Concentrations, compositional profiles, and health risks of benzophenones among the Taiwanese population based on analysis of 23 daily consumed foods.

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.

Interference with SPARC inhibits Benzophenone-3 induced ferroptosis in osteoarthritis: Evidence from bioinformatics analyses and biological experimentation.

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.

Effects of benzophenone-3 and its metabolites on the marine diatom Chaetoceros neogracilis: Underlying mechanisms and environmental implications.

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.

Branching morphogenesis of the mouse mammary gland after exposure to benzophenone-3.

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.

Toxicity comparison of benzophenone-3 and its metabolite benzophenone-8 in different tissues of zebrafish.

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.

Evaluation of the anti-androgenic and cytotoxic effects of benzophenone-3 in male Sprague-Dawley rats.

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.

Benzophenone-2 exerts reproductive toxicity in male rats.

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-).

Comparison between endocrine activity assessed using ToxCast/Tox21 database and human plasma concentration of sunscreen active ingredients/UV filters.

Sunscreen products are composed of ultraviolet (UV) filters and formulated to reduce exposure to sunlight thereby lessening skin damage. Concerns have been raised regarding the toxicity and potential endocrine disrupting (ED) effects of UV filters. The ToxCast/Tox21 program, that is, CompTox, is a high-throughput in vitro screening database of chemicals that identify adverse outcome pathways, key events, and ED potential of chemicals. Using the ToxCast/Tox21 database, octisalate, homosalate, octocrylene, oxybenzone, octinoxate, and avobenzone, 6 commonly used organic UV filters, were found to have been evaluated. These UV filters showed low potency in these bioassays with most activity detected above the range of the cytotoxic burst. The pathways that were most affected were the cell cycle and the nuclear receptor pathways. Most activity was observed in liver and kidney-based bioassays. These organic filters and their metabolites showed relatively weak ED activity when tested in bioassays measuring estrogen receptor (ER), androgen receptor (AR), thyroid receptor, and steroidogenesis activity. Except for oxybenzone, all activity in the endocrine assays occurred at concentrations greater than the cytotoxic burst. Moreover, except for oxybenzone, plasma concentrations (Cmax) measured in humans were at least 100× lower than bioactive (AC50/ACC) concentrations that produced a response in ToxCast/Tox21 assays. These data are consistent with in vivo animal/human studies showing weak or negligible endocrine activity. In sum, when considered as part of a weight-of-evidence assessment and compared with measured plasma concentrations, the results show these organic UV filters have low intrinsic biological activity and risk of toxicity including endocrine disruption in humans.

Health risks posed by environmental benzophenone-type ultraviolet filters (BP-UVFs): An investigation into the binding of BP-UVFs to trypsin and their adverse effects.

Benzophenone-type ultraviolet filters (BP-UVFs) are ubiquitous in the environment, and people frequently ingest them via food chain and drinking water. However, there is no clear information about whether BP-UVFs are detrimental to human health. Herein, experiments using multi-spectroscopy revealed typical BP-UVFs, i.e., benzophenone (BP), 2-hydroxybenzophenone (2-OHBP), 4-hydroxybenzophenone (4-OHBP), 2,2'-dihydroxybenzophenone (2,2'-OHBP), 2,4-dihydroxybenzophenone (2,4-OHBP), 4,4'-dihydroxybenzophenone (4,4'-OHBP), 2,4,4'-trihydroxybenzophenone (2,4,4'-OHBP), 2,2',4,4'-tetraphydroxybenzophenone (2,2',4,4'-OHBP), 2-hydroxy-4-methoxybenzophenone (2-OH-4-MeOBP) and 2,2'-dihydroxy-4-methoxybenzophenone (2,2'-OH-4-MeOBP), could bind to the active site of trypsin with different binding constants (2.69 × 104-1.07 × 106 L/mol), cause structural abnormalities and inhibit the enzymatic activity in varying degrees, indicating that the BP-UVFs ingestion poses a risk to human health. In contrast to previous research, this study systematically analysed the binding mechanism using an innovative combination of molecular docking and advanced quantum chemistry calculations, including molecular dynamics simulations, energy calculations, etc. The results revealed that most amino acids that make up trypsin have a greater positive electrostatic surface potential (ESP). Therefore, the greater the area and distribution of negative ESP in a particular BP-UVFs, the more easily it will bind to trypsin. This provides new insight into the binding of pollutants to proteins. This study suggests a need for better monitoring and control of environmental BP-UVFs.

Toxicity assessment of binary mixtures of BP3 with 4-MBC (UV-filters), and BP3 with DEET (insect repellent) using the aquatic midge Chironomus riparius.

