Expression Profiles of Genes Related to Development and Progression of Endometriosis and Their Association with Paraben and Benzophenone Exposure.

Increasing evidence has been published over recent years on the implication of endocrine-disrupting chemicals (EDCs), including parabens and benzophenones in the pathogenesis and pathophysiology of endometriosis. However, to the best of our knowledge, no study has been published on the ways in which exposure to EDCs might affect cell-signaling pathways related to endometriosis. We aimed to describe the endometriotic tissue expression profile of a panel of 23 genes related to crucial cell-signaling pathways for the development and progression of endometriosis (cell adhesion, invasion/migration, inflammation, angiogenesis, and cell proliferation/hormone stimulation) and explore its relationship with the exposure of patients to parabens (PBs) and benzophenones (BPs). This cross-sectional study included a subsample of 33 women with endometriosis from the EndEA study, measuring their endometriotic tissue expressions of 23 genes, while urinary concentrations of methyl-, ethyl-, propyl-, butyl-paraben, benzophenone-1, benzophenone-3, and 4-hydroxybenzophenone were determined in 22 women. Spearman's correlations test and linear and logistic regression analyses were performed. The expression of 52.2% of studied genes was observed in >75% of endometriotic tissue samples and the expression of 17.4% (n = 4) of them in 50-75%. Exposure to certain PB and BP congeners was positively associated with the expression of key genes for the development and proliferation of endometriosis. Genes related to the development and progression of endometriosis were expressed in most endometriotic tissue samples studied, suggesting that exposure of women to PBs and BPs may be associated with the altered expression profile of genes related to cellular pathways involved in the development of endometriosis.

A new case of photoallergic contact dermatitis caused by benzophenones in magazine covers.

BACKGROUND: Allergic contact dermatitis (ACD) and photoallergic contact dermatitis (PACD) to benzophenone present in printing ink have been reported. However, precise chemical analyses and extended photo-patch tests have not been performed in these cases. OBJECTIVES: To determine which components present in a magazine cover are responsible for a patient's skin reaction, to determine the primary sensitizer, and precisely diagnose ACD and PACD. METHODS: After initial photo-patch tests were performed on a patient with a history of reaction to magazine covers after sun exposure, gas chromatography-mass spectrometry and high-performance liquid chromatography analyses of the magazine covers, and additional photo-patch tests were performed. RESULTS: The first photo-patch test results confirmed PACD to ketoprofen and fenofibrate and evoked PACD to the magazine covers. 4-methyl benzophenone (4-MBP) and 1-hydroxy-cyclohexyl-phenyl-ketone (1-HCPK) were found in the magazine cover. Additional photo-patch tests confirmed PACD to 1-HCPK and to benzophenone, and photo-aggravated ACD to 4-MBP. The primary sensitizer was ketoprofen. CONCLUSIONS: Benzophenones are present in a wide variety of products, without always being listed on the packaging. Patients previously sensitized to other ketones, such as ketoprofen, may react to benzophenones without being able to avoid contact with these molecules. New regulations may be needed for more efficient eviction advice.

A phase 1 dose-escalation and dose-expansion study to assess the safety and efficacy of CKD-516, a novel vascular disrupting agent, in combination with Irinotecan in patients with previously treated metastatic colorectal cancer.

Introduction The combination of an anti-angiogenic agent with cytotoxic chemotherapy is a standard treatment strategy for metastatic colorectal cancer. CKD-516 is an oral vascular disrupting agent that was preliminarily shown to be safe and efficacious as a monotherapy in refractory solid cancers. We evaluated the recommended phase 2 dose, safety, and preliminary efficacy of CKD-516 in combination with irinotecan in treatment-refractory metastatic colorectal cancer. Methods This phase 1 dose-escalation and dose-expansion study included patients with treatment-refractory metastatic colorectal cancer. CKD-516 tablets were administered for five consecutive days followed by two days off in combination with intravenous irinotecan (120 mg/m2) administered on day one of each treatment cycle every two weeks. A traditional 3 + 3 dose-escalation design was used. Results In total, 16 and 23 patients were enrolled in the dose-escalation and dose-expansion cohorts, respectively. The most common adverse events included diarrhea (79%), nausea (74%), vomiting (67%), and neutropenia (62%). No dose-limiting toxicity occurred, and the recommended phase 2 dose was determined at CKD-516/irinotecan doses of 11/120 mg/m2. No cases of cardiac ischemia, cardiac dysfunction, or thromboembolism were reported. Among the 34 patients with available tumor response assessments, one patient achieved partial response (3%) and 26 patients achieved stable disease (76%). The median progression-free survival and overall survival were 4.1 and 11.6 months, respectively. Conclusion This phase 1 study showed that the combination of oral CKD-516 and irinotecan is safe and tolerable in metastatic, treatment-refractory colorectal patients and showed favorable efficacy outcomes. Further studies to confirm these preliminary findings are warranted. Trial registration number NCT03076957 (Registered at March 10, 2017).

