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Werner Kloas – 1st expert on this subject based on the ideXlab platform

  • p p dichlordiphenyldichloroethylene p p dde can elicit Antiandrogenic and estrogenic modes of action in the amphibian xenopus laevis
    Physiology & Behavior, 2016
    Co-Authors: Frauke Hoffmann, Werner Kloas


    Abstract p,p′-Dichlordiphenyldichloroethylene (DDE) is a metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT), an organochloride which was massively used from its discovery in 1939 until the early 1970’s. Due to the tremendous half-life of DDT and DDE, both substances are to date environmentally relevant. Furthermore, DDT is still employed in many African countries in the context of the WHO’s antimalaria campaign. In amphibians, DDE was found to act as Antiandrogenic endocrine disrupting chemical (EDC), whereas in other species DDE was found to act as an estrogen. To determine the mode of action (MOA) of DDE in adult male Xenopus laevis, we exposed adult male frogs to different concentrations of DDE, as well as to the estrogenic EDC ethinylestradiol (EE2) and the Antiandrogenic fungicide vinclozolin (VIN) for four consecutive nights. We then analyzed the mate calling behavior, which was previously shown to be affected by (anti)androgenic and (anti)estrogenic EDC in a MOA-specific manner, in order to assess whether DDE exposure results in estrogen-specific or antiandrogen-specific alterations of the mate calling behavior. Our results demonstrate that DDE alters the reproductive behavior of male X. laevis. Lowered sexual arousal of exposed males was indicated by a decreased production of advertisement calls and higher amounts of calls that suggest a sexually unaroused state of the males. Our results further indicate that DDE can display both, estrogenic and Antiandrogenic MOA, either of which can have adverse effects on reproductive physiology and behavior in X. laevis. The disruption of the affected mating behavior, which is crucial for a successful reproduction, might result in a reduced reproductive success of DDE exposed animals.

  • mate calling behavior of male south african clawed frogs xenopus laevis is suppressed by the Antiandrogenic endocrine disrupting compound flutamide
    General and Comparative Endocrinology, 2010
    Co-Authors: Thomas Behrends, Ralph Urbatzka, Werner Kloas, Sven Krackow, Andreas Elepfandt


    Several environmental pollutants have been identified as Antiandrogenic endocrine disrupting chemicals (EDC), with flutamide (FLU) being a model compound for this type of action. Despite impacts of EDC interfering with sexual differentiation and reproduction in amphibians, established information about suggested effects on sexual behavior is still lacking. In this study adult male Xenopus laevis were injected with human chorionic gonadotropin (hCG) to initiate mate calling behavior. After one day hCG-stimulated frogs were treated via aqueous exposure over three days without and with FLU at concentrations of 10 8 and 10 6 M in comparison to untreated frogs. Androgen controlled mate calling behavior was recorded during the 12 h dark period. At the end of exposure circulating levels of testosterone (T) and 17b-estradiol (E2) were determined and furthermore gene expression was measured concerning reproductive biomarkers such as hypophysial luteinizing hormone (LH), follicle-stimulating hormone (FSH), testicular aromatase (ARO), 5a reductase type 1 (SRD5a1) and 5a reductase type 2 (SRD5a2). Both concentrations of FLU caused a significant decrease in calling activity starting at the second day of exposure. HCG injected positive controls had elevated levels of T compared to negative control frogs while in parallel treatment with FLU did not affect significantly the hCG elevated sex steroid levels. Furthermore, hCG treatment led to significantly decreased levels of gene expression for ARO and SRD5a2 but no impacts were detected on LH, FSH or SRD5a1 mRNA levels compared to negative controls. In summary, the behavioral parameter mate calling is the most sensitive biomarker detecting Antiandrogenic modes of action in this challenge-experiment indicating that this non-invasive method could markedly contribute for sensitive assessment of Antiandrogenic EDC.

  • androgenic and Antiandrogenic activities in water and sediment samples from the river lambro italy detected by yeast androgen screen and chemical analyses
    Chemosphere, 2007
    Co-Authors: Ralph Urbatzka, Werner Kloas, Anne Van Cauwenberge, Silvia Maggioni, Luigi Vigano, A Mandich, Emilio Benfenati, Ilka Lutz