Personal care products have various organic ultraviolet filters (UV filters) in their composition to increase protection against ultraviolet radiation. Some of these products also contain insect repellents in their formulations. Consequently, these compounds reach freshwater ecosystems, exposing aquatic organisms to a cocktail of anthropogenic contaminants. In this study, the joint effects of two most frequently detected UV filters (Benzophenone - 3 (BP3) and Enzacamene (4-MBC)) and joint effects of BP3 combined with an insect repellent (N, N diethyl-3-methylbenzamide - DEET) were evaluated using life-history traits of the aquatic midge Chironomus riparius such as emergence rate, time to emergence and imagoes body weight. The results showed synergistic effects between BP3 and 4-MBC for C. riparius emergence rate. Regarding the effects of BP3 and DEET mixture, our analysis suggests synergism in the case of males but antagonism in the case of females' time to emergence. Our results imply that the effects of UV filters present in sediments within chemical mixtures are complex and that the evaluation of effects using different life-history traits can yield different patterns of responses. This study demonstrates the importance of assessing the combined effects of pollutants used/found concomitantly in aquatic systems for a more accurate risk assessment, as individual chemical testing can underestimate the toxicity of organic UV filters.

Size-dominated biotoxicity of microplastics laden with benzophenone-3 and ciprofloxacin: Enhanced integrated biomarker evaluation on mussels.

Microplastics (MPs) are emerging pollutants with diverse sizes in aquatic environments. This paper investigates the toxicity of micron- and nano-scale polystyrene (50 µm, 5 µm, 0.5 µm) loaded with 2-hydroxy-4-methoxy-benzophenone (BP-3) and ciprofloxacin (CIP) by eight biomarker responses in mussels, perna viridis. The mussels were exposed to MPs and chemicals for 7 days before 7 days of depuration. Eight biomarkers were measured to determine biotoxicity over time by using the weighted integrated biomarkers index evaluation (EIBR). Mussels exposed to MPs on a daily basis demonstrated a cumulative toxic effect. The toxicity of MPs for mussels was inversely related to the size at which they can be ingested. Then toxicity was reversed when exposure was halted. EIBR mold has shown a significant difference in the biotoxicity of each biological level under different exposure scenarios. In general, the mussel toxicity influenced by BP-3 and CIP exposure without an adsorbent was insignificant. MPs laden with them increased the toxicity of mussels. Under condition of lower concentration of ECs (Emerging contaminants), the presence of MPs as a component of a combined pollutant in water dominated the biotoxicity for mussels. The EIBR assessment further validated that the biotoxicity of mussels was size-dependent. Its application simplified the biomarkers' response index and enhanced the accuracy of evaluation by weighing on molecular, cellular and physiological level. Specifically, mussels were physiologically sensitive to nano-scale plastics, with nano-scale plastics causing a higher level of cellular immunity destruction and genotoxicity than micron-scale plastics. Enzymatic antioxidant systemswere upregulated based on size-differential plastics; however, the total antioxidant effect of non-enzymatic defenses appeared to be least affected by the size effect.

Benzophenone-3 causes oxidative stress in the brain and impairs aversive memory in adult zebrafish.

Oxybenzone (BP-3) is an ultraviolet (UV) filter widely used in industries that is directly or indirectly released into the aquatic environment. However, little is known about its effects on brain performance. Here, we investigated whether BP-3 exposure affects the redox imbalance in zebrafish and how they respond to a task that requires memory of an aversive situation. Fish were exposed to BP-3 10 and 50 µg L-1 for 15 days and then tested using an associative learning protocol with electric shock as a stimulus. Brains were extracted for reactive oxygen species (ROS) measurement and qPCR analysis of antioxidant enzyme genes. ROS production increased for exposed animals, and catalase (cat) and superoxide dismutase 2 (sod 2) were upregulated. Furthermore, learning and memory were reduced in zebrafish exposed to BP-3. These results suggested that BP-3 may lead to a redox status imbalance, causing impaired cognition and reinforcing the need to replace the toxic UV filters with filters that minimize environmental effects.