The Beneficial Effect of Rosmarinic Acid on Benzophenone-3-Induced Alterations in Human Skin Fibroblasts.

Benzophenone-3 (BP-3) is one of the most widely used chemical sunscreens. The results of many in vitro and in vivo tests confirm its high percutaneous penetration and systemic absorption, which question the safety of its wide use. The aim of our research was to assess the effect of this compound on components of the skin extracellular matrix, and to investigate whether rosmarinic acid (RA) could reduce BP-3-induced changes in human skin fibroblasts. BP-3 used at concentrations of 0.1-100 µM caused a number of unfavorable changes in the level of type I collagen, decorin, sulfated glycosaminoglycans, hyaluronic acid, elastin, and expression or activity of matrix metalloproteinases (MMP-1, MMP-2), elastase and hyaluronidase. Moreover, the intracellular retention of collagen was accompanied by changes in the expression of proteins modifying and controlling the synthesis and secretion of this protein. Most importantly, RA at a concentration of 100 µM significantly reduced or completely abolished the adverse effects of BP-3. Based on these findings, it can be concluded that this polyphenol may provide effective protection against BP-3-induced disturbances in skin cells, which may have important clinical implications.

The use of patient-derived breast tissue explants to study macrophage polarization and the effects of environmental chemical exposure.

Ex vivo mammary explant systems are an excellent model to study interactions between epithelium and stromal cell types because they contain physiologically relevant heterotypic interactions in the background of genetically diverse patients. The intact human mammary tissue, termed patient-derived explant (PDE), can be used to investigate cellular responses to a wide variety of external stimuli in situ. For this study, we examined the impact of cytokines or environmental chemicals on macrophage phenotypes. We demonstrate that we can polarize macrophages within human breast tissue PDEs toward M1 or M2 through the addition of interferon-γ (IFNγ) + lipopolysaccharide (LPS) or interleukin (IL)-4 + IL-13, respectively. Elevated expression levels of M(IFNγ + LPS) markers (HLADRA and CXCL10) or M(IL-4 + IL-13) markers (CD209 and CCL18) were observed in cytokine-treated tissues. We also examined the impact of the endocrine-disrupting chemical, benzophenone-3, on PDEs and measured significant, yet varying effects on macrophage polarization. Furthermore, a subset of the PDEs respond to IL-4 + IL-13 through downregulation of E-cadherin and upregulation of vimentin which is reminiscent of epithelial-to-mesenchymal transition (EMT) changes. Finally, we were able to show immortalized nonmalignant breast epithelial cells can exhibit EMT characteristics when exposed to growth factors secreted by M(IL-4 + IL-13) macrophages. Taken together, the PDE model system is an outstanding preclinical model to study early tissue-resident immune responses and effects on epithelial and stromal responses to stimuli found both endogenously in the breast and exogenously as a result of exposures.

Review of environmental effects of oxybenzone and other sunscreen active ingredients.

