RESUMEN

Benzophenones (BPs) are widely used as photoinitiators (PIs) or printing inks in food packaging, which may migrate into foods. However, the toxicity information of some BP analogues, such as 4,4'-bis(diethylamino)-benzophenone (DEAB), 4-phenylbenzophenone (4-PBP), 4 (hydroxymethyl)benzophenone (4-HMBP), those are used as PIs is lacking. Developmental toxicity is a health concern associated with PIs exposure. Recently, alternative non-in vivo methods have been proposed to evaluate the concerned chemicals or better understand the modes of action of certain toxicological endpoints. In this study, using in silico methods, we predicted that BP, DEAB, 4-PBP and 4-HMBP might exhibit developmental toxicity. However, we found that only DEAB is strong embryotoxic and disturbs the early differentiation of mouse embryonic stem cells into three germ layers and cardiomyocytes. DEAB treatment also prevented cardiomyocyte differentiation in human induced pluripotent stem cells (hiPSCs) on day 10. However, BP, 4-PBP and 4-HMBP had no similar effects on cardiomyocyte differentiation on day 10. Transcriptomic analysis revealed that treatment with DEAB significantly decreased the mRNA levels of differentiation-related transcription factors SOX17 and FOXA1, in hiPSCs on day 4. Furthermore, DEAB treatment caused tail malformations and yolk sac edema in zebrafish embryos. To conclude, DEAB may be embryotoxic because it disturbs the early differentiation of stem cells. Further studies are warranted to better understand the health effects of DEAB exposure.

Asunto(s)

Benzofenonas , Diferenciación Celular , Embrión no Mamífero , Células Madre Pluripotentes Inducidas , Pez Cebra , Animales , Pez Cebra/embriología , Pez Cebra/anomalías , Benzofenonas/toxicidad , Embrión no Mamífero/efectos de los fármacos , Embrión no Mamífero/anomalías , Ratones , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Diferenciación Celular/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Células Madre Embrionarias de Ratones/efectos de los fármacos , Células Madre Embrionarias de Ratones/metabolismo , Teratógenos/toxicidad

RESUMEN

Estrogen receptor (ER) and androgen receptor (AR) transactivation assays for the benzophenone compounds (BPs) were performed using hERα-HeLa-9903 cells for ER and MMTV/22Rv1_GR-KO cells for AR. Results showed that some BPs, such as BP-1, BP-2, 4OH-BP, 4DHB, and 4-MBP, showed agonistic activity on ER with a higher RPCmax than 1 nM 17-ß estradiol. The other BPs (BP, BP-3, BP-6, BP-7, and BP-8) showed low RPCmax in accordance with the OECD Test guideline (TG) 455 criteria, with BP-4 as the only ER-negative. However, the potency of the BPs was at least 1000 times less than the reference chemical, 17-ß-estradiol. None of the BPs exhibited agonistic activity on AR except BP-2 which showed a small increase in activity. For further evaluation of the estrogenic effect of BPs based on the integrated approaches to testing and assessment (IATA) approach, existing data on ER binding, steroidogenesis, MCF-7 cell proliferation, and in vivo uterotrophic assays were collected and evaluated. There seemed to be a close association between the in vitro data on BPs, especially ER transcriptional activity, and the in vivo results of increased uterine weight. This case study implied that integrated approaches using in vitro data can be a useful tool for the prediction of in vivo data for estrogenic effects, without the need for additional animal toxicity tests.

Asunto(s)

Benzofenonas , Receptores Androgénicos , Receptores de Estrógenos , Activación Transcripcional , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Humanos , Benzofenonas/toxicidad , Benzofenonas/farmacología , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/genética , Animales , Activación Transcripcional/efectos de los fármacos , Femenino , Estrógenos/toxicidad , Disruptores Endocrinos/toxicidad , Células MCF-7 , Útero/efectos de los fármacos , Útero/metabolismo

RESUMEN

Conventional wastewater treatment methods cannot completely remove the ultraviolet (UV) filters or dissolved organic matter. The transformation characteristics of these substances during chlorination disinfection and the varying species-specific toxicities of their combinations remain unclear. Here, Daphnia magna and zebrafish were exposed to benzophenone-3 (BP-3) and humic acid (HA) before and after chlorination disinfection. The results from chemical indicators showed that chlorination treatment decreased UV254 values and changed the intensity of parallel factors in three-dimensional fluorescence. Based on chemical analysis, the chlorine concentration and chlorination time for the toxicity experiments were set at 5 mg/L and 6 h, respectively. Exposure to HA and BP-3 before and after chlorination decreased the heart rate (by 1.37-28.12 %) in both species. However, species-specific responses, including survival rate, swimming distance, and expression of genes related to neurodevelopment, growth, and oxidative stress, were induced by chlorination. Chlorination reduced the impact of HA exposure but worsened the effects of HA and BP-3 co-exposure on D. magna. However, in zebrafish, the toxic effects intensified in most of the exposure groups after chlorination. Correlation analysis showed that the parallel factors of three-dimensional fluorescence were correlated with toxic effects on zebrafish, whereas UV254 was more significantly correlated with toxic effects on D. magna. This study provides insights into the combined toxicity of UV filters and dissolved organic matter in different aquatic organisms during chlorination, which is useful for risk control and optimization of the chlorination process.

