Epigenetic implications of common brominated flame retardants (PBDEs and TBBPA): Understanding the health risks of BFRs exposure.

Brominated flame retardants (BFRs) are synthetic chemicals incorporated into a wide variety of products, both for industrial applications and everyday use, with the primary aim of reducing their flammability or reducing the material burning rate. These compounds find widespread use in plastics, textiles, and electrical/electronic devices. However, BFRs can be released from products and, thus are determined in many environmental matrices such as soil, water and air.This review discuss the potential health implications of selected BFRs (PBDEs and TBBPA) exposure arising from their impact on the epigenetic mechanisms. Epigenetic modifications, such as DNA methylation and histone acetylation or methylation, as well as changes in miRNA pattern, play significant roles in gene expression and cell function and can be influenced by environmental factors.The studies indicate that PBDEs exposure can lead to global DNA hypomethylation, disrupting normal gene regulation and contributing to genomic instability. In animal models, PBDEs have been associated with adverse effects on neurodevelopment, including impairments in memory and learning. TBBPA exposure has also been linked to changes in DNA methylation patterns, alterations in histone posttranslational modifications and non-coding RNA expression. These epigenetic changes may contribute to health issues related to growth, development, and endocrine functions.The growing evidence of epigenetic modifications induced by BFRs exposure highlights the importance of understanding their potential risks to human health. Further investigations are needed to fully elucidate the long-term consequences of altered epigenetic marks and their impact on human health.

An In Vitro Comparative Study of the Effects of Tetrabromobisphenol A and Tetrabromobisphenol S on Human Erythrocyte Membranes-Changes in ATP Level, Perturbations in Membrane Fluidity, Alterations in Conformational State and Damage to Proteins.

Brominated flame retardants (BFRs) are substances used to reduce the flammability of plastics. Among this group, tetrabormobisphenol A (TBBPA) is currently produced and used on the greatest scale, but due to the emerging reports on its potential toxicity, tetrabromobisphenol S (TBBPS)-a compound with a very similar structure-is used as an alternative. Due to the fact that the compounds in question are found in the environment and in biological samples from living organisms, including humans, and due to the insufficient toxicological knowledge about them, it is necessary to assess their impacts on living organisms and verify the validity of TBBPA replacement by TBBPS. The RBC membrane was chosen as the research model. This is a widely accepted research model for assessing the toxicity of xenobiotics, and it is the first barrier to compounds entering circulation. It was found that TBBPA and TBBPS caused increases in the fluidity of the erythrocyte membrane in their hydrophilic layer, and conformational changes to membrane proteins. They also caused thiol group elevation, an increase in lipid peroxidation (TBBPS only) and decreases in the level of ATP in cells. They also caused changes in the size and shape of RBCs. TBBPA caused changes in the erythrocyte membrane at lower concentrations compared to TBBPS at an occupational exposure level.

Evaluation of the Effect of Selected Brominated Flame Retardants on Human Serum Albumin and Human Erythrocyte Membrane Proteins.

Brominated flame retardants (BFRs) have been using to reduce the flammability of plastics contained in many products, such as household articles, furniture, mattresses, textiles or insulation. Considering the fact that these compounds may be released into the environment leading to the exposure of living organisms, it is necessary to study their possible effects and mechanisms of action. Proteins play a crucial role in all biological processes. For this reason, a simple model of human serum albumin (HSA) was chosen to study the mechanism of BFRs' effect on proteins. The study determined interactions between selected BFRs, i.e., tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4-dibromophenol (2,4-DBP), 2,4,6-tribromophenol (2,4,6-TBP) and pentabromophenol (PBP), and HSA by measurement of fluorescence of intrinsic tryptophan and absorbance of circular dichroism (CD). In addition, in order to understand the possible effect of these compounds in their native environment, the effect of BFRs on membrane proteins of human erythrocytes (red blood cells, RBCs) was also assessed. Among bromophenols, PBP had the strongest oxidative effect on RBC membrane, and 2,4-DBP demonstrated the weakest fluorescence-quenching effect of both membrane tryptophan and HSA. By contrast to PBP, 2,4-DBP and 2,4,6-TBP caused spatial changes of HSA. We have observed that among all analyzed BFRs, TBBPA caused the strongest oxidation of RBC membrane proteins and the model HSA protein, causing reduction of fluorescence of tryptophan contained in them. TBBPA also changed albumin conformation properties, leading to impairment of the α-helix structure. However, TBBPS had the weakest oxidative effect on proteins among studied BFRs and did not affect the secondary structure of HSA.

