Legislative Documents

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Synthetic Progestins Medroxyprogesterone Acetate and Dydrogesterone and Their Binary Mixtures Adversely Affect Reproduction and Lead to Histological and Transcriptional Alterations in Zebrafish (<i>Danio rerio</i>)

Medroxyprogesterone acetate (MPA) and dydrogesterone (DDG) are synthetic progestins widely used in human and veterinary medicine. Although aquatic organisms are exposed to them through wastewater and animal farm runoff, very little is known about their effects in the environment. Here we provide a comprehensive analysis of the responses of zebrafish (<i>Danio rerio</i>) to MPA, DDG, and their binary mixtures at measured concentrations between 4.5 and 1663 ng/L. DDG and both mixtures impaired reproductive capacities (egg production) of breeding pairs and led to histological alterations of ovaries and testes and increased gonadosomatic index. Transcriptional analysis of up to 28 genes belonging to different pathways demonstrated alterations in steroid hormone receptors, steroidogenesis enzymes, and specifically, the circadian rhythm genes, in different organs of adult zebrafish and eleuthero-embryos. Alterations occurred even at environmentally relevant concentrations of 4.5–4.8 ng/L MPA, DDG and the mixture in eleuthero-embryos and at 43–89 ng/L in adult zebrafish. Additionally, the mixtures displayed additive effects in most but not all parameters in adults and eleuthero-embryos, suggesting concentration addition. Our data suggest that MPA and DDG and their mixtures induce multiple transcriptional responses at environmentally relevant concentrations and adverse effects on reproduction and gonad histology at higher levels

Environmental Progestins Progesterone and Drospirenone Alter the Circadian Rhythm Network in Zebrafish (<i>Danio rerio</i>)

Progestins alter hormone homeostasis and may result in reproductive effects in humans and animals. Thus far, studies in fish have focused on the hypothalamic–pituitary–gonadal (HPG)-axis and reproduction, but other effects have little been investigated. Here we report that progesterone (P4) and drospirenone (DRS) interfere with regulation of the circadian rhythm in fish. Breeding pairs of adult zebrafish were exposed to P4 and DRS at concentrations between 7 and 13 650 ng/L for 21 days. Transcriptional analysis revealed significant and dose-dependent alterations of the circadian rhythm network in the brain with little effects in the gonads. Significant alterations of many target transcripts occurred even at environmental relevant concentrations of 7 ng/L P4 and at 99 ng/L DRS. They were fully consistent with the well-described circadian rhythm negative/positive feedback loops. Transcriptional alterations of the circadian rhythm network were correlated with those in the HPG-Liver-axis. Fecundity was decreased at 742 (P4) and 2763 (DRS) ng/L. Dose-dependent alterations in the circadian rhythm network were also observed in F1 eleuthero-embryos. Our results suggest a potential target of environmental progestins, the circadian rhythm network, in addition to the adverse reproductive effects. Forthcoming studies should show whether the transcriptional alterations in circadian rhythm translate into physiological effects

Occurrence and Ecotoxicological Effects of Free, Conjugated, and Halogenated Steroids Including 17α-Hydroxypregnanolone and Pregnanediol in Swiss Wastewater and Surface Water

Apart from estrogens, the occurrence and ecotoxicity of steroids in aquatic environments is poorly known. Here, we analyzed 33 steroids, including estrogens, androgens, progestins, and glucocorticoids, in hospital wastewaters, river water, and municipal wastewater treatment plant (WTP) influents and effluents at different sites in Switzerland. In addition, wastewater from different treatment steps of two WTPs with advanced treatment, such as ozonation or pulverized activated carbon, were analyzed to study the steroid’s behavior during treatment. Considerable levels of different steroids occurred in hospital and raw municipal wastewater, but they were low (lower than 1 ng/L) or below the detection level in effluents of WTPs and river water. In WTP influents, estrogens (estrone, 17β-estradiol, and estriol), androgens (androstenedione, androsterone, <i>trans</i>-androsterone, and testosterone), progestins and metabolites (progesterone, medroxyprogesterone acetate, megestrol acetate, mifepristone, pregnanediol, 17α-hydroxypregnanolone, 17α-hydroxyprogesterone, and 21α-hydroxyprogesterone) were detected and removed effectively during biological treatment. Ozonation further removed the steroids. Exposure of zebrafish embryos demonstrated negligible effects of pregnanediol and 17α-hydroxypregnanolone, while mixtures that mimic wastewater and river water composition affected embryo development and led to the alteration of steroidogenesis gene transcripts at nanogram per liter concentrations. Although steroid concentrations are low in Swiss rivers, the possibility of additive effects may be of concern