Asunto(s)

Benzofenonas , Desinfección , Halogenación , Sustancias Húmicas , Contaminantes Químicos del Agua , Animales , Benzofenonas/toxicidad , Cloro/toxicidad , Cloro/química , Daphnia magna/efectos de los fármacos , Daphnia magna/fisiología , Desinfección/métodos , Frecuencia Cardíaca/efectos de los fármacos , Sustancias Húmicas/toxicidad , Rayos Ultravioleta , Contaminantes Químicos del Agua/toxicidad , Purificación del Agua/métodos , Pez Cebra/fisiología

RESUMEN

Benzophenone-3 (BP-3), utilized as a UV filter in cosmetic products, is an emerging contaminant that constitutes a threat to natural resources and environmental health. This study investigated the assimilation of the UV filter BP-3 in Crassostrea gigas oysters collected in Florianópolis, Santa Catarina, Brazil. Lyophilized oyster tissue extracts were prepared using the QuEChERS method, and LC-MS/MS was employed to determine the BP-3 concentration in the samples. The method was applied to specimens intentionally exposed to two concentrations of the contaminant, for different periods of exposure (1 and 7 days). Samples from treatment 1 (T1) were exposed to a concentration of 1 µg L-1 of the BP-3 standard, and samples from treatment 2 (T2) were exposed to a concentration of 100 µg L-1 of the BP-3 standard. The results revealed rapid absorption of BP-3, with an increase of 126% for lower concentrations, reaching 1.13 µg of BP-3 per gram of oyster tissue, and 17% for higher concentrations, reaching 34.6 µg of BP-3 per gram of oyster tissue after 7 days. The presence of BP-3 even in samples not directly exposed to the contaminant indicates its widespread environmental distribution. The rapid bioaccumulation suggests the need to consider seasonal variations, such as increased tourism in the summer. The validated analytical method demonstrated efficacy in quantifying BP-3, providing an integrated approach for long-term monitoring of pollution levels and their dynamic variations over time. In addition, variation in BP-3 levels in the samples may be related to transport patterns influenced by tides and discharges from septic system, highlighting the need to improve wastewater treatment. These findings underscore the necessity for continuous biomonitoring and effective environmental management to safeguard the health of marine ecosystems and humans.

Asunto(s)

Benzofenonas , Crassostrea , Protectores Solares , Contaminantes Químicos del Agua , Animales , Benzofenonas/análisis , Benzofenonas/metabolismo , Benzofenonas/toxicidad , Brasil , Crassostrea/metabolismo , Crassostrea/efectos de los fármacos , Monitoreo del Ambiente/métodos , Cromatografía Líquida con Espectrometría de Masas , Protectores Solares/análisis , Protectores Solares/metabolismo , Protectores Solares/toxicidad , Espectrometría de Masas en Tándem , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/metabolismo , Contaminantes Químicos del Agua/toxicidad

RESUMEN

Benzophenone-2 (2,2', 4,4'- Tetrahydroxybenzophenone; BP-2) is widely used as a sunscreen in Personal and Care Products (PCPs) for protection against ultraviolet (UV) radiation. The effects of BP-2 on random-sex adult zebrafish (Danio rerio) cytochrome P450 (CYP450) were studied. The main goal was to investigate the detoxification mechanisms underlying the adverse consequences of exposure to xenobiotic chemicals such as BP-2. Total protein content, CYP450 content, and erythromycin N-demethylase (ERND) activity were evaluated as indicators of protein CYP3A expression. Five sets of pooled random-sex adult zebrafish were exposed to 0.0, 0.1, 5.0, and 10.0 mg/L of BP-2 to evaluate their acute and chronic toxicity (4 and 15 days, respectively). ERND activity was significantly increased in the chronic toxicity group compared to that in the control group, whereas CYP450 remained unchanged. The results suggest a sufficiently fast catalytic process that does not alter the total CYP450 content. It implies a mediation of CYP450 3A induction by BP-2 and the pregnane X receptor ligand-binding domain (PXR LBD) interaction. Ligand-protein interactions were confirmed via in silico docking with AutoDock Vina. Further computational studies indicate BP-2 potential binding affinity for the Estrogen receptor alpha ligand binding domain (ERα LBD). These results suggest that CYPs effects may result in significant toxicity in the zebrafish. Our study highlights the importance of studying biomarkers in aquatic organisms to assess xenobiotic exposure and the potential toxicity of UV filters to humans.

