Induction of hemangiosarcoma in mice after chronic treatment with S1P-modulator siponimod and its lack of relevance to rat and human.

A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse. In mice, these effects were sustained over the 9-month study duration, while in rats increased mitotic gene expression was present at day 3 only and PLGF2 was induced only during the first week of treatment. In the mouse, the persistent VEC activation, mitosis induction, and PLGF2 stimulation likely led to sustained neo-angiogenesis which over life-long treatment may result in HSA formation. In rats, despite sustained VEC activation, the transient mitotic and PLGF2 stimuli did not result in the formation of HSA. In vitro, the mouse and rat primary endothelial cell cultures mirrored their respective in vivo findings for cell proliferation and PLGF2 release. Human VECs, like rat cells, were unresponsive to siponimod treatment with no proliferative response and no release of PLGF2 at all tested concentrations. Hence, it is suggested that the human cells also reproduce a lack of in vivo response to siponimod. In conclusion, the molecular mechanisms leading to siponimod-induced HSA in mice are considered species specific and likely irrelevant to humans.

Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids.

UNLABELLED: Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N'-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N'-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE: Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.

Sunscreens: are they beneficial for health? An overview of endocrine disrupting properties of UV-filters.

Today, topical application of sunscreens, containing ultraviolet-filters (UV-filters), is preferred protection against adverse effects of ultraviolet radiation. Evidently, use of sunscreens is effective in prevention of sunburns in various models. However, evidence for their protective effects against melanoma skin cancer is less conclusive. Three important observations prompted us to review the animal data and human studies on possible side effects of selected chemical UV-filters in cosmetics. (1) the utilization of sunscreens with UV-filters is increasing worldwide; (2) the incidence of the malignant disorder for which sunscreens should protect, malignant melanoma, is rapidly increasing and (3) an increasing number of experimental studies indicating that several UV-filters might have endocrine disruptive effects. The selected UV-filters we review in this article are benzophenone-3 (BP-3), 3-benzylidene camphor (3-BC), 3-(4-methyl-benzylidene) camphor (4-MBC), 2-ethylhexyl 4-methoxy cinnamate (OMC), Homosalate (HMS), 2-ethylhexyl 4-dimethylaminobenzoate (OD-PABA) and 4-aminobenzoic acid (PABA). The potential adverse effects induced by UV-filters in experimental animals include reproductive/developmental toxicity and disturbance of hypothalamic-pituitary-thyroid axis (HPT). Few human studies have investigated potential side effects of UV-filters, although human exposure is high as UV-filters in sunscreens are rapidly absorbed from the skin. One of the UV-filters, BP-3, has been found in 96% of urine samples in the US and several UV-filters in 85% of Swiss breast milk samples. It seems pertinent to evaluate whether exposure to UV-filters contribute to possible adverse effects on the developing organs of foetuses and children.

Association between exposure to alkylbenzenes and cardiovascular disease among National Health and Nutrition Examination Survey (NHANES) participants.

Numerous studies have demonstrated that air pollution is associated with an increased risk of mortality and morbidity due to cardiovascular disease (CVD). Alkylbenzenes are ubiquitous in outdoor and indoor air environments. Yet few studies have evaluated the potential links between exposures to alkylbenzenes and CVD independent of tobacco smoking. In this study, we used the 1999-2004 National Health and Nutrition Examination Survey (NHANES) to examine the relationship between alkylbenzenes (toluene, styrene, ethylbenzene, and the xylenes) and CVD prevalence. All five alkylbenzenes suggested linear trends. Subjects in higher exposure categories of blood alkylbenzenes had higher prevalence of CVD, as compared to subjects in the reference group, of below the limit of detection (LOD) and less than the 50th percentile in the case of toluene and styrene. For the remainder of the alkylbenzes, similar statistically significant associations were observed. Further studies are needed to explore associations between these highly prevalent pollutants and CVD.

Contact allergy to 5,5'-di-tert-butyl-2,2'-dihydroxy-(hydroxymethyl)-dibenzyl ethers, sensitizers, in p-tert-butylphenol-formaldehyde resin.