    Abstract The river Lambro is the most polluted tributary of the river Po in North Italy and was chosen as a representative water course discharging industrialized areas. Water and sediment samples of the river Lambro were investigated regarding the presence of endocrine disrupting compounds. A combined procedure was used consisting of solid-phase extraction and HPLC based fractionation of samples, of screening for (anti)androgenic activity using the yeast androgen screen (YAS) and of chemical analysis using HPLC–MS/MS and GC–MS. Androgenic and Antiandrogenic activities were found in specific fractions of the water and sediment while the total extracts showed Antiandrogenic activity only. The chemical analysis of the fractions and total extracts with Antiandrogenic activities revealed the presence of compounds with suspected Antiandrogenic potency such as bisphenol A, iprodione, nonylphenol, p , p ′-DDE and tert -octylphenol but other unknown compounds contributed mainly to the observed Antiandrogenic activities. The Antiandrogenic load of the river Lambro ranged between 1.34 and 17.1 μM flutamide-equivalents and may pose a risk to aquatic environments. Future screenings for EDC in the environment that have the potential to interfere with reproduction of aquatic organisms should be extended to different modes of actions including (anti)androgenic ones.

Karl Fent – 2nd expert on this subject based on the ideXlab platform

  • effects of Antiandrogenic progestins chlormadinone and cyproterone acetate and the estrogen 17α ethinylestradiol ee2 and their mixtures transactivation with human and rainbowfish hormone receptors and transcriptional effects in zebrafish danio rerio
    Aquatic Toxicology, 2017
    Co-Authors: Patricia Franziska Siegenthaler, Karl Fent, Peter A Bain, Francesco Riva


    Abstract Synthetic progestins act as endocrine disrupters in fish but their risk to the environment is not sufficiently known. Here, we focused on an unexplored Antiandrogenic progestin, chlormadinone acetate (CMA), and the Antiandrogenic progestin cyproterone acetate (CPA). The aim was to evaluate whether their in vitro interaction with human and rainbowfish ( Melanotaenia fluviatilis ) sex hormone receptors is similar. Furthermore, we investigated their activity in zebrafish (Danio rerio) eleuthero-embryos. First, we studied agonistic and antagonistic activities of CMA, CPA, and 17α-ethinylestradiol (EE2), in recombinant yeast expressing either the human progesterone (PGR), androgen (AR), or estrogen receptor. The same compounds were also investigated in vitro in a stable transfection cell system expressing rainbowfish nuclear steroid receptors. For human receptors, both progestins exhibited progestogenic, androgenic and antiestrogenic activity with no Antiandrogenic or estrogenic activity. In contrast, interactions with rainbowfish receptors showed no progestogenic, but Antiandrogenic, antiglucocorticoid, and some antiestrogenic activity. Thus, interaction with and transactivation of human and rainbowfish PGR and AR were distinctly different. Second, we analyzed transcriptional alterations in zebrafish eleuthero‐embryos at 96 and 144 h post fertilization after exposure to CPA, CMA, EE2, and binary mixtures of CMA and CPA with EE2, mimicking the use in oral contraceptives. CMA led to slight down-regulation of the ar transcript, while CPA down-regulated ar and pgr transcripts. EE2 exposure resulted in significant transcriptional alterations of several genes, including esr1 , pgr , vtg1 , cyp19b , and gonadotropins ( fshb , lhb ). The mixture activity of CMA and EE2 followed the independent action model, while CPA and EE2 mixtures showed additive action in transcriptional alterations. Third, we analyzed the interactions of binary mixtures of CMA and CPA, and of CMA and EE2 for their joint activity in vitro and in eleuthero-embryos. Both mixtures behaved according to the concentration addition model in their in vitro interaction with human and rainbowfish receptors, often showing antagonism. In zebrafish eleuthero-embryos, binary mixtures of CMA and EE2 showed the same expression patterns as EE2 alone, indicating an independent action in vivo . Our study demonstrates that CMA and CPA interact distinctly with human and rainbowfish receptors, suggesting that activities of these and possibly additional environmental steroids determined with yeast expressing human receptors cannot simply be translated to fish. The lack of agonistic activities of both progestins to rainbowfish PGR and AR is the probable reason for the low activity found in zebrafish eleuthero-embryos.