Additional file 1: of EHD1 confers resistance to cisplatin in non-small cell lung cancer by regulating intracellular cisplatin concentrations

The relationship between the cisplatin peak area and concentration was linear and characterized by a correlation coefficient of 0.998. (JPG 200 kb

Additional file 2: of EHD1 confers resistance to cisplatin in non-small cell lung cancer by regulating intracellular cisplatin concentrations

Intra-day precision and Inter-day precision. CDDP was added to a blank cellular lysate, and the level of CDDP was monitored. The statistical analysis of the data revealed the recovery of CDDP from cellular lysates and the relative standard deviation of the assay. (PDF 52 kb

Modulation of Benzo[a]pyrene-Induced Toxic Effects in Japanese Medaka (<i>Oryzias latipes</i>) by 2,2′,4,4′-Tetrabromodiphenyl Ether

Because polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenylethers (PBDEs) are ubiquitous and coexist in the environment and in wildlife, there are potential interactions between them that could cause toxic effects. In this study, the modulating effects of 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) and benzo­[a]­pyrene (BaP)-induced reproductive and developmental toxic effects in Japanese medaka (Oryzias latipes) were investigated by exposing adult Japanese medaka to BaP alone, BDE47 alone, and coexposing them with both BaP and BDE47 at different concentrations, respectively. Exposure to BaP alone significantly suppressed fecundity and egg protein content and markedly induced skeletal deformation in F1 generation eleutheroembryos. BDE47 significantly recovered reproductive functions, fecundity, and egg protein content, suppressed by BaP when the concentration of BDE47 increased to 0.44 μg/L. Such effects can be at least partly explained by the decreased BaP levels in the coexposure groups and the accompanying increase in the circulating level of 17β-estradiol in female medaka fish. The prevalence of skeletal deformations markedly increased to 19.3 ± 2.4% and 16.0 ± 1.6% in fish coexposed to BaP and BDE47 at 0.44 and 2.58 μg/L compared with that of fish exposed to 1.21 μg/L BaP alone (9.7 ± 1.7%), and the impacts on male medaka fish in the coexposure groups would be the crucial reason leading to these effects. Considering that the measured water concentrations of BaP and BDE47 in the present study were comparable with those reported in rivers and harbors, BaP and BDE47 contamination in the real world would have a significant level of interactive effects on wild fish

Biosensor Medaka for Monitoring Intersex Caused by Estrogenic Chemicals

Estrogenic chemicals can induce intersex in fish species leading to disturbance of spermatogenesis and impairment of reproductive success. To overcome the shortcomings of conventional histopathological observation on intersex (low sensitivity, relatively poor accuracy, long experimental periods, as well as laborious and time-consuming), we generated a pMOSP1-EGFP transgenic medaka fish model. In this transgenic fish, the green fluorescence protein (GFP) reporter gene was derived by the regulatory elements of the OSP1 gene, which is a specific and sensitive molecular biomarker for indicating intersex occurrence in male medaka fish exposed to estrogenic chemicals. The transgenic GFP was faithfully expressed in ovaries and in testes with intersex, perfectly mimicking the expression pattern of endogenous OSP1. In intersex testis, the diameters of primary oocytes which could be distinguished by GFP fluorescence observation were as small as 10 μm, lower than that (more than 20 μm) which is observable by histopathology. Using the novel transgenic medaka fish, intersex was observed after 90-day exposure to 0.75 ng/L 17α-ethinyloestradiol (EE₂) (0–90 dph), but only at concentrations of at least 1.38 ng/L EE₂ by histopathology. An effectiveness of a short-term in vivo assay for screening estrogenic chemicals that can monitor intersex appearance at early sex developmental stage (about 30 dph) in male medaka fish was also demonstrated by assessing the intersex induction of EE₂, 17β-estradiol and 4-nonylphenol. This newly developed assay provides an enhanced ability for screening and testing estrogenic chemicals with the potential to induce intersex and studying their biological impacts