Asunto(s)

Benzofenonas , Sistema Enzimático del Citocromo P-450 , Protectores Solares , Contaminantes Químicos del Agua , Pez Cebra , Animales , Benzofenonas/toxicidad , Contaminantes Químicos del Agua/toxicidad , Protectores Solares/toxicidad , Sistema Enzimático del Citocromo P-450/metabolismo , Simulación del Acoplamiento Molecular , Masculino , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Femenino , Rayos Ultravioleta

RESUMEN

The increasing use of UV filters, such as benzophenone-3 (BP-3) and titanium dioxide nanoparticles (TiO2 NPs), has raised concerns regarding their ecotoxicological effects on the aquatic environment. The aim of the present study was to examine the embryo-larval toxicity attributed to BP-3 or TiO2 NPs, either alone or in a mixture, utilizing zebrafish (Danio rerio) as a model after exposure to environmentally relevant concentrations of these compounds. Zebrafish embryos were exposed to BP-3 (10, 100, or 1000 ng/L) or TiO2 NPs (1000 ng/L) alone or in a mixture (BP-3 10, 100, or 1000 ng/L plus 1000 ng/L of TiO2 NPs) under static conditions for 144 hr. After exposure, BP-3 levels were determined by high-performance liquid chromatography (HPLC). BP-3 levels increased in the presence of TiO2 NPs, indicating that the BP-3 degradation decreased in the presence of the NPs. In addition, in the presence of zebrafish, BP-3 levels in water decreased, indicating that zebrafish embryos and larvae might absorb BP-3. Data demonstrated that, in general, environmentally relevant concentrations of BP-3 and TiO2 NPs, either alone or in a mixture, did not significantly induce changes in heart and spontaneous contractions frequencies, levels of reactive oxygen species (ROS), morphological and morphometric parameters as well as mortality rates during 144 hr exposure. However, the groups exposed to TiO2 NPs alone and in a mixture with BP-3 at 10 ng/L exhibited an earlier significant hatching rate than the controls. Altogether, the data indicates that a potential ecotoxicological impact on the aquatic environment exists.

Asunto(s)

Benzofenonas , Embrión no Mamífero , Protectores Solares , Titanio , Contaminantes Químicos del Agua , Pez Cebra , Animales , Titanio/toxicidad , Titanio/química , Benzofenonas/toxicidad , Protectores Solares/toxicidad , Protectores Solares/química , Embrión no Mamífero/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Nanopartículas/toxicidad , Nanopartículas del Metal/toxicidad , Ecotoxicología , Larva/efectos de los fármacos

RESUMEN

Oxybenzone (OBZ; benzophenone-3, CAS# 131-57-7), as a new pollutant and ultraviolet absorbent, shows a significant threat to the survival of phytoplankton. This study aims to explore the acute toxic effects of OBZ on the growth of the microalga Selenastrum capricornutum, as well as the mechanisms for its damage to the primary metabolic pathways of photosynthesis and respiration. The results demonstrated that the concentrations for 50 % of maximal effect (EC50) of OBZ for S. capricornutum were 9.07 mg L-1 and 8.54 mg L-1 at 72 h and 96 h, respectively. A dosage of 4.56 mg L-1 OBZ significantly lowered the photosynthetic oxygen evolution rate of S. capricornutum in both light and dark conditions for a duration of 2 h, while it had no effect on the respiratory oxygen consumption rate under darkness. OBZ caused a significant decline in the efficiency of photosynthetic electron transport due to its damage to photosystem II (PSII), thereby decreasing the photosynthetic oxygen evolution rate. Over-accumulated H2O2 was produced under light due to the damage caused by OBZ to the donor and acceptor sides of PSII, resulting in increased peroxidation of cytomembranes and inhibition of algal respiration. OBZ's damage to photosynthesis and respiration will hinder the conversion and reuse of energy in algal cells, which is an important reason that OBZ has toxic effects on S. capricornutum. The present study indicated that OBZ has an acute toxic effect on the microalga S. capricornutum. In the two most important primary metabolic pathways in algae, photosynthesis is more sensitive to the toxicity of OBZ than respiration, especially in the dark.

