Background: Bisphenol A (BPA) is a chemical with widespread human exposure suspected of causing low-dose effects. Thus, a need for developing alternatives to BPA exists. Structural analogues of BPA ...have already been detected in foods and humans. Due to the structural analogy of the alternatives, there is a risk of effects similar to BPA.
Objectives: The aim was to elucidate and compare the hazards of bisphenol B (BPB), bisphenol E (BPE), bisphenol F (BPF), bisphenol S (BPS) and 4-cumylphenol (HPP) to BPA.
Methods: In vitro studies on steroidogenesis, receptor activity, and biomarkers of effect, as well as Quantitative Structure-Activity Relationship (QSAR) modeling.
Results: All test compounds caused the same qualitative effects on estrogen receptor and androgen receptor activities, and most of the alternatives exhibited potencies within the same range as BPA. Hormone profiles for the compounds indicated a specific mechanism of action on steroidogenesis which generally lead to decreased androgen, and increased estrogen and progestagen levels. Differential effects on corticosteroid synthesis were observed suggesting a compound-specific mechanism. Overall, BPS was less estrogenic and antiandrogenic than BPA, but BPS showed the largest efficacy on 17α-hydroxyprogesterone (17α-OH progesterone). Finally, there were indications of DNA damage, carcinogenicity, oxidative stress, effects on metabolism, and skin sensitization of one or more of the test compounds.
Conclusions: Interference with the endocrine system was the predominant effect of the test compounds. A substitution of BPA with these structural analogues should be carried out with caution.
This research developed an ultrasound-assisted membrane extraction coupled with liquid chromatography-tandem mass spectrometry method for the determination of nineteen bisphenols and their ...derivatives in infant and toddler ready-to-feed meals. The calibration curves for all analytes were linear in the tested range, and the limit of detection and limit of quantitation were in the range 0.27–0.79 ng/g and 0.80–2.4 ng/g, respectively. The recovery values were in the range of 76–138%. This method was successfully applied to determine the content of bisphenols in 56 real samples of ready-to-eat meals for infants and toddlers. All of the analytes were quantified in at least one sample in the range of 1.0–371.9 ng/g. Mean exposures to bisphenols were estimated to be 9.01–769.49 ng/kg bw/day for both female and male babies. The health risk assessment revealed hazard quotient < 1, indicating that consumption of ready-to-eat meals is unlikely to pose any health risks to babies, even at the highest concentrations found in this study.
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•Bisphenols and their derivatives present in infant and toddler food.•Ultrasound-assisted membrane extraction of ready-to-eat meals samples.•Estimated intake and risk assessment of bisphenols and their derivatives.•Quantitation of bisphenols and diglycidyl ether derivatives in food samples.
Disruption of non-differentiated endometrial stromal cells could have noxious consequences in female reproduction, impairing endometrial remodelling and implantation. Following the classification of ...bisphenol A (BPA) as an endocrine disrupting chemical, it started to be gradually withdrawn from the market, being substituted by structural analogues, whose effects in human health are not fully understood. This work used a telomerase-immortalized human endometrial stromal cell line (St-T1b) to study the effects of BPA and its three most commercialized structural analogues (ranked: bisphenols S, F and AF) on endometrial stromal cells to understand their effects on female reproductive function. Bisphenols showed dissimilar effects. All four compounds generated endoplasmic reticulum (ER) stress. In addition, bisphenols A, F and AF induced apoptosis through different mechanisms, with bisphenol AF causing cell cycle arrest at G2/M phase. Bisphenol AF decreased mitochondrial transmembrane potential and bisphenols A, F and AF produced oxidative stress.
•Bisphenols A, F and AF induce apoptosis in endometrial stromal cells.•Bisphenols A, F, S and AF induce ER-stress in endometrial stromal cells.•Bisphenols AF and S were, respectively, the most and least toxic compounds.
