both clinical and pharmaceutical research. With this in mind, the objective of this article is to review both current technologies and recent advancements in evaluating neurotoxicants using stem cell-based approaches, with an emphasis on developmental neurotoxicants (DNTs) as these have the most potential to lead to irreversible critical damage on brain function. In the next section, attempts to develop novel predictive model approaches for the study of both neural cell fate and developmental neurotoxicity are discussed. Finally, this article concludes with a discussion of the future use of in silico methods within developmental neurotoxicity testing, and the role of regulatory bodies in promoting advancements within the space.

Introduction: The nematode, Caenorhabditis elegans (C. elegans), is an advantageous model for studying developmental toxicology due to its well-defined developmental stages and homology to humans. It has been established that across species, dopaminergic neurons are highly vulnerable to neurotoxicant exposure, resulting in developmental neuronal dysfunction and age-induced degeneration. C. elegans, with genetic perturbations in dopamine system proteins, can provide insight into the mechanisms of dopaminergic neurotoxicants. In this study, we present a comprehensive analysis on the effect of gene mutations in dopamine-related proteins on body size, development, and behavior in C. elegans.

Methods: We studied C. elegans that lack the ability to sequester dopamine (OK411) and that overproduce dopamine (UA57) and a novel strain (MBIA) generated by the genetic crossing of OK411 and UA57, which both lack the ability to sequester dopamine into vesicles and, additionally, endogenously overproduce dopamine. The MBIA strain was generated to address the hypothesis that an endogenous increase in the production of dopamine can rescue deficits caused by a lack of vesicular dopamine sequestration. These strains were analyzed for body size, developmental stage, reproduction, egg laying, motor behaviors, and neuronal health utilizing multiple methods.

Results: Our results further implicate proper dopamine synthesis and sequestration in the regulation of C. elegans body size, development through larval stages into gravid adulthood, and motor functioning. Furthermore, our analyses demonstrate that body size in terms of length is distinct from the developmental stage as fully developed gravid adult C. elegans with disruptions in the dopamine system have decreased body lengths. Thus, body size should not be used as a proxy for the developmental stage when designing experiments.

Discussion: Our results provide additional evidence that the dopamine system impacts the development, growth, and reproduction in C. elegans. Furthermore, our data suggest that endogenously increasing the production of dopamine mitigates deficits in C. elegans lacking the ability to package dopamine into synaptic vesicles. The novel strain, MBIA, and novel analyses of development and reproduction presented here can be utilized in developmental neurotoxicity experiments.

Microplastics (MPs) and nanoplastics (NPs) have increasingly been found in the environment. Until recently, most MPs/NPs toxicological research has been done in aquatic systems resulting in a gap in knowledge regarding terrestrial systems. Plastics have been shown to enter the circulatory system of humans, and can accumulate within organs, little is known about the effect this has on health. Heart disease is the leading cause of death globally, so it's critical to understand the possible impacts MPs/NPs have on the heart. The Drosophila model has been growing in popularity within the toxicology field, it allows for affordable and rapid research on the impacts of a variety of toxins, including plastics. Some research has examined toxicological effects of plastics on the fly, evaluating the effects on mortality, fecundity, development, and locomotion. However, no one has studied the effects on the Drosophila heart. We utilize the Drosophila model to identify the potential effects of oral exposure to polystyrene MPs (1 µm in diameter) and NPs (0.05 µm in diameter) particles on heart function. Flies were exposed to 1.4 × 10¹¹ particles/d/kg of larvae for MPs and 1.2 × 10¹⁸ particles/d/kg of larvae for NPs from egg to pupal eclosion. Heart function was then analyzed utilizing semi-intact dissections and Semi-automatic Optic Heartbeat Analysis software (SOHA). Following exposure to MPs and NPs we see sexually dimorphic changes to heart size and function. This study highlights the importance of additional Drosophila MPs/NPs research to identify the molecular mechanisms behind these changes.