Asunto(s)

Benzofenonas , Microalgas , Fotosíntesis , Protectores Solares , Fotosíntesis/efectos de los fármacos , Benzofenonas/toxicidad , Microalgas/efectos de los fármacos , Protectores Solares/toxicidad , Contaminantes Químicos del Agua/toxicidad , Peróxido de Hidrógeno/metabolismo , Complejo de Proteína del Fotosistema II/metabolismo , Complejo de Proteína del Fotosistema II/efectos de los fármacos , Rayos Ultravioleta , Transporte de Electrón/efectos de los fármacos

RESUMEN

The aim of this study is to investigate the adverse effects of benzophenones (BPs) on the intestinal tract of mice and the potential mechanism. F1-generation ICR mice were exposed to BPs (benzophenone-1, benzophenone-2, and benzophenone-3) by breastfeeding from birth until weaning, and by drinking water after weaning until maturity. The offspring mice were executed on postnatal day 56, then their distal colons were sampled. AB-PAS staining, HE staining, immunofluorescence, Transmission Electron Microscope, immunohistochemistry, Western Blot and RT-qPCR were used to study the effects of BPs exposure on the colonic tissues of offspring mice. The results showed that colonic microvilli appeared significantly deficient in the high-dose group, and the expression of tight junction markers Zo-1 and Occludin was significantly down-regulated and the number of goblet cells and secretions were reduced in all dose groups, and the expression of secretory cell markers MUC2 and KI67 were decreased, as well as the expression of intestinal stem cell markers Lgr5 and Bmi1, suggesting that BPs exposure caused disruption of intestinal barrier and imbalance in the composition of the intestinal stem cell pool. Besides, the expression of cellular inflammatory factors such as macrophage marker F4/80 and tumor necrosis factor TNF-α was elevated in the colonic tissues of all dose groups, and the inflammatory infiltration was observed, which means the exposure of BPs caused inflammatory effects in the intestinal tract of F1-generation mice. In addition, the contents of Notch/Wnt signaling pathway-related genes, such as Dll-4, Notch1, Hes1, Ctnnb1and Sfrp2 were significantly decreased in each high-dose group (P < 0.05), suggesting that BPs may inhibit the regulation of Notch/Wnt signaling pathway. In conclusion, exposure to BPs was able to imbalance colonic homeostasis, disrupt the intestinal barrier, and trigger inflammation in the offspring mice, which might be realized through interfering with the Notch/Wnt signaling pathway.

Asunto(s)

Benzofenonas , Homeostasis , Inflamación , Ratones Endogámicos ICR , Animales , Ratones , Homeostasis/efectos de los fármacos , Benzofenonas/toxicidad , Inflamación/inducido químicamente , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efectos de los fármacos , Femenino , Masculino , Intestinos/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos

RESUMEN

Immune homeostasis is key to guarantee that the immune system can elicit effector functions against pathogens and at the same time raise tolerance towards other antigens. A disturbance of this delicate balance may underlie or at least trigger pathologies. Endocrine disrupting chemicals (EDCs) are increasingly recognized as risk factors for immune dysregulation. However, the immunotoxic potential of specific EDCs and their mixtures is still poorly understood. Thus, we aimed to investigate the effect of bisphenol A (BPA) and benzophenone-3 (BP-3), alone and in combination, on in vitro differentiation of T helper (TH)17 cells and regulatory T (Treg) cells. Naïve T cells were isolated from mouse lymphoid tissues and differentiated into the respective TH population in the presence of 0.001-10 µM BP-3 and/or 0.01-100 µM BPA. Cell viability, proliferation and the expression of TH lineage specific transcription factors and cytokines was measured by flow cytometry and CBA/ELISA. Moreover, the transcription of hormone receptors as direct targets of EDCs was quantified by RT-PCR. We found that the highest BPA concentration adversely affected TH cell viability and proliferation. Moreover, the general differentiation potential of both TH populations was not altered in the presence of both EDCs. However, EDC exposure modulated the emergence of TH17 and Treg cell intermediate states. While BPA and BP-3 promoted the development of TH1-like TH17 cells under TH17-differentiating conditions, TH2-like Treg cells occurred under Treg polarization. Interestingly, differential effects could be observed in mixtures of the two tested compounds compared with the individual compounds. Notably, estrogen receptor ß expression was decreased under TH17-differentiating conditions in the presence of BPA and BP-3 as mixture. In conclusion, our study provides solid evidence for both, the immune disruptive potential and the existence of cumulative effects of real nature EDC mixtures on T cell in vitro differentiation.

Asunto(s)

Compuestos de Bencidrilo , Benzofenonas , Diferenciación Celular , Fenoles , Linfocitos T Reguladores , Células Th17 , Fenoles/toxicidad , Fenoles/farmacología , Animales , Compuestos de Bencidrilo/toxicidad , Benzofenonas/farmacología , Benzofenonas/toxicidad , Diferenciación Celular/efectos de los fármacos , Ratones , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Células Th17/efectos de los fármacos , Células Th17/citología , Células Th17/metabolismo , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Proliferación Celular/efectos de los fármacos , Disruptores Endocrinos/toxicidad , Disruptores Endocrinos/farmacología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/citología , Células Cultivadas