Benzophenone-type ultraviolet filters inhibit human and rat placental 3ß-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Benzophenones (BPs) are a class of chemicals found in various personal care and cosmetic products, such as sunscreens and lotions. Their usage is known to cause reproductive and hormonal health risks, but the exact mechanism of action remains unknown. In this study, we investigated the effects of BPs on human and rat placental 3ß-hydroxysteroid dehydrogenases (3ß-HSDs), which play a crucial role in the biosynthesis of steroid hormones, particularly progesterone. We tested inhibitory effects of 12 BPs, and performed structure-activity relationship (SAR) and in silico docking analysis. The potency of BPs to inhibit human 3ß-HSD1 (h3ß-HSD1) is BP-1 (IC50, 8.37 µM)>BP-2 (9.06 µM)>BP-12 (94.24 µM)>BP-7 (1160 µM) >BP-8 (1257 µM) >BP-6 (1410 µM) > other BPs (ineffective at 100 µM). The potency of BPs on rat r3ß-HSD4 is BP-1 (IC50, 4.31 µM)>BP-2 (117.3 µM)>BP-6 (669 µM) >BP-3 (820 µM)>other BPs (ineffective at 100 µM). BP-1, BP-2, and BP-12 are mixed h3ß-HSD1 inhibitors and BP-1 is a mixed r3ß-HSD4 inhibitor. LogP, lowest binding energy, and molecular weight were positively associated with IC50 for h3ß-HSD1, while LogS was negatively associated with IC50. The 4-OH substitution in the benzene ring plays a key role in enhancing the effectiveness of inhibiting h3ß-HSD1 and r3ß-HSD4, possibly through increasing water solubility and decreasing lipophilicity by forming hydrogen bonds. BP-1 and BP-2 inhibited progesterone production in human JAr cells. Docking analysis shows that 2-OH of BP-1 forms hydrogen bonds with catalytic residue Ser125 of h3ß-HSD1 and Thr125 of r3ß-HSD4. In conclusion, this study demonstrates that BP-1 and BP-2 are moderate inhibitors of h3ß-HSD1 and BP-1 is a moderate inhibitor of r3ß-HSD4. There is a significant SAR differences for 3ß-HSD homologues between BPs and distinct species-dependent inhibition of placental 3ß-HSDs.

Human Exposure to Bisphenols, Parabens, and Benzophenones, and Its Relationship with the Inflammatory Response: A Systematic Review.

Bisphenols, parabens (PBs), and benzophenones (BPs) are widely used environmental chemicals that have been linked to several adverse health effects due to their endocrine disrupting properties. However, the cellular pathways through which these chemicals lead to adverse outcomes in humans are still unclear, suggesting some evidence that inflammation might play a key role. Thus, the aim of this study was to summarize the current evidence on the relationship between human exposure to these chemicals and levels of inflammatory biomarkers. A systematic review of peer-reviewed original research studies published up to February 2023 was conducted using the MEDLINE, Web of Science, and Scopus databases. A total of 20 articles met the inclusion/exclusion criteria. Most of the reviewed studies reported significant associations between any of the selected chemicals (mainly bisphenol A) and some pro-inflammatory biomarkers (including C-reactive protein and interleukin 6, among others). Taken together, this systematic review has identified consistent positive associations between human exposure to some chemicals and levels of pro-inflammatory biomarkers, with very few studies exploring the associations between PBs and/or BPs and inflammation. Therefore, a larger number of studies are required to get a better understanding on the mechanisms of action underlying bisphenols, PBs, and BPs and the critical role that inflammation could play.

Comparison of developmental toxicity of benzophenone-3 and its metabolite benzophenone-8 in zebrafish.

Benzophenone-3 (BP-3) as one of frequently used organic UV filters has been considered an emerging pollutant due to its toxicities. Benzophenone-8 (BP-8) is one of the main metabolites of BP-3 in organisms. Current reports show that BP-8 may be more toxic than BP-3. However, difference of their toxicities on embryonic development has rarely been reported. In this study, zebrafish embryos were chosen as the target organism to explore the developmental toxicities of BP-3 and BP-8. Non-targeted metabolomic analysis was performed to compare their modes of action. Results showed that BP-8 exposures led to higher bioaccumulation and lower hatching rate of zebrafish larvae than BP-3. Both BP-8 and BP-3 exposures caused behavioral abnormalities of zebrafish larvae, but no significant difference was found between them. At the metabolome level, 1 µg/L BP-3 and 1 µg/L BP-8 exposures altered neuroactive ligand-receptor interaction pathway and FoxO signaling pathway, respectively, which might be involved in the abnormal behaviors in zebrafish larvae. For higher exposure groups (30 and 300 µg/L), both BP-3 and BP-8 exposures changed metabolism of cofactors and vitamins of zebrafish larvae. Exposure of BP-3 altered the metabolism by pantothenate and CoA biosynthesis pathway, while BP-8 exposure changed riboflavin metabolism and folate biosynthesis. The above results indicated different modes of action of BP-3 and BP-8 in zebrafish embryonic development. This study sheds new light to biological hazards of BP-3 due to its metabolism in aquatic organisms.

Safety of benzophenone-type UV filters: A mini review focusing on carcinogenicity, reproductive and developmental toxicity.

