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Norgestrel (NGT) is a synthetic progestin used in human and veterinary medicine. Adult female mosquitofish were exposed to NGT for 42 d at 377 ng L−1. The fin morphology and the liver transcriptome were assessed. NGT exposure increased ray 4:6 length ratio. As compared to the control, NGT treatment affected the expression of 11,772 annotated transcripts in female mosquitofish. Specifically, we found 5780 were repressed while 5992 were significantly induced. Gene ontology (GO) analysis showed that 53 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and 158 GO terms were significantly over expressed. Genes showing the largest magnitude of expression changes were related to fin development, androgen biosynthesis, and lipid and fatty acid metabolisms, suggesting the involvement of these biological processes in response to NGT exposure in G. affinis. This first comprehensive study on the transcriptomic alterations by NGT in G. affinis not only provides valuable information on the development of molecular markers but also opens new avenues for studies on the molecular mechanisms of effects of NGT in particular and possibly other progestins in G. affinis.

Natural and synthetic progestins may pose a threat to wild fish populations living in receiving waters. In this study, the effects of norethindrone (NET) on the sex differentiation of zebrafish (Dario renio) and the mechanisms underlying these effects were investigated. Juvenile zebrafish (20 days post fertilization, pdf) were exposed to environmentally relevant concentrations (5, 50, 500, and 1000 ng L-1) for 45 d. Sex ratio of the NET-exposed populations, the histology of the gonads and the transcriptional profile of the regulatory genes involved in sex differentiation and steroidogenesis were examined. The results showed that a significantly higher ratio of male/female was induced in the zebrafish populations exposed to NET at concentrations higher than 32.3 ng L-1. Exposure to NET caused acceleration of sexual mature in males and a delay in ovary maturation in female zebrafish. Among the genes regulating sexual differentiation, transcripts of Dmrt1 showed a dose-dependent increase while transcripts of Figa and Fox12 showed a dose-dependent decrease in response to exposure to NET. For genes regulating the steroidogenesis, the expressions of Cyp11a1, Cyp17, Cyp19a1a, and Cyp11b were significantly down-regulated by exposure to NET, while Hsd17b3 expression was significantly up-regulated by exposure to NET at 421.3 and 892.9 ng L-1. For the receptor genes in the gonads, the transcriptional expression of Pgr, Ar, and Mr was significantly up-regulated at 421.3 and 892.9 ng L-1 of NET. For genes involved in the hypothalamic-pituitary axis, the transcriptional expression of Gnrh3 and Pomc was significantly up-regulated by exposure to NET with the exception for Gnrh3 at 4.2 ng L-1. The results demonstrated that exposure to NET at the juvenile stage could affect gonad differentiation and sex ratio, which might be accounted for by the alterations of the transcriptional expressions of genes along the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes.

Synthetic hormones in wastewater effluents released into the aquatic environments may interfere with the normal endocrine systems of fish in receiving streams. Norgestrel (NGT) is a synthetic progestin widely used in oral contraceptives and frequently detected in wastewater effluents. In this study, adult female mosquitofish (Gambusia affinis) were exposed to three environmentally relevant concentrations of norgestrel (NGT) (i.e., 3.6, 35.8, and 368.0 ng L-1) for 42 d, fin morphology, histology of the ovary, and reproductive behaviors were evaluated. The results showed that NGT at all three concentrations caused an increased frequency of atretic follicular cells in ovaries and impaired mating behaviors exhibited by males toward the NGT-exposed females. In mosquitofish exposed to NGT at 35.8 and 368 ng L-1, the anal fin of females had an increased length ratio of ray4/ray 6, an increased width of ray 3, and increased number of segments in ray 3. The histopathological analysis showed that exposure to NGT increased the incidence of spermatogenesis in ovaries. Mating behavior was impaired 58.4%, 65.7%, and 76.4% (P

(2S,4R)-methyl 1-acetyl-4-(N-(4-bromophenyl)sulfamoyloxy)pyrrolidine-2-carboxylate (CIP-A5) is the N1-acetyl substituted pyrrolidine derivative which was designed against the structure of matrix metalloproteinase (MMP-2) and MMP-9. CIP-A5 has been considered as a candidate compound for treatment of liver cirrhosis. In this study, we evaluated the efficacy of CIP-A5 on the activity of hepatic stellate cells. CIP-A5 prevented the transforming growth factor β (TGF-β)-induced proliferation of hepatic stellate HSC-T6 cells as estimated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. CIP-A5 stimulated MMPs activity as evidenced by an increase of degradation of succinylated gelatin. Gelatin zymography analysis showed that CIP-A5 stimulated the secretion and activity of MMP-2 and MMP-9 in HSC-T6 cells. This stimulatory effect on MMPs was verified by the observation of increased expression of MMP-2 and MMP-9 as evaluated by Western blot assay. At the same time, a significant decrease of the expression of tissue inhibitors of matrix metalloproteinases-1 (TIMP-1) was observed, suggesting a modulation of the balance of MMPs/TIMPs in hepatic stellate cells. CIP-A5 treatment also resulted in suppression of the profibrogenic cytokines, such as TGF-β, tumor necrosis factor alpha (TNF-α) and connective tissue growth factor (CTGF) in HSC-T6 cells. CIP-A5 did not have cytotoxicity to human normal hepatic cells. These results implied that CIP-A5 could selectively ameliorate the process of liver cirrhosis through modulation of activated hepatic stellate cell activity, which offers hope for prevention and treatment of this devastating end-stage liver disease.

To determine the reliability of MEMS devices in shock environments, in this paper, we present a method that can be used to formulate the responses of microcantilever under shock loads by taking it as a distributed-parameter system. The displacements and stresses of microcantilever are formulated with the mode superposition method. The failure modes may be estimated by the maximum displacement and stress. This method can be also used in other complicated MEMS structures and devices, therefore the reliability designs of MEMS can be improved greatly.