  • additive and synergistic Antiandrogenic activities of mixtures of azol fungicides and vinclozolin
    Toxicology and Applied Pharmacology, 2014
    Co-Authors: Verena Christen, Karl Fent, Pierre Crettaz


    Objective: Many pesticides including pyrethroids and azole fungicides are suspected to have an endocrine disrupting property. At present, the joint activity of compound mixtures is only marginally known. Here we tested the hypothesis that the Antiandrogenic activity of mixtures of azole fungicides can be predicted by the concentration addition (CA) model. Methods: The Antiandrogenic activity was assessed in MDA-kb2 cells. Following assessing single compounds activities mixtures of azole fungicides and vinclozolin were investigated. Interactions were analyzed by direct comparison between experimental and estimated dose–response curves assuming CA, followed by an analysis by the isobole method and the toxic unit approach. Results: The Antiandrogenic activity of pyrethroids deltamethrin, cypermethrin, fenvalerate and permethrin was weak, while the azole fungicides tebuconazole, propiconazole, epoxiconazole, econazole and vinclozolin exhibited strong Antiandrogenic activity. Ten binary and one ternary mixture combinations of five Antiandrogenic fungicides were assessed at equi-effective concentrations of EC{sub 25} and EC{sub 50}. Isoboles indicated that about 50% of the binary mixtures were additive and 50% synergistic. Synergism was even more frequently indicated by the toxic unit approach. Conclusion: Our data lead to the conclusion that interactions in mixtures follow the CA model. However, a surprisingly high percentage of synergistic interactions occurred. Therefore, themore » mixture activity of Antiandrogenic azole fungicides is at least additive. Practice: Mixtures should also be considered for additive Antiandrogenic activity in hazard and risk assessment. Implications: Our evaluation provides an appropriate “proof of concept”, but whether it equally translates to in vivo effects should further be investigated. – Highlights: • Humans are exposed to pesticide mixtures such as pyrethroids and azole fungicides. • We assessed the Antiandrogenicity of pyrethroids and azole fungizides. • Many azole fungicides showed significant Antiandrogenic activity . • Many binary mixtures of Antiandrogenic azole fungicides showed synergistic interactions. • Concentration addition of pesticides in mixtures should be considered.« less

  • Antiandrogenic activity of phthalate mixtures validity of concentration addition
    Toxicology and Applied Pharmacology, 2012
    Co-Authors: Verena Christen, Pierre Crettaz, Aurelia Oberlischrammli, Karl Fent


    Abstract Phthalates and bisphenol A have very widespread use leading to significant exposure of humans. They are suspected to interfere with the endocrine system, including the androgen, estrogen and the thyroid hormone system. Here we analyzed the Antiandrogenic activity of six binary, and one ternary mixture of phthalates exhibiting complete Antiandrogenic dose–response curves, and binary mixtures of phthalates and bisphenol A at equi-effective concentrations of EC 10 , EC 25 and EC 50 in MDA-kb2 cells. Mixture activity followed the concentration addition (CA) model with a tendency to synergism at high and antagonism at low concentrations. Isoboles and the toxic unit approach (TUA) confirmed the additive to synergistic activity of the binary mixtures BBP + DBP, DBP + DEP and DEP + BPA at high concentrations. Both methods indicate a tendency to antagonism for the EC 10 mixtures BBP + DBP, BBP + DEP and DBP + DEP, and the EC 25 mixture of DBP + BPA. A ternary mixture revealed synergism at the EC 50 , and weak antagonistic activity at the EC 25 level by the TUA. A mixture of five phthalates representing a human urine composition and reflecting exposure to corresponding parent compounds showed no Antiandrogenic activity. Our study demonstrates that CA is an appropriate concept to account for mixture effects of Antiandrogenic phthalates and bisphenol A. The interaction indicates a departure from additivity to antagonism at low concentrations, probably due to interaction with the androgen receptor and/or cofactors. This study emphasizes that a risk assessment of phthalates should account for mixture effects by applying the CA concept.

Anne Marie Vinggaard – 3rd expert on this subject based on the ideXlab platform

  • Antiandrogenic effects in short term in vivo studies of the fungicide fenarimol
    Toxicology, 2005
    Co-Authors: Anne Marie Vinggaard, Helene Jacobsen, Stine Broeng Metzdorff, Helle Raun Andersen, Christine Nellemann