Consumer products containing benzophenone-type ultraviolet (UV) filters (BPs) have been widely accepted by the public, resulting in the widely existence of various BPs in the human body and environment. In recent years, more and more evidences show that BPs are endocrine disruptors. In view of the continuous exposure risk of BPs and their endocrine disrupting characteristics, the carcinogenicity of BPs and their effects on reproduction and development are of particular concern. However, due to the wide varieties of BPs and the scattered toxicity studies on BPs, people have a limited understanding on the safety of BPs. Therefore, this paper systematically reviews the carcinogenicity, reproductive and developmental toxicity of BPs in order to expand people's knowledge on the health risks of BPs and screen for more safe BPs. Although existing toxicological studies are insufficient, it can be determined that BPs have different potentials for carcinogenicity, and reproductive and developmental toxicity. Among those BPs, 2-hydroxyl-4-methoxyl benzophenone needs to be used with caution due to its adverse effects on cancer cell proliferation and migration, reproductive ability, sex differentiation, neurodevelopment, and so on. It is worth noting that functional group substitutions significantly affect the interaction between BPs and biomolecules such as DNA, cancer cells, and seminal fluid, resulting in different levels of toxicity. In short, it is very necessary to evaluate the carcinogenicity, reproductive and developmental toxicity of BPs, which is of great significance for establishing reasonable BPs content standards in cosmetics, water quality treatment standards for BPs, and so on.

Benzophenone-3: Comprehensive review of the toxicological and human evidence with meta-analysis of human biomonitoring studies.

BACKGROUND: Benzophenone-3 (BP-3) and its major metabolite benzophenone-1 (BP-1) are widely used as UV filters in sunscreens and cosmetics to prevent sunburn and skin damage, or as stabilizers to prevent photodegradation in many commercial products. As a result, their presence is ubiquitous in the environment, wildlife and humans. Based on endocrine disruption concerns, international regulatory agencies are performing a closer evaluation. OBJECTIVE AND METHODS: This work aimed to comprehensively review the available human relevant evidence for safety issues in MEDLINE/PubMed in order to create a structured database of studies, as well as to conduct an integrative analysis as part of the Human Biomonitoring for Europe (HBM4EU) Initiative. RESULTS: A total of 1,635 titles and abstracts were screened and 254 references were evaluated and tabulated in detail, and classified in different categories: i) exposure sources and predictors; ii) human biomonitoring (HBM) exposure levels to perform a meta-analysis; iii) toxicokinetic data in both experimental animals and humans; iv) in vitro and in vivo rodent toxicity studies; and v) human data on effect biomarkers and health outcomes. Our integrative analysis showed that internal peak BP-3 concentrations achieved after a single whole-body application of a commercially available sunscreen (4% w/w) may overlap with concentrations eliciting endocrine disrupting effects in vitro, and with internal concentrations causing in vivo adverse female reproductive effects in rodents that were supported by still limited human data. The adverse effects in rodents included prolonged estrous cycle, altered uterine estrogen receptor gene expression, endometrium hyperplasia and altered proliferation and histology of the mammary gland, while human data indicated menstrual cycle hormonal alterations and increased risk of uterine fibroids and endometriosis. Among the modes of action reported (estrogenic, anti-androgenic, thyroid, etc.), BP-3 and especially BP-1 showed estrogenic activity at human-relevant concentrations, in agreement with the observed alterations in female reproductive endpoints. The meta-analysis of HBM studies identified a higher concern for North Americans, showing urinary BP-3 concentrations on average 10 and 20 times higher than European and Asian populations, respectively. DISCUSSION AND CONCLUSIONS: Our work supports that these benzophenones present endocrine disrupting properties, endorsing recent European regulatory efforts to limit human exposure. The reproducible and comprehensive database generated may constitute a point of departure in future risk assessments to support regulatory initiatives. Meanwhile, individuals should not refrain from sunscreen use. Commercially available formulations using inorganic UV filters that are practically not absorbed into systemic circulation may be recommended to susceptible populations.

Lifetime exposure to benzophenone-3 at an environmentally relevant concentration leads to female-biased social behavior and cognition deficits in zebrafish.

