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Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17β-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies. [ABSTRACT FROM AUTHOR]

Oral health is a crucial aspect of overall well‐being in both humans and nonhuman primates. Understanding the oral pathologies and dental conditions in apes can provide valuable insights into their evolutionary history, dietary habits, and overall health. The present study evaluates dental findings in wild great apes from museum specimens to gain insights into the influence of natural nutrition on dental health. Complete macerated skulls of wild, adult great apes from the collection of the Museum of Natural History, Berlin, Germany, were examined. We analyzed skulls of 53 gorillas (Gorilla gorilla), 63 chimpanzees (Pan troglodytes), and 41 orangutans (Pongo spp.). For each skull, we recorded wear of dental hard tissues (Lussi and Ganss index), carious lesions, and periodontal bone loss. Incisal and occlusal dental hard tissue defects were found in all skulls, as well as considerable external staining. In all species, incisors and canines showed the greatest loss of tissue, followed by molars. The wear of molars decreased from the first to the third molars, premolars showed the least pronounced defects. Some individuals had apical osteolytic defects along with severe dental hard tissue loss with pulp involvement or after dental trauma, respectively (n = 5). Our study did not observe any carious lesions among the examined great ape skulls. However, we did find evidence for localized or generalized periodontal bone loss in a subset of the specimens (n = 3 chimpanzees, n = 7 orangutans). The natural diet and foraging behavior of great apes induces abrasion and attrition of dental hard tissue but does not yield carious lesions. The occurrence of periodontitis in individual apes indicates that the natural circumstances can induce periodontal bone loss even in the wild, despite physiological nutrition. Research Highlights: The natural diet and foraging behavior of great apes induces wear of dental hard tissues but not carious lesions.The occurrence of periodontitis in individual apes indicates that the natural microbiome, in conjunction with the host's defense, can induce periodontal bone loss even in the wild. [ABSTRACT FROM AUTHOR]

Background: Despite the high number of synthetic androgenic–anabolic steroids, testosterone is still misused for doping in amateur and professional sports. However, only few studies investigated the dose–response effects of testosterone beyond its physiological concentrations and in over 90 years of research, no saturation dosage has been experimentally described for exogenous testosterone administration. Objectives: We want to elucidate the physiological and pathophysiological effects of supra‐physiological testosterone application and close this gap in testosterone dose–response data. Materials and methods: Male orchiectomized rats were treated with different testosterone doses ranging from 0.1 to 50 mg/kg body weight for 3 weeks. Several physiological endpoints (e.g., body weight, organ and muscle weight, muscle strength, muscle fiber size) were examined during and after the termination of the treatment with an adjusted Hershberger assay, open‐field‐test, and (immuno‐)histologic. Results: The wet weights of androgen responsive organs (penis, prostate, seminal vesicle) showed a significant increase in a dose‐dependent manner. Histological evaluation of the prostate showed a significant higher percentage of KI67 positive prostate nuclei in the highest dosage group and an increasing hyperplasia with increasing testosterone administered. A significant anabolic effect was only observed in Levator ani wet weight, and to minor degree for the cardiac muscle. Regarding other skeletal muscles (Musculus soleus and Musculus gastrognemicus), no significant testosterone effects were observed. We showed a significant increasing dosage–response effect for testosterone in androgen responsive organs with saturation at the two highest concentration of 10 and 50 mg/kg body weight. Discussion and conclusion: The dose‐dependent androgenic effects of testosterone were well observable and the anabolic effects on muscle tissue were visible although to a lesser degree, without the support of aerobic exercise and a protein rich diet. Future studies should investigate a combinatorial effect of testosterone and training. Nevertheless, with the chosen range of applied testosterone, we showed a saturation of testosterone effects in prostate, seminal vesicle, penis, and Levator ani. [ABSTRACT FROM AUTHOR]

The elucidation of the metabolic fate of prohibited substances is crucial for the abuse detection. The human hepatocyte cell line HepG2 can be used to study biotransformation. In order to improve this in vitro model system, we compared the HepG2 spheroid generation using three different techniques: a forced floating, a scaffold‐free and a scaffold‐based method. We characterized the spheroids with regard to the expression levels of the proliferation marker Mki67, the liver‐specific marker albumin and biotransformation enzymes. Moreover, the metandienone metabolite pattern was comparatively analysed by high‐performance liquid chromatography mass spectrometry. With all three techniques, HepG2 spheroids were generated showing a degree of differentiation. The forced floating method resulted in very large spheroids (1 mm in diameter) showing signs of necrosis in the centre and a very low metandienone conversion rate. The spheroids formed by the two other techniques were comparable in size with 0.5 mm in diameter on average. Among the three different 3D cultivation methods, the HepG2 spheroids formed on Matrigel® as extracellular matrix were the most promising regarding biotransformation studies on anabolic androgenic steroids. Prospectively, HepG2 spheroids are a promising in vitro model system to study multidrug setups, drug–drug interactions and the biotransformation of other substance classes. [ABSTRACT FROM AUTHOR]