RESUMEN

Oxybenzone is an ultraviolet filter frequently used in Personal Care Products, plastics, furniture, etc. and is listed as an Emerging Contaminant. This report studied the acute toxicity of Oxybenzone to Lemna minor after exposure to graded concentrations of Oxybenzone for 7 days. IC50 for growth was found to be 8.53 mg L-1. The hormesis effect was reported at lower concentrations, while growth and pigments reduced from 2.5 to 12.5 mg L-1 in a concentration-related manner. The impact of Oxybenzone on protein and antioxidant enzymes- Catalase and Guaiacol Peroxidase revealed less stress up to 2.5 mg L-1 than control, increasing further from 5 to 10 mg L-1. Enzyme activity decreased over-time but always remained higher than control over a period of 7 days. Thus, our findings reveal that indiscriminate discharge of Oxybenzone could be potentially toxic to the aquatic primary producers at higher concentrations, causing an ecological imbalance in aquatic ecosystems.

Asunto(s)

Araceae , Benzofenonas , Catalasa , Peroxidasa , Contaminantes Químicos del Agua , Contaminantes Químicos del Agua/toxicidad , Benzofenonas/toxicidad , Catalasa/metabolismo , Araceae/efectos de los fármacos , Araceae/crecimiento & desarrollo , Peroxidasa/metabolismo , Pruebas de Toxicidad Aguda , Protectores Solares/toxicidad , Clorofila/metabolismo

RESUMEN

In this study, we analyzed the occurrence and distribution of 11 benzophenone-type ultraviolet filters (BPs) in 893 food samples spanning 7 food categories in Taiwan. We conducted a Monte Carlo simulation to determine the carcinogenic and noncarcinogenic risks of BPs. The results indicated that cornflakes had the highest mean level of BPs (103 ng/g), followed by bread (101 ng/g) and pastries (59 ng/g). BP was the most prevalent category, followed by 4-methylbenzophenone (4-MBP), 2-hydroxybenzophenone, and benzophenone-3. Estimation of the lifetime cancer risk (LTCR) of BP (average life expectancy of 80 years) placed them in the 50th and 97.5th percentiles [P50 (P97.5)] LTCR of 1.9 × 10-7 (5.7 × 10-6), indicating that BP in food poses a low renal hazard to the Taiwanese population. The noncarcinogenic risk of BPs was evaluated using a hazard quotient and combined margin of exposure (MOET), revealing a P50 (P97.5) hazard index of < 1 for BP, 4-MBP, and methyl-2-benzoylbenzoate. Although the P50 MOET values for all age groups were within the moderate range of concern, with a more conservative extreme (P2.5), the MOET values for the 0-3, 3-6, and 6-12 age groups fell below 100, indicating a high concern for renal degeneration and hyperplasia.

Asunto(s)

Benzofenonas , Contaminación de Alimentos , Benzofenonas/análisis , Benzofenonas/toxicidad , Taiwán , Humanos , Medición de Riesgo , Contaminación de Alimentos/análisis , Protectores Solares/análisis , Protectores Solares/toxicidad , Método de Montecarlo , Análisis de los Alimentos

RESUMEN

Benzophenone-3 (BP3) is a common ingredient in personal care products (PCPs) due to its well-established effectiveness in absorbing UV radiation. Sunscreen products are among the most widely used PCPs-containing BP3 applied to the skin, resulting in significant human exposure to BP3 primarily through a dermal application. In the present work, we have tested the action of three environmentally relevant concentrations of BP3 (2, 20 and 200 µg/L) on an in vitro model of implantation of murine blastocysts and on migration ability of the human trophoblast cell line Swan 71. We showed that BP3 caused a significant reduction of blastocyst expansion and a delayed hatching in a non-monotonic way. Besides, embryos displayed a delayed attachment in the three BP3 groups, resulting in a smaller implantation area on the 6th day of culture: BP3(2) (0.32 ± 0.07 mm2); BP3(20) (0.30 ± 0.08 mm2) and BP3(200) (0.25 ± 0.06 mm2) in comparison to the control (0.42 ± 0.07 mm2). We also found a reduced migration capacity of the human first-trimester trophoblast cell line Swan 71 in a scratch assay when exposed to BP3: the lowest dose displayed a higher uncovered area (UA) at 6h when compared to the control, whereas a higher UA of the wound was observed for the three BP3 concentrations at 18 and 24 h of exposure. The changes in UA provoked by BP3 restored to normal values in the presence of flutamide, an androgen receptor (AR) inhibitor. These results indicate that a direct impairment on early embryo implantation and a defective migration of extravillous trophoblast cells through the androgen receptor pathway can be postulated as mechanisms of BP3-action on early gestation with potential impact on fetal growth.