With increasing awareness regarding the risks of sunburn, photoaging, and skin cancer, the use of sunscreens has increased. Organic and inorganic filters are used in sunscreen products worldwide. Concerns have been raised regarding the environmental effects of commonly used organic ultraviolet (UV) filters, including oxybenzone (benzophenone-3), 4-methylbenzylidene camphor, octocrylene, and octinoxate (ethylhexyl methoxycinnamate). Studies have identified UV filters such as oxybenzone, octocrylene, octinoxate, and ethylhexyl salicylate in almost all water sources around the world and have commented that these filters are not easily removed by common wastewater treatment plant techniques. Additionally, in laboratory settings, oxybenzone has been implicated specifically as a possible contributor to coral reef bleaching. Furthermore, UV filters such as 4-methylbenzylidene camphor, oxybenzone, octocrylene, and octinoxate have been identified in various species of fish worldwide, which has possible consequences for the food chain. As dermatologists, it is important for us to continue to emphasize the public health impact of excessive sun exposure and advise our patients about proper photoprotection practice, which consists of seeking shade, wearing photoprotective clothing (including hats and sunglasses), and applying appropriate sunscreens.

European photopatch test baseline series: A 3-year experience.

BACKGROUND: In 2012, a consensus was reached regarding a baseline photopatch test series on the basis of the results of a European multicentre study. OBJECTIVES: To describe experience with the European photopatch test series. METHODS: A retrospective analysis of 116 patients tested with the European photopatch test series between 2014 and 2016 was performed. RESULTS: Fifty-five positive photopatch test reactions in 25 subjects were recorded, most commonly caused by the topical non-steroidal anti-inflammatory drugs ketoprofen, dexketoprofen, and etofenomate. Organic ultraviolet (UV) absorbers constituted the second main category of agents eliciting positive photopatch test reactions. Among UV absorbers, benozophenone-3 and octocrylene were the most frequent photoallergens. UV absorbers that have been introduced more recently rarely elicited positive photopatch test reactions. Positive patch test reactions were less commonly observed than positive photopatch test reactions, namely, 21 reactions in 14 patients. CONCLUSIONS: We present the largest clinical experience with the European photopatch test baseline series hitherto reported. The results are similar to those underlying the above consensus process, reaffirming the usefulness of this series.

Update About the Effects of the Sunscreen Ingredients Oxybenzone and Octinoxate on Humans and the Environment.

As skin cancer prevalence continues to rise, the importance of sun protection, including sunscreen use, has become accepted in the public. Sunscreens are divided into two main categories based on the type of their active ingredient, organic and inorganic ultraviolet (UV) filters. It has been shown that inorganic filters are more effective at blocking forms of UV light, both UVA and UVB, as compared with organic filters because organic sunscreens absorb and convert radiation whereas inorganic sunscreens reflect radiation. The use of the two most common organic filters, oxybenzone and octinoxate, has recently been restricted in Hawaii due to their harmful effect on the coral reefs. Here, we discuss recent studies about these specific filters related to the adverse health risks they pose for humans and other organisms, as well as environmental repercussions.

Update About the Effects of the Sunscreen Ingredients Oxybenzone and Octinoxate on Humans and the Environment.

As skin cancer prevalence continues to rise, the importance of sun protection, including sunscreen use, has become accepted in the public. Sunscreens are divided into two main categories based on the type of their active ingredient, organic and inorganic ultraviolet (UV) filters. It has been shown that inorganic filters are more effective at blocking forms of UV light, both UVA and UVB, as compared with organic filters because organic sunscreens absorb and convert radiation whereas inorganic sunscreens reflect radiation. The use of the two most common organic filters, oxybenzone and octinoxate, has recently been restricted in Hawaii due to their harmful effect on the coral reefs. Here, we discuss recent studies about these specific filters related to the adverse health risks they pose for humans and other organisms, as well as environmental repercussions.

Benzophenone-3 increases metastasis potential in lung cancer cells via epithelial to mesenchymal transition.

Exposure to compounds with cancer-potentiating effects can contribute to the progression of cancer. Herein we have discovered for the first time that benzophenone-3 (BP-3), a chemical used as sunscreen in various cosmetic products, enhances the ability of lung cancer cells to undergo metastasis. The exposure of the lung cancer cells to BP-3 at non-toxic concentrations significantly increased the number of anoikis resistant cells in a dose-dependent manner. Also, BP-3 increased the growth rate as well as the number of colonies accessed by anchorage-independent growth assay. We found that the underlying mechanisms of such behaviors were the epithelial to mesenchymal transition (EMT) process of cancer cells, and the increase in caveolin-1 (Cav-1) expression. As both mechanistic events mediated anoikis resistance via augmentation of cellular survival signals, our results further revealed that the BP-3 treatment significantly up-regulated extracellular-signal-regulated kinase (ERK). Also, such compounds increased the cellular levels of anti-apoptotic Bcl-2 and Mcl-1 proteins. As the presence of a substantial level of BP-3 in plasma of the consumers has been reported, this finding may facilitate further investigations that lead to better understanding and evidence concerning the safety of use in cancer patients.