Background: Cross-talk between the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) plays a major role in signaling processes in female reproductive organs. OBJECTIVES: We investigated the influence of the AHR ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) rats. METHODS: After 14 days of hormonal decline, ovx rats were treated for 3 days with 4 µg/kg 17β-estradiol (E2), 15 mg/kg 8-prenylnaringenin (8-PN), 15 mg/kg 3-MC, or a combination of these compounds (E2 + 3-MC, 8-PN + 3-MC). Whole-mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (immunohistochemistry, immunofluorescence), a cDNA microarray, pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways. RESULTS: E2 treatment increased the number of TEBs and the levels of Ki-67 protein and progesterone receptor (PR); this treatment also changed the expression of 325 genes by more than 1.5-fold. Although 3-MC treatment alone had marginal impact on gene or protein expression, when rats were co-treated with 3-MC and E2, 3-MC strongly inhibited E2-induced TEB development, protein synthesis, and the expression of nearly half of E2-induced genes. This inhibitory effect of 3-MC was partially mirrored when 8-PN was used as an ER ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ERα in ductal epithelial cells. CONCLUSION: Our data show transcriptome-wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing an explanation for the chemopreventive and endocrine-disrupting potential of AHR ligands. http://dx.doi.org/10.1289/ehp.1509680, Introduction To evaluate the influence of endocrine-disrupting natural compounds or selective estrogen receptor modulators, it is crucial to understand the underlying mechanisms. This study was designed to investigate the impact [...]

Eurycoma longifolia Jack (Tongkat Ali, Simaroubaceae) is a medicinal plant endemic to South‐East Asia. For centuries, different parts of the plant have been used as a natural remedy to treat fever, hypertension, or sexual insufficiency. Today, Eurycoma longifolia preparations are commercially available and advertised to enhance athletic performance and muscle strength. Several studies have demonstrated a testosterone‐boosting effect that might be caused by the release of free testosterone from the sex‐hormone‐binding globulin. To date, many phytochemical constituents of Eurycoma longifolia root extracts have been identified and physiological effects have been examined, while studies on their biotransformation and monitoring are still lacking. Within this study, eurycomalide C, eurycomalactone, 5,6‐dehydro‐eurycomalactone, longilactone, 14,15β‐dihydroklaieanone, 11‐dehydroklaieanone, 9‐hydroxycanthin‐6‐one, and 9‐methoxycanthin‐6‐one isolated from E. longifolia root were incubated with liver microsomes. Respective metabolites were analyzed by liquid chromatography–tandem (high‐resolution) mass spectrometry. The compounds were chosen based on their potential androgenic effects (estimated by in vitro assays), their concentrations in plant extracts, and presumptive metabolic pathways. Hydroxylated phase I metabolites were only observed for 5,6‐dehydro‐eurycomalactone, 11‐dehydroklaieanone, 9‐hydroxycanthin‐6‐one, and 9‐methoxycanthin‐6‐one. Moreover, an O‐demethylated metabolite of 9‐methoxycanthin‐6‐one was found. Besides, the glucuronide of 9‐hydroxycanthin‐6‐one was detected after in vitro glucuronidation using liver microsomes. The in vitro generated metabolites were comparable to that detected in urine and serum after a single ingestion of either 9‐methoxycanthin‐6‐one or an Eurycoma longifolia root extract. Hence, 9‐methoxycanthin‐6‐one, its glucuronide, and the glucuronide of its O‐demethylated biotransformation product are proposed to be the most suitable targets for detection of 9‐methoxycanthin‐6‐one or Tongkat Ali application in urine and serum. Tongkat Ali is used as dietary supplement with anabolic effects among bodybuilders. In vitro and in vivo metabolism of Tongkat Ali compounds are described. LC‐MS/MS analysis of parent compounds and metabolites identified target analytes suitable for doping routine analysis. [ABSTRACT FROM AUTHOR]