Comprehensive Characterization of Organic Light-Emitting Materials in Breast Milk by Target and Suspect Screening

Organic light-emitting materials (OLEMs) are emerging contaminants in the environment and have been detected in various environment samples. However, limited information is available regarding their contamination within the human body. Here, we developed a novel QuEChERS (quick, easy, cheap, effective, rugged, and safe) method coupled with triple quadrupole/high-resolution mass spectrometry to determine OLEMs in breast milk samples, employing both target and suspect screening strategies. Our analysis uncovered the presence of seven out of the 39 targeted OLEMs in breast milk samples, comprising five liquid crystal monomers and two OLEMs commonly used in organic light-emitting diode displays. The cumulative concentrations of the seven OLEMs in each breast milk sample ranged from ND to 1.67 × 103 ng/g lipid weight, with a mean and median concentration of 78.76 and 0.71 ng/g lipid weight, respectively, which were higher compared to that of typical organic pollutants such as polychlorinated biphenyls and polybrominated diphenyl ethers. We calculated the estimated daily intake (EDI) rates of OLEMs for infants aged 0–12 months, and the mean EDI rates during lactation were estimated to range from 30.37 to 54.89 ng/kg bw/day. Employing a suspect screening approach, we additionally identified 66 potential OLEMs, and two of them, cholesteryl hydrogen phthalate and cholesteryl benzoate, were further confirmed using pure reference standards. These two substances belong to cholesteric liquid crystal materials and raise concerns about potential endocrine-disrupting effects, as indicated by in silico predictive models. Overall, our present study established a robust method for the identification of OLEMs in breast milk samples, shedding light on their presence in the human body. These findings indicate human exposure to OLEMs that should be further investigated, including their health risks

Comprehensive Characterization of Organic Light-Emitting Materials in Breast Milk by Target and Suspect Screening

Organic light-emitting materials (OLEMs) are emerging contaminants in the environment and have been detected in various environment samples. However, limited information is available regarding their contamination within the human body. Here, we developed a novel QuEChERS (quick, easy, cheap, effective, rugged, and safe) method coupled with triple quadrupole/high-resolution mass spectrometry to determine OLEMs in breast milk samples, employing both target and suspect screening strategies. Our analysis uncovered the presence of seven out of the 39 targeted OLEMs in breast milk samples, comprising five liquid crystal monomers and two OLEMs commonly used in organic light-emitting diode displays. The cumulative concentrations of the seven OLEMs in each breast milk sample ranged from ND to 1.67 × 103 ng/g lipid weight, with a mean and median concentration of 78.76 and 0.71 ng/g lipid weight, respectively, which were higher compared to that of typical organic pollutants such as polychlorinated biphenyls and polybrominated diphenyl ethers. We calculated the estimated daily intake (EDI) rates of OLEMs for infants aged 0–12 months, and the mean EDI rates during lactation were estimated to range from 30.37 to 54.89 ng/kg bw/day. Employing a suspect screening approach, we additionally identified 66 potential OLEMs, and two of them, cholesteryl hydrogen phthalate and cholesteryl benzoate, were further confirmed using pure reference standards. These two substances belong to cholesteric liquid crystal materials and raise concerns about potential endocrine-disrupting effects, as indicated by in silico predictive models. Overall, our present study established a robust method for the identification of OLEMs in breast milk samples, shedding light on their presence in the human body. These findings indicate human exposure to OLEMs that should be further investigated, including their health risks