Comparison of topically applied flurbiprofen or bromfenac ophthalmic solution on post-operative ocular hypertension in canine patients following cataract surgery.

OBJECTIVE: To compare the prevalence and kinetics of ocular hypertension after routine cataract extraction when using a predominately COX-2 inhibitor (bromfenac) versus a predominately COX-1 inhibitor (flurbiprofen) in combination with a topical corticosteroid. PROCEDURES: Patients undergoing unilateral or bilateral cataract surgery were randomly assigned to receive flurbiprofen or bromfenac at the day of surgery and continued for 6 weeks postoperatively, along with topical neo poly dexamethasone. No systemic nonsteroidal anti-inflammatory medications were administered before or after surgery. Intraocular pressure was monitored pre and postoperatively. When an IOP of >25 mmHg was detected, therapeutic intervention was performed. RESULTS: Eyes in both treatment groups showed a similar IOP profile with the highest mean IOP occurring two hours postsurgery and slowly declining during the next 6 weeks. However, eyes receiving bromfenac had a higher mean IOP at 2 h post-op (22.1 mmHg) than eyes receiving flurbiprofen (18.8 mmHg) and a slower decrease in IOP in the weeks after surgery. Over the course of the study, a higher percentage of eyes receiving bromfenac had therapy discontinued over concerns of elevated IOP compared to eyes receiving flurbiprofen (bromfenac 23.1% and flurbiprofen 9.8%). On average, the risk of having elevated intraocular pressure with bromfenac is 1.04 times higher than with flurbiprofen. CONCLUSION: Elevated postoperative IOP was observed in both treatment groups; however, bromfenac-treated eyes were more likely to require intervention for elevated IOP.

[Comparison of clinical effects of bromfenac sodium ophthalmic solution 0.1% versus glucocorticoids for post-LASEK usage].

OBJECTIVE: To evaluate the safety, effectiveness and compliance of Bronuck (bromfenac sodium ophthalmic solution 0.1%) following LASEK in comparison with glucocorticoids. METHODS: In this prospective trial, 60 patients (120 eyes) undergoing LASEK were randomized into the bromfenac sodium group (60 eyes) and control group (60 eyes). Patients in both groups initially received dexamethasone 0.1% four times a day after LASEK for 7 days, and then the patients in the bromfenac sodium group were given Bronuck twice a day for the next 11 weeks, while the patients from the control group were given fluorometholone 0.1% with gradually decreased doses during the same period. Results of the routine examinations done before and 3, 10, 30, 90 and 180 days after LASEK were recorded, including uncorrected visual acuity, best corrected visual acuity, intraocular pressure (IOP), corneal topography, ocular symptoms and signs, which were used for comparison between the two groups. All data of right eyes were analyzed for their independence, normality and homogeneity of variance. Independent samples t-test or non-parametric Mann-Whitney test was performed accordingly. RESULTS: There was no statistically significant difference in IOP and corneal topography (K1, K2, SAI, SRI and CY) between the two groups postoperatively. The IOP was (16.33 ± 6.21) mmHg(1 mmHg = 0.133 kPa), (15.67 ± 2.82) mmHg, (15.35 ± 2.22) mmHg and (13.10 ± 3.41) mmHg in the bromfenac sodium group, and (16.87 ± 3.68) mmHg, (14.05 ± 2.23) mmHg, (14.39 ± 2.22) mmHg and (13.18 ± 2.49) mmHg in the control group at 10, 30, 90 and 180 days, respectively. The bromfenac sodium group showed significantly better uncorrected visual acuity (5.16 ± 0.08) than the control group (5.02 ± 0.09) on day 30 (t = 2.32, P < 0.05). In the bromfenac sodium group, four eyes had visual fatigue, and four eyes had dry eye symptoms on day 180. Epithelial flaps were all well positioned with satisfying healing process. Each group had one case (two eyes) of haze on day 30, and the bromfenac sodium group had another case (2 eyes) of new-onset haze on day 60. But all the cases of haze were graded 0.5 according to the Fantes Standard, too mild to compromise their visual acuities, and were resolved after frequent topical medication for 1 month. Four patients from the control group were prescribed antiglaucoma medications due to elevated IOP. The refractive status remained stable for patients from both groups. CONCLUSIONS: Administration of Bronuck can reduce the amount of or partially substitute for corticosteroids. Mild haze early after LASEK may disappear after intensive treatment.