Benzophenone-3 (BP3) is an organic UV filter widely used in the commercial formulations of various personal care products. It has been detected ubiquitously in the environment and human tissues. Recently, BP3-induced neurotoxicity has been identified as the main health risk to humans and aquatic organisms. However, most research has been focused on embryonic development, and few studies explore chronic lifetime exposure. In the present study, we evaluated the neurotoxicity of lifetime exposure to an environmentally relevant concentration of BP3 in zebrafish. Our findings revealed that continuous BP3 exposure at 10 µg/L (0.04 µM) from 6 h post fertilization (hpf) to adulthood at 5 months led to female-biased social behavioral deficits and learning and memory impairment. These neurobehavioral effects were characterized by decreased prosocial activities in the social preference test and mirror biting assay, and reduced learning and memory in a T-maze test. Furthermore, these effects were accompanied by female-specific decreases in brain weight and brain dopamine concentration, female-biased decrease of neurogenesis in the telencephalon as well as female-specific increases in apoptotic cells and expression levels of genes and proteins related to the apoptosis pathway in the brain. Our results suggest that BP3-induced social behavior and learning/memory deficits are correlated to the cell loss in the telencephalon region of the zebrafish brain.

Low concentrations of benzophenone-type UV-filters impair testis development in the amphibian Xenopus laevis.

Benzophenone-type UV filters (BPs) are ubiquitous contaminants in aquatic environments, possibly posing ecological risks to aquatic populations. So far, little is known about the potential adverse effects of BPs on amphibians. Given their potential estrogenic property, we investigated the detrimental effects of the commonly used BPs, BP-3, BP-2, and BP-1, on testis development in amphibians using Xenopus laevis as a model species. Following exposure to 10, 100, 1000 nM BP-3, BP-2, or BP-1 from stages 45/46 to 52, tadpoles presented morphological abnormal testes, characterized by reduced gonomere size and testis area, coupled with suppressed cell proliferation. Meanwhile, the downregulation of testis-biased gene expression and the upregulation of ovary-biased gene expression were observed in BPs-treated testes. Moreover, the estrogen receptor (ER) antagonist ICI 182780 significantly antagonized ovary-biased gene upregulation caused by BPs, suggesting that the effects of BPs on testis differentiation could be mediated by ER, at least partially. Of note, the effects of BPs were not concentration-dependent, but the lowest concentration generally exerted significant effects. Altogether, these observations indicate that the three BPs inhibited testis differentiation and exerted feminizing effects. Importantly, when BP-2 exposure was extended to two months post-metamorphosis, testes of froglets were generally less-developed, with relatively fewer spermatocytes, more spermatogonia, and poorly formed seminiferous tubules. Considering the fact that the lowest concentration (10 nM) of BPs in this study are detectable in aquatic environments, we conclude that BP-3, BP-2, and BP-1, even at environmentally relevant concentrations, can retard testis differentiation at pre-metamorphic stages and cause testis dysgenesis after metamorphosis in the amphibian X. laevis. Our findings suggest that ubiquitous BPs in aquatic environments could pose a potential risk to amphibians.

Toxicological effects of oxybenzone on the growth and bacterial composition of Symbiodiniaceae.

Oxybenzone, a common ultraviolet (UV) filter, is a growing environmental concern due to its ecotoxicological effects. However, the responses of Symbiodiniaceae and their bacterial communities to oxybenzone are largely unknown. In this study, the effects of oxybenzone on Effrenium voratum and Cladocopium goreaui were investigated. The results revealed that sensitivity of Symbiodiniaceae to oxybenzone was species-dependent. 50 µg L-1 of oxybenzone significantly impacted the cell density of C. goreaui, causing a 36.73% decrease. When oxybenzone concentration increased to 500 µg L-1 and 5000 µg L-1, cell division was completely suppressed; meanwhile, chl-a content declined to zero. Compared to C. goreaui, E. voratum had higher resistance to oxybenzone. There was no significant difference in cell density between 50 µg L-1 group and control group. At higher dosage of oxybenzone (500 µg L-1 and 5000 µg L-1), the cell density declined 32.02% and 45.45% compared to the control group, respectively. Additionally, we revealed that the diversity and structure of bacterial community were affected by oxybenzone. Briefly, 500 µg L-1 and 5000 µg L-1 of oxybenzone altered the diversity of bacterial community in C. goreau. Furthermore, the relative abundances of Costertonia, Roseitalea, Rhodopirellula, and Roseobacter were negatively affected by oxybenzone ranging 50 µg L-1 to 5000 µg L-1. Compare to C. goreaui, the bacterial community composition associated with E. voratum was more stable. As revealed by KEGG pathway analysis, oxybenzone affected energy metabolism and inhibited the metabolism of cofactors and vitamins in C. goreaui, while 5000 µg L-1 of oxybenzone significantly altered the carbohydrate metabolism, membrane transport and amino acid metabolism in E. voratum. The changes of bacterial composition may contribute to the variation in algal growth. These results indicated that oxybenzone pollution could injury Symbiodiniaceae, even threaten coral reef ecosystems.