Chemicals showing structural or functional similarity to bisphenol A (BPA), commonly called BPA analogues, have recently drawn scientific attention due to their common industrial and commercial ...application as a substitute for BPA. In the European Union, the use of BPA has been severely restricted by law due to its endocrine disrupting properties. Unfortunately, it seems that all BPA analogues show comparable biological activity, including hormonal disruption, toxicity and genotoxicity. Until now, the knowledge about human exposure to BPA analogues is scarce, mainly due to the lack of the data concerning their occurrence in human derived biological samples. This study presents the development of an analytical method for determination of trace levels of eleven BPA analogues in human blood serum samples. The method involves fast and simple liquid-liquid extraction, using low sample and solvent volumes. Chromatographic separation of analytes was optimized using one-factor-at-a-time approach (mobile phase composition, gradient shape, chromatographic column selection, separation temperature, etc.).
The method allows for effective separation of the analytes, even in the case of configurational isomers (bisphenol M and bisphenol P). The calibration curves for all analytes were linear in the range tested. The limits of detection and quantitation were in the range of 0.0079÷0.039ng/mL and 0.024÷0.12ng/mL respectively. Compound-dependent recovery values were in the rage of 88÷138%. Matrix effects were mitigated with the help of matrix-matched calibration curves prepared for every batch of samples. Results obtained after the analysis of 245 real human blood serum samples indicate that human beings are exposed to different BPA analogues, that are present in the environment and in common, daily use products.
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•Chromatographic separation of bisphenol A and 10 bisphenol A analogues•Liquid-liquid extraction of bisphenol A analogues from 245 human serum samples•Matrix-matched calibration to compensate for matrix effects
Interactions between endocrine-disruptor chemicals (EDCs) and androgen receptor (AR) have adverse effects on the endocrine system, leading to human reproductive dysfunction. Bisphenol A (BPA) is an ...EDC that can damage both the environment and human health. Although numerous BPA analogues have been produced as substitutes for BPA, few studies have evaluated their endocrine-disrupting abilities. We assessed the (anti)-androgenic activities of BPA and its analogues using a yeast-based reporter assay. The BPA analogues tested were bisphenol S (BPS), 4-phenylphenol (4PP), 4,4′-(9-fluorenyliden)-diphenol (BPFL), tetramethyl bisphenol F (TMBPF), and tetramethyl bisphenol A (TMBPA). We also conducted molecular docking and dynamics simulations to assess the interactions of BPA and its analogues with the ligand-binding domain of human AR (AR-LBD). Neither BPA nor its analogues had androgenic activity; however, all except BPFL exerted robust anti-androgenic effects. Consistent with the in vitro results, anti-androgenic analogues of BPA formed hydrogen bonding patterns with key residues that differed from the patterns of endogenous hormones, indicating that the analogues display in inappropriate orientations when interacting with the binding pocket of AR-LBD. Our findings indicate that BPA and its analogues disrupt androgen signaling by interacting with the AR-LBD. Overall, BPA and its analogues display endocrine-disrupting activity, which is mediated by AR.
•A in vitro-in silico method assessed androgenic activity of BPA analogues on human AR.•Neither BPA nor its analogues had androgenic effects.•BPA, BPS, 4PP, TMBPF, and TMBPA showed strong anti-androgenic effects.•Compared with androgens, anti-androgens bound differently to the LBP of AR.•BPA and its analogues have endocrine-disrupting activity, which is mediated by human AR.
