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Zhao Y.,University of Applied Sciences and Arts Northwestern Switzerland | Castiglioni S.,Environmental Biomarkers Unit | Fent K.,University of Applied Sciences and Arts Northwestern Switzerland | Fent K.,ETH Zurich
Environmental Science and Technology | Year: 2015

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 (Danio rerio) 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. © 2015 American Chemical Society. Source


Zucchi S.,Northwestern University | Castiglioni S.,Environmental Biomarkers Unit | Fent K.,Northwestern University | Fent K.,ETH Zurich
Environmental Science and Technology | Year: 2013

Progesterone (P4) is a natural steroid hormone excreted by humans and animals. Noncomplete degradation in treatment plants result in levels in the ng/L range in surface waters. Very little is known of the effects on fish at such concentrations. Here we determine the global expression profile in the brain and ovary of female zebrafish exposed for 14 days to 3.5, 33 and 306 ng/L P4 to elucidate molecular effects. For validation selected transcripts were determined by RT-qPCR. In the brain, 54 and 255 transcripts were altered at 3.5 and 306 ng/L, respectively. Genes related to circadian rhythm (nr1d2b, per1b), cell cycle and reproduction (cdc20, ccnb1) were down-regulated. In the ovary, transcriptional changes occurred in 200, 84 and 196 genes at 3.5, 33 and 306 ng/L, respectively. The genes belong to different pathways including cardiac hypertrophy, cell cycle and its regulation. P4 slightly influenced oocyte maturation as revealed by histology of the ovaries. In the liver, vtg1 was down-regulated at all concentrations and VTG protein at 306 ng/L in the blood. The data show molecular effects and the modes of action of P4 at environmental concentrations. Ultimately they may translate to adverse effects on reproduction. © 2013 American Chemical Society. Source


Rossier N.M.,University of Applied Sciences and Arts Northwestern Switzerland | Rossier N.M.,University of Basel | Chew G.,University of Applied Sciences and Arts Northwestern Switzerland | Zhang K.,University of Applied Sciences and Arts Northwestern Switzerland | And 3 more authors.
Aquatic Toxicology | Year: 2016

Despite potential exposure of aquatic organisms to mixtures of steroid hormones, very little is known on their joint activity in fish. Drospirenone (DRS) is a new synthetic progestin used in contraceptive pills in combination with 17α-ethinylestradiol (EE2). Here we systematically analyzed effects of DRS in binary mixtures with progesterone (P4) and EE2. First, we determined the in vitro activity of single compounds in recombinant yeast assays that express the human progesterone, androgen, or estrogen receptor, followed by determination of mixture activities of DRS and P4, DRS and EE2, as well as medroxyprogesterone acetate (MPA) and dydrogesterone (DDG). Mixtures of DRS and P4, as well as of DRS and EE2 showed additive progestogenic and androgenic activities. However, DDG and MPA showed non-additive progestogenic and androgenic activities.We then analyzed the in vivo activity of single compounds and mixtures of DRS and P4, as well as DRS and EE2, by assessing transcriptional changes of up to 14 selected target genes in zebrafish embryos at 48 h post fertilization (hpf), and in eleuthero-embryos at 96 hpf and 144 hpf. DRS, P4, and EE2 led to significant transcriptional alteration of genes, including those encoding hormone receptors (pgr, esr1), a steroidogenic enzyme (hsd17b3), and estrogenic markers (vtg1, cyp19b), in particular at 144 hpf. In general, DRS showed stronger transcriptional changes than P4. In mixtures of DRS and P4, they were mainly non-additive (antagonistic interaction). In mixtures of DRS and EE2, transcriptional responses of esr1, vtg1 and cyp19b were dominated by EE2, suggesting an antagonistic interaction or independent action. Equi-effective mixtures of DRS and EE2, based on progesterone receptor transcripts, showed antagonistic interactions.Our data suggest that interactions in mixtures assessed in vitro in recombinant yeast cannot be translated to the in vivo situation. The receptor-based responses did not correspond well to the transcriptional responses in embryos which are much more complex due to the interplay between hormonal pathways, receptor crosstalk, and hormonal feedback loops. © 2016 Elsevier B.V. Source


Zhao Y.,University of Applied Sciences and Arts Northwestern Switzerland | Castiglioni S.,Environmental Biomarkers Unit | Fent K.,University of Applied Sciences and Arts Northwestern Switzerland | Fent K.,ETH Zurich
Environmental Science and Technology | Year: 2015

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. © 2015 American Chemical Society. Source


Castiglioni S.,Environmental Biomarkers Unit | Thomas K.V.,Norwegian Institute for Water Research | Kasprzyk-Hordern B.,University of Bath | Vandam L.,European Monitoring Center for Drugs and Drug Addiction | Griffiths P.,European Monitoring Center for Drugs and Drug Addiction
Science of the Total Environment | Year: 2014

Illicit drug use is a global phenomenon involving millions of individuals, which results in serious health and social costs. The chemical analysis of urban wastewater for the excretion products of illicit drugs is a potent approach for monitoring patterns and trends of illicit drug use in a community. The first international and multidisciplinary conference on this topic was recently organized to present the epidemiological knowledge of patterns in drug use and the information obtained from wastewater analysis. This paper gives an overview of the main issues that emerged during the conference, focusing on the identified research gaps and requirements and on the future challenges and opportunities from bringing together wastewater analysis and drug epidemiology. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) uses an established multi-indicator system to monitor illicit drug use and to identify the emergence of new psychoactive substances. The methodological challenges of monitoring a hidden and stigmatized behavior like drug use include the limitations of self-report data and reporting delays. An increasing evidence base suggests that wastewater analysis can address some of these problems. Specifically this technique can: monitor temporal and spatial trends in drug use at different scales, provide updated estimates of drug use, and identify changing habits and the use of new substances. A best practice protocol developed by a Europe-wide network of experts is available to produce homogeneous and comparable data at different sites. The systematic evaluation of uncertainties related to wastewater analysis has highlighted which areas require careful control and those that need further investigation to generally improve the approach. Wastewater analysis has considerable potential to complement existing approaches for monitoring drug use due to its ability to produce objective, real-time estimates of drug use and to give timely information of any change in the patterns of use. © 2013 Elsevier B.V. Source

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