Fent, Karl

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Karl
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Fent, Karl

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2015 - 2019382020 - 20211
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  • Vorschaubild nicht verfügbar
    Publikation
    Activity of binary mixtures of drospirenone with progesterone and 17?-ethinylestradiol in vitro and in vivo
    (Elsevier, 22.02.2016) Rossier, Nadine Madeleine; Chew, Geraldine; Zhang, Kun; Riva, Francesco; Fent, Karl [in: Aquatic Toxicology]
    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 48h post fertilization (hpf), and in eleuthero-embryos at 96hpf and 144hpf. 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.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Transcriptional and physiological effects of the pyrethroid deltamethrin and the organophosphate dimethoate in the brain of honey bees (Apis mellifera)
    (Elsevier, 01/2019) Christen, Verena; Joho, Yvonne; Vogel, Maren; Fent, Karl [in: Environmental Pollution]
    The pyrethroid deltamethrin and the organophosphate insecticide dimethoate are widely used in agriculture and in urban areas. Both plant protection products (PPPs) unintendedly result in adverse effects in pollinators. Currently, the sublethal effects of both compounds are poorly known, particularly on the molecular and biochemical level. Here we analysed effects of deltamethrin and dimethoate at environmental and sublethal concentrations in honey bee workers by focusing on transcriptional changes of target genes in the brain. In addition, expression of vitellogenin protein and activity of acetylcholinesterase were assessed upon dimethoate exposure to assess physiological effects. Deltamethrin resulted in induction of the cyp9q2 transcript at 0.53 ng/bee, while dimethoate led to induction of vitellogenin on the mRNA and protein level at 2 ng/bee. Transcripts of additional cytochrome P450-dependent monooxygenases (cyps) and genes related to immune system regulation were not differentially expressed upon PPP exposure. Dimethoate but not deltamethrin led to a strong and concentration-related inhibition of the acetylcholinesterase at 2 and 20 ng/bee. Our data demonstrate that deltamethrin and dimethoate exhibit transcriptional effects at environmental concentrations in the brain of honey bees. Dimethoate also strongly affected physiological traits, which may translate to adverse effects in forager bees.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Regulation of zebrafish (Danio rerio) locomotor behavior and circadian rhythm network by environmental steroid hormones
    (Elsevier, 01/2018) Fent, Karl; Zhao, Yanbin; Zhang, Kun [in: Environmental Pollution]
    Environmental exposure of fish to steroid hormones through wastewater and agricultural runoff may pose a health risk. Thus far, ecotoxicological studies have largely been focused on the disruption of the sex hormone system, but additional effects have been poorly investigated. Here we report on the effects of a series of different natural and synthetic steroid hormones on the locomotor behavior and the transcriptional levels of core clock genes in zebrafish eleuthero-embryos (Danio rerio). Of the 20 steroids analyzed, progestins and corticosteroids, including progesterone and cortisol, significantly decreased the locomotor activities of eleuthero-embryos at concentrations as low as 16 ng/L, while estrogens such as 17β-estradiol led to an increase. Consistently, progestins and corticosteroids displayed similar transcriptional effects on core clock genes, which were remarkably different from those of estrogens. Of these genes, per1a and nr1d2a displayed the most pronounced alterations. They were induced upon exposure to various progestins and corticosteroids and could be recovered using the progesterone receptor/glucocorticoid receptor antagonist mifepristone; this, however, was not the case for estrogens and the estrogen receptor antagonist 4-hydroxy-tamoxifen. Our results suggest that steroid hormones can modulate the circadian molecular network in zebrafish and provide novel insights into their mode of actions and potential environmental risks.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Mixtures of Aluminum and Indium Induce More than Additive Phenotypic and Toxicogenomic Responses in Daphnia magna
    (American Chemical Society, 01/2019) Brun, Nadja; Fent, Karl [in: Environmental Science & Technology]
    Aquatic systems are contaminated by many metals but their effects as mixtures on organisms are not well understood. Here, we assessed effects of aluminum with fairly well-known modes of actions and indium, an understudied emerging contaminant from electronics, followed by studying equi-effective mixtures thereof. We report acute and adverse phenotypic effects in Daphnia magna adults and global transcriptomic effects employing RNA sequencing in neonates. The mixture induced more than additive activity in mortality and in physiological effects, including growth and reproduction. Similarly, transcriptomic effects were more than additive, as indicated by a markedly higher number of 463 differentially expressed transcripts in the mixture and by distinct classes of genes assigned to several biological functions, including metabolic processes, suggesting depleted energy reserves, which may be responsible for the observed impaired reproduction and growth. A gene set enrichment analysis (GSEA) of a priori known response pathways for aluminum confirmed activation of distinct molecular pathways by indium. Our study is highlighting more than additive effects at the transcriptional and physiological level and is providing a state-of-the art approach to mixture analysis, which is important for risk assessment of these metals and metal mixtures.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Ecotoxicological Assessment of Solar Cell Leachates
    (2015) Fent, Karl; Brun, Nadja; Wehrli, Bernhard
    06 - Präsentation
  • Vorschaubild nicht verfügbar
    Publikation
    Binary mixtures of neonicotinoids show different transcriptional changes than single neonicotinoids in honeybees (Apis mellifera)
    (Elsevier, 11.11.2016) Christen, Verena; Bachofer, Sara; Fent, Karl; [in: Environmental Pollution]
    Among the many factors responsible for the decline of bee populations are plant protection products such as neonicotinoids. In general, bees are exposed to not only one but mixtures of such chemicals. At environmental realistic concentrations neonicotinoids may display negative effects on the immune system, foraging activity, learning and memory formation of bees. Neonicotinoids induce alterations of gene transcripts such as nicotinic acetylcholine receptor (nAChR) subunits, vitellogenin, genes of the immune system and genes linked to memory formation. While previous studies focused on individual compounds, the effect of neonicotinoid mixtures in bees is poorly known. Here we investigated the effects of neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam as single compounds, and binary mixtures thereof in honeybees. We determined transcriptional changes of nAChR subunits and vitellogenin in the brain of experimentally exposed honeybees after exposure up to 72 h. Exposure concentrations were selected on the basis of lowest effect concentrations of the single compounds. Transcriptional induction of nAChRs and vitellogenin was strongest for thiamethoxam, and weakest for acetamiprid. To a large extent, binary mixtures did not show additive transcriptional inductions but they were less than additive. Our data suggest that the joint transcriptional activity of neonicotinoids cannot be explained by concentration addition. The in vivo effects are not only governed by agonistic interaction with nAChRs alone, but are more complex as a result of interactions with other pathways as well. Further studies are needed to investigate the physiological joint effects of mixtures of neonicotinoids and other plant protection products on bees to better understand their joint effects.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Endocrine disruption and chronic effects of plant protection products in bees: Can we better protect our pollinators?