Bisphenol S derivatives (BDs) are being widely used as novel substitutes for BPA and BPA analogues (BPAs), causing pollution in various environmental compartments. However, the occurrence and fate of ...BDs in coastal waters are currently unknown. To broaden the lens on bisphenols in coastal waters, this study measured a broad suite of 23 bisphenols, including 12 BDs along with BPA and 10 BPAs, in water, suspended particulate matter (SPM), and sediment from eight major outlets of the Pearl River Delta, China (PRD). In addition to BPA and BPAs, all the 12 BDs were detected in the collected samples. The total concentration of 12 BDs ranged from 1.2 to 25 ng/L (median of 4.3 ng/L) in water samples, 0.80–13 ng/g dw (median of 3.0 ng/g dw) in SPM samples and 0.48–3.7 ng/g dw (median of 0.64 ng/g dw) in sediment samples. For most individual BDs, they had comparable concentrations to individual BPAs. In addition, logKd values of the frequently detected bisphenols, including BPA, BPS, BPF, 4-((4-Isopropoxyphenyl)sulfonyl)phenol (BPSIP), 2,4-bis(phenylsulfonyl)phenol (DBSP), and other 9 bisphenols, were significantly correlated with their logKow values (R2 = 0.38, p < 0.05), indicating that the partitioning of bisphenols between the aqueous and SPM phases were strongly influenced by hydrophobic interaction. Based on bisphenols’ concentrations in water from the eight outlets of PRD, the estimated input fluxes of novel BDs (1900 kg/y) were found to be even higher than that of BPAs (550 kg/y). This indicates that the riverine input of BDs into the coastal environment is gradually increasing, which should be taken seriously in the future.
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•First discovery of multiple bisphenol S derivatives (BDs) in coastal environment.•Estimate of field–derived partitioning coefficients of BDs between water and SPM.•Partitioning behavior of multiple bisphenols was associated with hydrophobic effects.•BDs had higher riverine input fluxes than did bisphenol A analogues.
Due to its endocrine-disrupting properties, bisphenol A (BPA) is being phased out from plastics, thermal paper and epoxy resins, and its replacements are being introduced into the market. Bisphenols ...are released into the environment, where they can undergo halogenation. Unlike BPA, the endocrine-disrupting potential of BPA analogues and their halogenated transformation products has not been extensively studied. The aim of this study was to evaluate the endocrine-disrupting potential of 18 BPA analogues and their halogenated derivatives by calculating affinities for 14 human nuclear receptors utilizing the Endocrine Disruptome and VirtualToxLab™ in silico tools.
Our simulations identified AR, ERs, and GR as the most favorable targets of bisphenols and their derivatives. Several BPA analogues displayed a higher predicted potential for endocrine disruption than BPA. Our models highlighted BPZ and BPPH as the most hazardous in terms of predicted endocrine activities. Halogenation, in general, was predicted to increase the binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ. Notably, mono- or 2,2′-di-halogenated bisphenols exhibited the highest potential for endocrine disruption. In vitro corroboration of the obtained results should be the next milestone in evaluating the safety of BPA substitutes and their halogenated transformation products.
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•Endocrine-disrupting potential of BPA, BPA analogues, and their halogenated derivatives was investigated in silico.•BPPH, BPTMC and BPZ were identified as the most potent endocrine disruptors.•Halogenation increases predicted binding affinity of bisphenols for AR, ERβ, MR, GR, PPARγ, and TRβ•Mono- or 2,2′-dihalogenated bisphenols exhibited the highest predicted endocrine disrupting potential.
BPA is used in a wide range of consumer products with very concern toxicological properties. The European Union has restricted its use to protect human health. Industry has substituted BPA by BPA ...analogues. However, there is a lack of knowledge about their impacts. In this work, BPA and 5 BPA analogues (BPS, BPAP, BPAF, BPFL and BPC) have been studied in classical SH-SY5Y and the alternative 3D in vitro models after 24 and 96 h of exposure. Cell viability, percentage of ROS, cell cycle phases as well as the morphology of the spheroids were measured. The 2D model was more sensitive than the 3D models with differences in cell viability higher than 60% after 24 h of exposure, and different mechanisms of ROS production. After chronic exposure, both models were more affected in comparison to the 24 h exposure. After a recovery time (96 h), the spheroids exposed to 2.5–40 µM were able to recover cell viability and the morphology. Among the BPs tested, BPFL>BPAF>BPAP and >BPC revealed higher toxicological effects, while BPS was the only one with lower effects than BPA. To conclude, the SH-SY5Y 3D model is a suitable candidate to perform more reliable in vitro neurotoxicity tests.