Urinary concentrations of benzophenone-type ultraviolet radiation filters and couples' fecundity.

Concern has arisen about benzophenone (BP) ultraviolet (UV) radiation filters, given their use in sunscreen and personal-care products and their reported estrogenic and antiandrogenic activity. We recruited 501 couples who were discontinuing use of contraceptives in order to become pregnant for the Longitudinal Investigation of Fertility and the Environment (LIFE) Study (Michigan and Texas, 2005-2009). Couples provided urine specimens and completed daily journals until they either achieved pregnancy or had tried for 12 months. Women used fertility monitors to time sexual intercourse and digital pregnancy tests. Urinary concentrations of 5 UV filters (ng/mL) were determined using triple-quadrupole mass spectrometry: 2,4-dihydroxybenzophenone (also called BP-1); 2,2',4,4'-tetrahydroxybenzophenone (BP-2); 2-hydroxy-4-methoxybenzophenone (BP-3); 2,2'-dihydroxy-4-methoxybenzophenone (BP-8); and 4-hydroxybenzophenone. Fecundability odds ratios were estimated for each UV filter (dichotomized at the 75th percentile) and adjusted for age, creatinine concentration, body mass index (weight (kg)/height (m)(2)), cotinine concentration, season, and site, while accounting for time off contraception. Separate models were fitted for each UV filter and partner; final models included partners' concentrations. Male partners' concentrations of BP-2 and 4-hydroxybenzophenone were associated with reduced fecundity in adjusted models (fecundability odds ratio (FOR) = 0.69 (95% confidence interval (CI): 0.50, 0.95) and FOR = 0.74 (95% CI: 0.54, 1.00), respectively). In models adjusting for both partners' concentrations, male BP-2 concentration remained associated with reduced fecundity (FOR = 0.69, 95% CI: 0.49, 0.97). These data suggest that male exposure to select UV filters may diminish couples' fecundity, resulting in a longer time to pregnancy.

Bromfenac ophthalmic solution 0.07% dosed once daily for cataract surgery: results of 2 randomized controlled trials.

PURPOSE: To evaluate the efficacy and ocular safety of bromfenac ophthalmic solution 0.07% (Prolensa) dosed once daily for the treatment of ocular inflammation and pain in subjects who underwent cataract surgery with posterior chamber intraocular lens implantation. DESIGN: Two phase 3, randomized, double-masked, placebo-controlled, multicenter clinical trials. PARTICIPANTS: Four hundred forty subjects (440 study eyes: 222 in the bromfenac group and 218 in the placebo group). METHODS: Two phase 3, prospective, randomized, double-masked, placebo-controlled clinical trials were conducted at 39 ophthalmology clinics in the United States. Subjects 18 years of age or older were randomized to receive either bromfenac 0.07% or placebo dosed once daily beginning 1 day before cataract surgery, on the day of surgery, and continuing for 14 days after surgery (for a total of 16 days). Subjects were evaluated on days 1, 3, 8, 15, and 22 after surgery. The primary efficacy end point was cleared ocular inflammation, as measured by the summed ocular inflammation score of zero (anterior chamber cell count = 0 and absence of flare) by day 15. Secondary end points included cleared ocular inflammation at day 15 and the number of subjects who were pain free at day 1. The data from the 2 clinical trials were integrated for analyses. MAIN OUTCOME MEASURES: Summed ocular inflammation score and ocular pain. RESULTS: A significantly higher proportion of subjects treated with bromfenac 0.07% achieved complete clearance of ocular inflammation by day 15 and at day 15 compared with placebo (P < 0.0001). A statistically significantly higher proportion of subjects in the bromfenac 0.07% group were pain free at all study visits compared with those in the placebo group (P < 0.0001). Fewer subjects in the bromfenac group (3.2%) discontinued investigational product early because of a lack of efficacy than in the placebo group (23.9%; P < 0.0001). The incidence of adverse events was significantly lower in the bromfenac 0.07% group compared with the placebo group (P = 0.0041). CONCLUSIONS: Bromfenac ophthalmic solution 0.07% dosed once daily was clinically safe and effective compared with placebo for the treatment of ocular inflammation and pain in subjects who had undergone cataract surgery and may be a beneficial addition to the current standard of care, which commonly includes ophthalmic antibiotics and corticosteroids.