Evaluation of apoptotic potential of glyphosate metabolites and impurities in human peripheral blood mononuclear cells (in vitro study).

Glyphosate is used for cereal, vegetable and fruit crops for reducing or inhibiting the growth of weeds as well as a desiccant for various grain crops. That is why, glyphosate has been shown to be accumulated in humans and animals through ingestion of food of both plant and animal origin. The study aimed to assessed the effect of glyphosate, its metabolites: aminomethylphosphonic acid (AMPA), methylphosphonic acid and its impurities: PMIDA, N-methylglyphosate, hydroxymethylphosphonic acid and bis(phosphonomethyl)amine on apoptosis induction in human peripheral blood mononuclear cells (PBMCs). PBMCs were exposed to the compounds studied at the concentrations ranging from 0.01 to 5 mM for 4 h. We have observed an increase in reactive oxygen species (including hydroxyl radical) and cytosolic calcium ions levels as well as reduction of transmembrane mitochondrial potential (ΔΨm) in PBMCs exposed to the compounds examined. All substances studied changed PBMCs membrane permeability, activated caspase-8, -9, -3 and caused chromatin condensation, which showed that they were capable of inducing apoptosis both via extrinsic and particularly intrinsic pathway. Generally the study demonstrated that there were no differences between apoptotic changes induced by glyphosate, its metabolites or impurities, and observed changes were provoked by high concentrations of investigated compounds.

Changes in the activities of antioxidant enzymes and reduced glutathione level in human erythrocytes exposed to selected brominated flame retardants.

Currently, more and more concerns are related to oxidative stress appearing in cells as a result of xenobiotics action. It has been found that selected brominated flame retardants (BFRs) can cause reactive oxygen species (ROS) induction at environmental concentrations. Excessive ROS induction can contribute to the redox imbalance in the cell. Therefore, the aim of our work was to evaluate the effect of selected BFRs on the activity of antioxidant enzymes, i.e. superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and the level of reduced glutathione (GSH) in human erythrocytes. Erythrocytes were incubated with tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4-dibromophenol (2,4-DBP), 2,4,6-tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) in the concentration ranging from 1 to 100 µg/ml. This study has shown that the BFRs studied disturbed redox balance in human erythrocytes. TBBPA caused more significant decrease in antioxidant enzymes activities than other compounds examined. Among bromophenols studied, 2,4-DBP most strongly affected antioxidant system, which indicated that the number of bromine atoms in the molecule did not significantly affect the pro-oxidative properties of the BFRs examined.

In vitro assessment of eryptotic potential of tetrabromobisphenol A and other bromophenolic flame retardants.

Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA) and tetrabromobisphenol S (TBBPS) as well as bromophenols, i.e. 2,4-dibromophenol (2,4-DBP), 2,4,6-tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) have raised wide concerns due to their widespread occurrence in the environment and adverse effects observed in living organisms including human. The effect of BFRs on apoptosis of human erythrocytes has not been examined, that is why we have decided to assess eryptotic potential of these substances by determining changes in phosphatidylserine (PS) translocation, alterations in intracellular ROS and calcium ion levels, as well as caspase-3 and calpain activation in this cell type. It has been found that all BFRs studied even in the concentration of 0.001 µg/mL induced ROS formation. The compounds examined caused apoptosis by PS externalization and caspase-3 activation in human red blood cells. It has also been shown that calcium ions and calpain did not play a significant role in eryptosis induction by BFRs studied in human erythrocytes.

The effect of two bromfenvinphos impurities: BDCEE and ß-ketophosphonate on oxidative stress induction, acetylcholinesterase activity, and viability of human red blood cells.