Allergy to p-tert-butylphenol-formaldehyde resin (PTBP-F-R) is not rare. This resin consists of a large number of substances, most of which are still unknown. More knowledge about the sensitizers in the resin is a good basis for development of diagnosis, treatment and prevention. The aim of this investigation was to study allergens in PTBP-F-R by isolation of some medium molecular weight substances from the resin and patch testing these in individuals hypersensitive to PTBP-F-R. 2 isolated substances were shown to be allergens in PTBP-F-R, 5,5'-di-tert-butyl-2,2'-dihydroxy-3,3'-dihydroxymethyl-dibenzyl ether and 5,5'-di-tert-butyl-2,2'-dihydroxy-3-hydroxymethyl-dibenzyl ether. 13 patients hypersensitive to PTBP-F-R were patch tested with serial dilutions of 5,5'-di-tert-butyl-2,2'-dihydroxy-3,3'-dihydroxymethyl-dibenzyl ether and 12 of them reacted positively. 12 patients hypersensitive to PTBP-F-R were patch tested with serial dilutions of 5,5'-di-tert-butyl-2,2'-dihydroxy-3-hydroxymethyl-dibenzyl ether and 11 of them reacted positively. Positive patch test reactions were seen down to 0.0000025 mmole x 1(-1) (approximately 0.01 ppm) for both 5,5'-di-tert-butyl-2,2'-dihydroxy-3,3'-dihydroxymethyl-dibenzyl ether and 5,5'-di-tert-butyl-2,2'-dihydroxy-3-hydroxymethyl-dibenzyl ether in the most sensitive patient. HPLC analysis of 2 PTBP-F-Rs showed the presence of 1.0-1.7% w/w 5,5'-di-tert-butyl-2,2'-dihydroxy-3,3'-dihydroxymethyl-dibenzyl ether and 0.75-0.90% w/w 5,5'-di-tert-butyl-2,2'-dihydroxy-3-hydroxymethyl-dibenzyl ether in the resins.

Biomonitoring studies and susceptibility markers for acrolein congeners and allylic and benzyl compounds.

The importance of genotoxic acrolein congeners and allylic and benzyl compounds as industrial compounds, ubiquitous environmental pollutants, and naturally occurring substances necessitates the availability of adequate biomonitoring techniques. Endogenously formed acrolein congeners are considered to play an important role in carcinogenesis. Our studies have demonstrated that acrolein congeners react with DNA components and form adducts with the guanine moiety. We have identified and characterized cyclic 1,N2-deoxyguanosine adducts, cyclic 7,8-guanine adducts, linear 7-guanine adducts, 1,N2,7,8-bis-cyclic adducts, and 1,N2-cyclic, 7-linear bis adducts. Both the reactivity of the acroleins toward nucleosides and their mutagenicity in S. typhimurium TA100 decrease with increasing degree of alkyl substitution. Adducts are now available as reference substances for developing sensitive detection methods. Of the biomonitoring methods investigated for allylic and benzyl compounds, the detection of cysteine and histidine adducts isolated from hemoglobin seems to be the most sensitive. Gas chromatography with electron capture detection of heptafluorobutyric acid derivatives allows a detection limit in the femtomole range, HPLC-fluorescence detection of O-phthalic dialdehyde derivatives allows a limit in the picomole range, and detection of 9-fluorenylmethyl-chlorofomiate derivatives allows a limit in the femtomole range.

A cohort mortality study of employees exposed to chlorinated chemicals.

The cohort of this historical prospective mortality study consisted of 697 male employees at a chlorination plant. A majority of the cohort was potentially exposed to benzotrichloride, benzyl chloride, benzoyl chloride, and other related chemicals. The mortality experience of the cohort was observed from 1943 through 1982. For the cohort as a whole, no statistically significant mortality excess was detected. The overall Standardized Mortality Ratio (SMR) was 100, and the SMR for all cancers combined was 122 (not significant). The respiratory cancer SMR for the cohort as a whole was 246 (7 observed vs. 2.8 expected). The excess was of borderline statistical significance, the lower 95% confidence limit being 99. Analysis by race showed that all 7 respiratory cancer deaths came from the white male employees, with an SMR of 265 (p less than 0.05). The respiratory cancer mortality excess was higher among employees in maintenance (SMR = 229) than among those in operations or production (SMR = 178). The lung cancer mortality excess among the laboratory employees was statistically significant (SMR = 1292). However, this observation should be viewed with caution, since it was based on only 2 deaths. Further analysis indicated that the respiratory cancer mortality excess was limited to the male employees with 15 or more years of employment (SMR = 379, p less than 0.05). Based on animal data as well as other epidemiologic studies, together with the internal consistency of analysis by length of employment, the data suggest an association between the chlorination process of toluene at the plant and an increased risk of respiratory cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of castor oil and benzyl benzoate used as a vehicle for antiandrogens on the adrenal cortex.

The use of benzyl benzoate as a vehicle constituent in administering cyproterone acetate caused morphological changes detectable at the ultrastructural level in the adrenal cortex. Xastor oil and benzyl benzoate in a 4:1 ratio caused intracellular as well as intercellular changes. In the zona fasciculata there were alterations in mitochondrial shape, size, and matrix. Intercellular changes affected the morphology of macrophages in the zona fasciculata and zona reticularis. It is believed that the castor oil and benzyl benzoate vehicle caused stress-induced changes.