Asunto(s)

Benzofenonas , Movimiento Celular , Implantación del Embrión , Protectores Solares , Trofoblastos , Rayos Ultravioleta , Benzofenonas/toxicidad , Protectores Solares/toxicidad , Protectores Solares/farmacología , Trofoblastos/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones , Animales , Humanos , Implantación del Embrión/efectos de los fármacos , Blastocisto/efectos de los fármacos , Femenino , Línea Celular

RESUMEN

The aim of this study is to conduct a thorough evaluation of the association between Benzophenone-3 (BP-3) exposure and OA, offering critical insights into the underlying mechanisms involved. The National Health and Nutrition Examination Survey (NHANES) database was utilized to investigate the correlation between BP-3 and osteoarthritis. Proteomic sequencing from clinical sample and the PharmMapper online tool were employed to predict the biological target of BP-3. Cellular molecular assays and transfection studies were performed to verify the prediction from bioinformatics analyses. Through cross-sectional analysis of the NHANES database, we identified BP-3 as a risk factor for OA development. The results of proteomic sequencing showed that Secreted Protein Acidic and Rich in Cysteine (SPARC) was significantly elevated in the area of damage compared to the undamaged area. SPARC was also among the potential biological targets of BP-3 predicted by the online program. Through in vitro cell experiments, we further determined that the toxicological effects of BP-3 may be due to SPARC, which elevates intracellular GPX4 levels, activates the glutathione system, and promotes lipid peroxidation to mitigate ferroptosis. Inhibiting SPARC expression has been shown to reduce inflammation and ferroptosis in OA contexts. This research provides an expansive understanding of BP-3's influence on osteoarthritis development. We have identified SPARC as a potent target for combating chondrocyte ferroptosis in BP-3-associated osteoarthritis.

Asunto(s)

Benzofenonas , Ferroptosis , Osteoartritis , Osteonectina , Humanos , Benzofenonas/metabolismo , Benzofenonas/toxicidad , Biología Computacional , Estudios Transversales , Ferroptosis/efectos de los fármacos , Encuestas Nutricionales , Osteoartritis/inducido químicamente , Osteonectina/antagonistas & inhibidores , Osteonectina/genética , Osteonectina/metabolismo , Proteómica

RESUMEN

Previously, we found that the ultraviolet filter benzophenone-3 (BP3) causes fetal growth restriction in mice when is applied when implantation occurs (first week of gestation). However, whether BP3 can affect gestation and fertility after implantation period is unknown. We aimed to study the effects on reproductive physiology of the offspring caused by perinatal exposure to BP3. C57BL/6 pregnant mice were dermally exposed to 50 mg BP3/kg bw.day or olive oil (vehicle) from gestation day 9 (gd9) to postnatal day 21 (pnd1). We observed no differences in mother's weights, duration of gestation, number of pups per mother, onset of puberty or sex ratio. The weights of the pups exposed to benzophenone-3 were transiently lower than those of the control. Estrous cycle was not affected by perinatal exposure to BP3. Besides, we performed a fertility assessment by continuous breeding protocol: at 10 weeks of age, one F1 female and one F1 male mouse from each group was randomly chosen from each litter and housed together for a period of 6 months. We noticed a reduction in the number of deliveries per mother among dams exposed to BP3 during the perinatal period. To see if this decreased fertility could be associated to an early onset of oocytes depletion, we estimated the ovarian reserve of germ cells. We found reduced number of oocytes and primordial follicles in BP3. In conclusion, perinatal exposure to BP3 leads to a decline in the reproductive capacity of female mice in a continuous breeding protocol linked to oocyte depletion.

Asunto(s)

Benzofenonas , Ratones Endogámicos C57BL , Oocitos , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Benzofenonas/toxicidad , Benzofenonas/administración & dosificación , Embarazo , Masculino , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Oocitos/efectos de los fármacos , Ratones , Fertilidad/efectos de los fármacos , Protectores Solares/toxicidad , Exposición Materna/efectos adversos

RESUMEN

The wide application of benzophenones (BPs), such as benzophenone-3 (BP3), as an ingredient in sunscreens, cosmetics, coatings, and plastics, has led to their global contamination in aquatic environments. Using the marine diatom Chaetoceros neogracilis as a model, this study assessed the toxic effects and mechanisms of BP3 and its two major metabolites (BP8 and BP1). The results showed that BP3 exhibited higher toxicity on C. neogracilis than BP8 and BP1, with their 72-h median effective concentrations being 0.4, 0.8 and 4 mg/L, respectively. Photosynthesis efficiencies were significantly reduced after exposure to environmentally relevant concentrations of the three benzophenones, while cell viability, membrane integrity, membrane potential, and metabolic activities could be further impaired at their higher concentrations. Comparative transcriptomic analysis, followed by gene ontology and KEGG pathway enrichment analyses unraveled that all the three tested benzophenones disrupted photosynthesis and nitrogen metabolism of the diatom through alteration of similar pathways. The toxic effect of BP3 was also attributable to its unique inhibitory effects on eukaryotic ribosome biosynthesis and DNA replication. Taken together, our findings underscore that benzophenones may pose a significant threat to photosynthesis, oxygen production, primary productivity, carbon fixation, and the nitrogen cycle of diatom in coastal waters worldwide.