Numerous research works have shown that synthesis of pesticides leads to the formation of impurities that may substantially enhance pesticide toxicity. In this study, the effect of manufacturing impurities of pesticide bromfenvinphos (BFVF) such as 1-bromo-2-(2,4-dichlorophenyl)-2-ethoxy ethene (BDCEE) and diethyl [2-(2,4-dichlorophenyl)-2-oxo-ethyl] phosphonate (ß-ketophosphonate) on human erythrocytes, being significantly exposed to xenobiotics has been studied. The cells were treated with the compounds studied in the concentrations ranging from 0.1 µM to 250 µM for 4 h. In order to assess the effect of BDCEE and ß-ketophosphonate on red blood cells hemolytic changes, changes in cell size (FSC parameter) and oxidation of hemoglobin were studied. Moreover, alterations in reactive oxygen species (ROS) formation, reduced glutathione (GSH) level and acetylcholinesterase (AChE) activity were determined. BDCEE induced an increase in ROS level and caused strong oxidation of hemoglobin as well as a slight change in erythrocytes size and hemolysis, while it did not change GSH level and AChE activity. ß-ketophosphonate has not been shown to affect most parameters studied, but it strongly reduced AChE activity. Because changes in the parameters examined were noted at low concentrations of BFVF impurities (5-250 µM), those substances should not negatively affect on red blood cells of humans environmentally exposed to this pesticide.

Evaluation of the effect of brominated flame retardants on hemoglobin oxidation and hemolysis in human erythrocytes.

Brominated flame retardants (BFRs) are widely used in many everyday products. Numerous studies have shown that BFRs can be released into the environment. Environmental pollution with these compounds raises concerns about their potentially adverse health effects. The aim of this study was to evaluate the effect of tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS), 2,4-dibromophenol (2,4-DBP), 2,4,6- tribromophenol (2,4,6-TBP) and pentabromophenol (PBP) on hemolysis induction and hemoglobin oxidation in human erythrocytes. The erythrocytes were incubated with selected BFRs in a wide concentrations ranging from 0.01 to 100 µg/ml for 24 h, 48 h and 72 h. All compounds studied, exhibited hemolytic potential and induced methemoglobin formation. Hemolytic and oxidative potential of BFRs increased along with the increasing concentrations of the compounds studied and elongation of the incubation time. Our study showed that both the number of aromatic rings and the number of bromine atoms in the molecule of the compounds examined influence hemoglobin oxidation and damage to the cellular membrane. Furthermore, we may conclude that 2,4-DBP is potentially most toxic compound because it causes statistically significant changes at the lowest concentration, while the highest toxicity at the highest concentrations was noted for TBBPA.

[Tetrabromobisphenol A - Toxicity, environmental and occupational exposures]. / Tetrabromobisfenol A ­ toksycznosc, narazenie srodowiskowe i zawodowe.

Brominated flame retardants (BFR), including tetrabromobisphenol A (TBBPA) represents 25% of the global market of flame retardants. Among them, TBBPA is used on the largest scale (approx. 60%) because of its firebreak properties and widespread occurrence in every day products such as furniture, upholstery, adhesives and electronic equipment. A broad application of TBBPA can contribute to environmental pollution. Tetrabromobisphenol A has been determined in soil, water, river sediments and the atmosphere. Tetrabromobisphenol A is characterized by a high value of coefficient n-octanol/water (log P = 4.5), low acidity, and it may exist in undissociated or dissociated form. Due to the high hydrophobicity, TBBPA may accumulate in living organisms, including humans at different food chain levels. The occurrence of TBBPA in humans, e.g., in blood, fat tissue and mother milk, has been reported. Tetrabromobisphenol A is classified as hazard statements (H) H400/H410, which means that it is toxic to aquatic biota, causing long-term changes in these organisms. Up to now, only a few studies have been conducted to assess potential toxicity of high doses of TBBPA to mammals. Although many people are occupationally exposed to TBBPA during production or processing of this substance in their workplaces, there are only a few studies that have assessed the real hazard associated with TBPPA exposure. The aim of the study was to discuss the latest literature (mainly from the years 2010-2016) referring to the presence of TBBPA in the environment and its effects to living organisms. Data concerning occupational exposure to TBBPA were also presented. Med Pr 2017;68(1):121-134.