Evaluation of von Willebrand factor and von Willebrand factor propeptide in models of vascular endothelial cell activation, perturbation, and/or injury.

Pharmacologically, vasoactive agents targeting endothelial and/or smooth muscle cells (SMC) are known to cause acute drug-induced vascular injury (DIVI) and the resulting pathology is due to endothelial cell (EC) perturbation, activation, and/or injury. Alteration in EC structure and/or function may be a critical event in vascular injury and, therefore, evaluation of the circulatory kinetic profile and secretory pattern of EC-specific proteins such as VWF and VWFpp could serve as acute vascular injury biomarkers. In rat and dog models of DIVI, this profile was determined using pharmacologically diverse agents associated with functional stimulation/perturbation (DDAVP), pathological activation (lipopolysaccharide [LPS]/endotoxin), and structural damage (fenoldopam [FD], dopamine [DA], and potassium channel opener (PCO) ZD6169). In rats, FD caused moderate DIVI and time-related increase in plasma VWF levels ∼33% while in control rats VWF increased ∼5%. In dogs, VWF levels transiently increased ∼30% when there was morphologic evidence of DIVI by DA or ZD6169. However, in dogs, VWFpp increased >60-fold (LPS) and >6-fold (DDAVP), respectively. This was in comparison to smaller dynamic 1.38-fold (LPS) and 0.54-fold (DDAVP) increases seen in plasma VWF. Furthermore, DA was associated with a dose-dependent increase in plasma VWFpp. In summary, VWF and VWFpp can discriminate between physiological and pathological perturbation, activation, and injury to ECs.

Maternal exposure to benzophenone derivatives and their impacts on offspring's birth outcomes in a Middle Eastern population.

Widespread use of benzophenones (BPs), a group of environmental phenolic compounds, is suspected of interfering with human health. The association of prenatal exposure to benzophenone derivatives with birth outcomes including birth weight and length, head, arm and thoracic circumference, abnormalities, corpulence index and anterior fontanelle diameter (AFD) was investigated. Mother-infant pairs of 166 within PERSIAN cohort population in Isfahan, Iran, in the 1st and 3rd trimesters of pregnancy were assessed. Four common benzophenone metabolites including 2,4-dihydroxy benzophenone (BP-1), 2-hydroxy-4-methoxy benzophenone (BP-3), 4-hydroxy benzophenone (4-OH-BP) and 2,2'-dihydroxy-4-methoxy benzophenone (BP-8) were measured in maternal urine samples. The median concentration of 4-OH-BP, BP-3, BP-1 and BP-8 were 3.15, 16.98, 9.95 and 1.04 µg/g Cr, respectively. In the 1st trimester, 4-OH-BP showed a significant correlation with AFD in total infants, decreasing 0.034 cm AFD per a log unit increase of 4-OH-BP. Within the male neonates, 4-OH-BP in the 1st and BP-8 in the 3rd trimester were significantly associated with head circumference and AFD increase, respectively. Among female neonates in the 3rd trimester, increasing 4-OH-BP and BP-3 concentration was correlated with a decrease in birth weight and AFD, respectively. This study demonstrated that all the target BP derivatives can influence normal fetal growth at any age of the pregnancy, nevertheless, to support these findings further studies are needed in a large and different group population.