    Abstract The fungicide fenarimol has estrogenic and Antiandrogenic activity and inhibits aromatase activity in vitro. We tested, whether fenarimol had Antiandrogenic effects in vivo. In a Hershberger assay, fenarimol given orally to castrated testosterone-treated male rats caused markedly reduced weights of ventral prostate, seminal vesicles, musc. levator ani/bulbocavernosus, and bulbourethral glands. Qualitatively similar, but weaker, effects were also evident in intact fenarimol-exposed young adult males, except that prostates were not significantly affected. Changes in androgen-regulated gene expression were determined by real-time RT-PCR in ventral prostates and fenarimol caused a pronounced decrease of prostate binding protein C3 (PBP C3), ornithin decarboxylase (ODC), and insulin-like-growth factor 1 (IGF-1) mRNA levels. The antiandogenic drug flutamide, included as a positive control, caused down-regulation of PBP C3 mRNA and up-regulation of TRPM-2 mRNA levels. Serum T4 levels were reduced after fenarimol treatment and a tendency towards increased LH levels was seen. However, no effects on testosterone levels or testosterone production ex vivo could be revealed. Taken together these results indicate that fenarimol acts as an antiandrogen in vivo having effects qualitatively comparable to those of flutamide on organ level, whereas differential effects on gene expression were observed. In an additional Hershberger test, the effects of fenarimol were compared to those of estradiol benzoate, prochloraz and the aromatase inhibitor fadrozole. The data indicate a similar mode of action of fenarimol and prochloraz in the males, whereas no indications were found that the estrogenic or aromatase inhibitory properties had important impact on the effects observed in the males. Thus, it is suggested that fenarimol mediates its Antiandrogenic effects at least partly via antagonism of androgen receptors.

  • the combined Antiandrogenic effects of five commonly used pesticides
    Toxicology and Applied Pharmacology, 2004
    Co-Authors: Mia Birkhoj, Christine Nellemann, Helene Jacobsen, Helle Raun Andersen, Majken Dalgaard, Kirsten Jarfelt, Anne Marie Vinggaard


    In this study, mixture effects of five dissimilarly acting pesticides were analyzed for Antiandrogenic effects in vitro and in vivo. Deltamethrin, methiocarb, prochloraz, simazine, and tribenuron-methyl are all commonly used for agricultural and horticultural purposes.

    Concentration–response curves for the inhibition of R1881-induced transcriptional activity of the androgen receptor (AR) in vitro of each pesticide alone and in an equimolar mixture were obtained. The IC25 values for deltamethrin, methiocarb, prochloraz, and the mixture were 5.8, 5.8, 3.5, and 7.5 μM, respectively. Simazine and tribenuron-methyl were ineffective. Applying the isobole method resulted in an isobole coefficient of 0.94 at IC25 for the effect of the mixture, indicating additive effects of the compounds. Comparison of observed effects and effects calculated by assuming additivity also strongly indicated additive effects of the pesticides in vitro. In vivo, each of the five pesticides and a mixture of the pesticides were tested for Antiandrogenic effects in castrated testosterone-treated Wistar rats. The mixture induced a significant change of weights of the levator ani/bulbocavernosus muscle and adrenal glands. Changes in gene expression in ventral prostates were observed as distinct effects on levels of ornithin decarboxylase (ODC) mRNA and effects on levels of prostate binding protein subunit C3 (PBP C3) mRNA. No pesticide-induced effect on the level of testosterone-repressed prostatic message 2 (TRPM-2) mRNA was observed, whereas flutamide increased TRPM-2 levels.

    In conclusion, the pesticides were found to act additively in vitro. In vivo, the organ weight changes indicated that the pesticides had an accumulating effect that was not observed for the individual pesticides. Several pesticide-induced gene expression changes were observed, indicating that these are either very sensitive Antiandrogenic end-points or that these changes are induced by a pathway not related to AR.

  • di 2 ethylhexyl adipate deha induced developmental toxicity but not Antiandrogenic effects in pre and postnatally exposed wistar rats
    Reproductive Toxicology, 2003
    Co-Authors: Majken Dalgaard, Anne Marie Vinggaard, Ulla Hass, Kirsten Jarfelt, Ilona Kryspin Sorensen, Helle M Sommer, Ole Ladefoged


    Abstract Di(2-ethylhexyl) adipate (DEHA) has replaced the phthalates in thin plasticized polyvinyl chloride films used for food packaging, mainly because some phthalates induce testis toxicity and Antiandrogenic effects. A dose-range finding study followed by a dose–response/effect study in Wistar rats investigated whether pre- and postnatal DEHA doses of 0, 800, or 1200 mg/kg/day body weight and doses of 0, 200, 400, or 800 mg/kg/day (main study) elicited developmental toxicity including Antiandrogenic effects. In the main study, DEHA induced a prolonged gestation period (800 mg/kg/day) and a dose-related increase in postnatal death (400 and 800 mg/kg/day). DEHA also induced a permanent decrease in offspring body weight (800 mg/kg/day). No Antiandrogenic endpoints were affected. We conclude that DEHA induced developmental toxicity and the NOAEL is 200 mg/kg. DEHA did not induce Antiandrogenic effects similar to those of di(2-ethylhexyl) phthalate even though the chemical structures have similarities and the two chemicals have a common metabolite.