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•Cytotoxicity of BPA analogues were assessed in the SH-SY5Y neuroblastoma cell line.•The sensitivity of SH-SY5Y 2D and 3D in vitro models was studied under BPs exposure.•BPFL>BPAF>BPAP>BPC had greater effects on both in vitro models than BPA and BPS.•2D in vitro models demonstrated higher sensitivity than 3D models at 24 and 96 h.•Under chronic exposure both in vitro models demonstrated more toxic consequences.
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•Different BPP exposure concentrations and different exposure durations altered the gut microbiota diversity and structural composition.•M (30 µg/kg body weight (BW)/day) and H ...(3000 µg/kg BW/day) groups exposed to BPP displayed an intestine inflammatory response.•M and H groups exposed to BPP experienced disruption of the intestinal barrier.•M and H groups exposed to BPP experienced bacterial translocation and endotoxemia.•An antibiotic combination alleviated intestinal inflammation and barrier disruption due to gut microbiota dysbiosis.
Despite being one of the most world's widely used and mass-produced compounds, bisphenol A (BPA) has a wide range of toxic effects. Bisphenol P (BPP), an alternative to BPA, has been detected in many foods. The effects of BPP dietary exposure on gut microbiota and the intestinal barrier were unclear. We designed three batches of animal experiments: The first studied mice were exposed to BPP (30 µg/kg BW/day) for nine weeks and found that they gained weight and developed dysbiosis of the gut microbiota. The second, using typical human exposure levels (L, 0.3 µg/kg BW/day BPP) and higher concentrations (M, 30 µg/kg BW/day BPP; H, 3000 µg/kg BW/day BPP), caused gut microbiota dysbiosis in mice, activated the Lipopolysaccharide (LPS) /TLR4/NF-κB signaling pathway, triggered an inflammatory response, increased intestinal permeability, and promoted bacterial translocation leading to intestinal barrier disruption. The third treatment used a combination of antibiotics and alleviated intestinal inflammation and injury. This study demonstrated the mechanism of injury and concentration effects of intestinal damage caused by BPP exposure, providing reference data for BPP use and control and yielding new insights for human disease prevention.
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•Cyto-/genotoxic effects of BPA and its analogues were assessed in in vitro 3D HepG2 cell model.•BPFL and BPC proved to be the most cytotoxic analogues after short (24-h) and ...prolonged (96-h) exposure.•BPA, BPAP, and BPAF induced DNA double-strand breaks.•BPAF and BPC increased the percentage of p-H3-positive cells.•All BPs induced DNA single-strand breaks, with BPAP being the most and BPA and BPC the least effective.
Bisphenol A (BPA) is one of the most widely used and versatile chemical compounds in polymer additives and epoxy resins for manufacturing a range of products for human applications. It is known as endocrine disruptor, however, there is growing evidence that it is genotoxic. Because of its adverse effects, the European Union has restricted its use to protect human health and the environment. As a result, the industry has begun developing BPA analogues, but there are not yet sufficient toxicity data to claim that they are safe. We investigated the adverse toxic effects of BPA and its analogues (BPS, BPAP, BPAF, BPFL, and BPC) with emphasis on their cytotoxic and genotoxic activities after short (24-h) and prolonged (96-h) exposure in in vitro hepatic three-dimensional cell model developed from HepG2 cells. The results showed that BPFL and BPC (formed by an additional ring system) were the most cytotoxic analogues that affected cell viability, spheroid surface area and morphology, cell proliferation, and apoptotic cell death. BPA, BPAP, and BPAF induced DNA double-strand break formation (γH2AX assay), whereas BPAF and BPC increased the percentage of p-H3-positive cells, indicating their aneugenic activity. All BPs induced DNA single-strand break formation (comet assay), with BPAP (≥0.1 μM) being the most effective and BPA and BPC the least effective (≥1 μM) under conditions applied. The results indicate that not all of the analogues studied are safer alternatives to BPA and thus more in-depth research is urgently needed to adequately evaluate the risks of BPA analogues and assess their safety for humans.
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