Asunto(s)

Cosméticos , Diatomeas , Diatomeas/metabolismo , Protectores Solares/toxicidad , Protectores Solares/metabolismo , Cosméticos/metabolismo , Benzofenonas/toxicidad , Benzofenonas/metabolismo

RESUMEN

Benzophenone-3 (BP-3) is a commonly used ultraviolet absorber that has the potential to accumulate in organisms, leading to toxicity. Benzophenone-8 (BP-8) is one of the major metabolites of BP-3. In this study, zebrafish were exposed to different concentrations of BP-3 and BP-8 (1 µg/L, 30 µg/L, and 300 µg/L) to investigate their accumulation and toxic effects in various tissues, including zebrafish brain, gut, and liver. The analysis focused on neurotoxicity, oxidative damage, inflammation, and gene expressions. The results showed that both BP-3 and BP-8 accumulated in the tissues, with the highest concentration observed in the gut, followed by the liver and brain. BP-8 exhibited a stronger ability to accumulate. In the brain, exposure to 1 µg/L of BP-3 and BP-8 promoted cortisol production, while higher exposures (30 µg/L and 300 µg/L) inhibited acetylcholinesterase activity and suppressed cortisol production. In the gut, both BP-3 and BP-8 exposures disrupted oxidative stress, inflammatory immunity, and apoptosis functions. In the liver, BP-3 and BP-8 affected hepatic metabolism, oxidative stress, apoptosis, and inflammatory immunity. Comparing gene expression in the brain, gut, and liver, it was found that BP-3 and BP-8 had a lower effect on gene expression in the brain, while the effect on the gut and liver was significantly higher. BP-8 generally had a higher effect than BP-3, which aligns with the observed accumulation pattern. These findings provide valuable insights for the risk assessment of BP-3 and BP-8 in the aquatic environment.

Asunto(s)

Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/metabolismo , Acetilcolinesterasa/metabolismo , Hidrocortisona , Contaminantes Químicos del Agua/toxicidad , Benzofenonas/toxicidad

RESUMEN

Pubertal mammary branching morphogenesis is a hormone-regulated process susceptible to exposure to chemicals with endocrine disruptive capacity, such as the UV-filter benzophenone-3 (BP3). Our aim was to assess whether intrauterine or in vitro exposure to BP3 modified the branching morphogenesis of the female mouse mammary gland. For this, pregnant mice were dermally exposed to BP3 (0.15 or 50 mg/kg/day) from gestation day (GD) 8.5 to GD18.5. Sesame oil treatment served as control. Changes of the mammary glands of the offspring were studied on postnatal day 45. Further, mammary organoids from untreated mice were cultured under branching induction conditions and exposed for 9 days to BP3 (1 × 10-6 M, 1 × 10-9 M, or 1 × 10-12 M with 0.01% ethanol as control) to evaluate the branching progression. Mice that were exposed to BP3 in utero showed decreased mRNA levels of progesterone receptor (PR) and WNT4. However, estradiol and progesterone serum levels, mammary histomorphology, proliferation, and protein expression of estrogen receptor alpha (ESR1) and PR were not significantly altered. Interestingly, direct exposure to BP3 in vitro also decreased the mRNA levels of PR, RANKL, and amphiregulin without affecting the branching progression. Most effects were found after exposure to 50 mg/kg/day or 1 × 10-6 M of BP3, both related to sunscreen application in humans. In conclusion, exposure to BP3 does not impair mammary branching morphogenesis in our models. However, BP3 affects PR transcriptional expression and its downstream mediators, suggesting that exposure to BP3 might affect other developmental stages of the mammary gland.

Asunto(s)

Benzofenonas , Estradiol , Embarazo , Humanos , Ratones , Femenino , Animales , Benzofenonas/toxicidad , Estradiol/metabolismo , Morfogénesis , ARN Mensajero/metabolismo , Glándulas Mamarias Animales

RESUMEN

Benzophenone-3 (BP-3, 2-hydroxy-4-methoxybenzophenone, oxybenzone) is one of the most widely used types of benzophenone organic sunscreen. However, this compound is a potentially harmful toxicant. The aim of this study was 2-fold to: (1) utilize a Hershberger bioassay in vivo in castrated male Sprague-Dawley rats to investigate the anti-androgenic activities of BP-3, and (2) use in vitro a methyl tetrazolium assay to compare the toxicity between Leydig cells (TM3 cells) and mouse fibroblast (NIH-3T3) cell lines. In the Hershberger assay, rats were divided into 6 groups (each of n = 7): a vehicle control, negative control, positive control, PB-3 low (40 mg/kg), BP-3 intermediate (200 mg/kg), and BP-3 high (1000 mg/kg)-dose. The weight of the ventral prostate was significantly decreased at BP-3 doses of 200 or 1,000 mg/kg/day. In addition, the levator anibulbocavernosus muscle weights were also significantly reduced at BP-3 doses of 40, 200, or 1,000 mg/kg/day. In the MTT assay, the viability of NIH-3T3 mouse fibroblast cells was within the normal range. However, the TM3 mouse testis Leydig cell viability was significantly lowered in a concentration-dependent manner. Therefore, data indicate that BP-3 might exert in vivo anti-androgenic and in vitro cytotoxic effects in cells associated with the male reproductive system compared to normal non-reproductive cells.Abbreviation: BP-3: benzophenone-3; CG: Cowper's gland; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; GP: glans penis; LABC: levator anibulbocavernosus muscle; MTT: methyl tetrazolium; NC: negative control; PC: positive control; SV: seminal vesicle; TP: testosterone propionate; VC: vehicle control; VP: ventral prostate.

Asunto(s)

Antineoplásicos , Orquiectomía , Ratones , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Antagonistas de Andrógenos/farmacología , Benzofenonas/toxicidad , Antineoplásicos/farmacología , Tamaño de los Órganos , Genitales Masculinos

RESUMEN

Melanoma, an aggressive and potentially fatal skin cancer, is constrained by immunosuppression, resistance, and high toxicity in its treatment. Consequently, there is an urgent need for innovative antineoplastic agents. Therefore, this study investigated the antimelanoma potential of guttiferone E (GE). In an allogeneic murine B16 melanoma model, GE was administered subcutaneously and intraperitoneally. Antitumor evaluation included tumor volume/weight measurements and histopathological and immunohistochemical analysis. Furthermore, the toxicity of the treatments was evaluated through body/organ weights, biochemical parameters, and genotoxicity. Subcutaneous administration of 20 mg/kg of GE resulted in a significant reduction in both tumor volume and weight, effectively suppressing melanoma cell proliferation as evidenced by a decrease in mitotic figures. The tumor growth inhibition rate was equivalent to 54%. This treatment upregulated cleaved caspase-3, indicating apoptosis induction. On the other hand, intraperitoneal administration of GE showed no antimelanoma effect. Remarkably, GE treatments exhibited no toxicity, evidenced by non-significant differences in body weight gain, as well as organ weight, biochemical parameters of nephrotoxicity and hepatotoxicity, and genotoxic damage. This study revealed, for the first time, the efficacy of subcutaneous administration of GE in reducing melanoma, in the absence of toxicity. Furthermore, it was observed that the apoptotic signaling pathway is involved in the antimelanoma property of GE. These findings offer valuable insights for further exploring GE's therapeutic applications in melanoma treatment.

Asunto(s)

Melanoma Experimental , Ratones Endogámicos C57BL , Animales , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Melanoma Experimental/metabolismo , Apoptosis/efectos de los fármacos , Ratones , Masculino , Antineoplásicos/toxicidad , Antineoplásicos/administración & dosificación , Benzofenonas/farmacología , Benzofenonas/administración & dosificación , Benzofenonas/toxicidad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Proliferación Celular/efectos de los fármacos , Carga Tumoral/efectos de los fármacos , Línea Celular Tumoral , Inyecciones Subcutáneas , Femenino

RESUMEN

Benzophenone derivatives such as benzophenone-2 (BP-2) belong to the group of endocrine disrupting compounds (EDCs). Increased exposure to EDCs is considered to be an important factor behind the decline of human fertility. The main aim of the present study was to determine the effect of BP-2 on testicular function specified by sperm analysis, the level of sex hormones and their receptors. Since BP-2 has been shown to activate the immune system, another aim of the research was to verify the hypothesis that the immune system may be contributing to the testis toxicity of this compound and for this purpose changes in macrophage and lymphocyte populations in the testes were determined. BP-2 at a dose of 100 mg/kg was administered dermally, twice daily at a dose of 100 mg/kg for 4-weeks. It was shown that BP-2 reduced the number and motility of sperm and increased the number of sperm showing morphological changes. By determining the concentration of sex hormones, a significant decrease in testosterone levels and an increase in the blood levels of 17ß-estradiol were demonstrated. Similar to the results obtained from the blood samples, testosterone levels in the testes were lowered, which could affect sperm parameters. The effect of BP-2 on lowering testosterone levels and the number of sperm cells may be due to immunoactivation in the testes, because it has been detected that this compound significantly decreased the number of the immunosuppressive resident testicular macrophages (TMs) (CD68-CD163+), but increased pro-inflammatory TMs with monocyte-like properties (CD68+CD163-).

Asunto(s)

Semen , Testículo , Ratas , Masculino , Humanos , Animales , Hormonas Esteroides Gonadales , Benzofenonas/toxicidad , Testosterona , Recuento de Espermatozoides