    (Elsevier, 09/2018) Christen, Verena; Kunz, Petra Y.; Fent, Karl [in: Environmental Pollution]
    Exposure to plant protection products (PPPs) is one of the causes for the population decline of pollinators. In addition to direct exposure, pollinators are exposed to PPPs by pollen, nectar and honey that often contain residues of multiple PPPs. While in legislation PPPs are regarded mainly for their acute toxicity in bees, other effects such as neurotoxicity, immunotoxicity, behavioural changes, stress responses and chronic effects that may harm different physiologically and ecologically relevant traits are much less or not regarded. Despite the fact that endocrine disruption by PPPs is among key effects weakening survival and thriving of populations, pollinators have been poorly investigated in this regard. Here we summarize known endocrine disruptive effects of PPPs in bees and compare them to other chronic effects. Endocrine disruption in honey bees comprise negative effects on reproductive success of queens and drones and behavioural transition of nurse bees to foragers. Among identified PPPs are insecticides, including neonicotinoids, fipronil, chlorantraniliprole and azadirachtin. So far, there exists no OECD guideline to investigate possible endocrine effects of PPPs. Admittedly, investigation of effects on reproduction success of queens and drones is rarely possible under laboratory conditions. But the behavioural transition of nurse bees to foragers could be a possible endpoint to analyse endocrine effects of PPPs under laboratory conditions. We identified some genes, including vitellogenin, which regulate this transition and which may be used as biomarkers for endocrine disruptive PPPs. We plea for a better implementation of the adverse outcome pathway concept into bee's research and propose a procedure for extending and complementing current assessments, including OECD guidelines, with additional physiological and molecular endpoints. Consequently, assessing potential endocrine disruption in pollinators should receive much more relevance.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Silica nanoparticles induce endoplasmic reticulum stress response and activate mitogen activated kinase (MAPK) signalling
    (Elsevier, 2016) Christen, Verena; Fent, Karl [in: Toxicology Reports]
    Humans may be exposed to engineered silica nanoparticles (SiO2-NPs) but potential adverse effects are poorly understood, in particular in relation to cellular effects and modes of action. Here we studied effects of SiO2-NPs on cellular function in human hepatoma cells (Huh7). Exposure for 24 h to 10 and 50 μg/ml SiO2-NPs led to induction of endoplasmic reticulum (ER) stress as demonstrated by transcriptional induction of DNAJB9, GADD34, CHOP, as well as CHOP target genes BIM, CHAC-1, NOXA and PUMA. In addition, CHOP protein was induced. In addition, SiO2-NPs induced an inflammatory response as demonstrated by induction of TNF-α and IL-8. Activation of MAPK signalling was investigated employing a PCR array upon exposure of Huh7 cells to SiO2-NPs. Five of 84 analysed genes, including P21, P19, CFOS, CJUN and KSR1 exhibited significant transcriptional up-regulation, and 18 genes a significant down-regulation. Strongest down-regulation occurred for the proto-oncogene BRAF, MAPK11, one of the four p38 MAPK genes, and for NFATC4. Strong induction of CFOS, CJUN, FRA1 and CMYC was found after exposure to 50 μg/ml SiO2-NPs for 24 h. To analyse for effects derived from up-regulation of TNF-α, Huh7 cells were exposed to SiO2-NPs in the presence of the TNF-α inhibitor sauchinone, which reduced the induction of the TNF-α transcript by about 50%. These data demonstrate that SiO2-NPs induce ER stress, MAPK pathway and lead to inflammatory reaction in human hepatoma cells. Health implications of SiO2-NPs exposure should further be investigated for a risk assessment of these frequently used nanoparticles.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Effects of antiandrogenic progestins, chlormadinone and cyproterone acetate, and the estrogen 17a-ethinylestradiol (EE2), and their mixtures: Transactivation with human and rainbowfish hormone receptors and transcriptional effects in zebrafish (Danio rerio) eleuthero-embryos
    (Elsevier, 01/2017) Siegenthaler, Patricia Franziska; Bain, Peter; Riva, Francesco; Fent, Karl [in: Aquatic Toxicology]
    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.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    Reproductive and transcriptional effects of the antiandrogenic progestin chlormadinone acetate in zebrafish (Danio rerio)
    (Elsevier, 2017) Zhang, Kun; Fent, Karl; Siegenthaler, Patricia Franziska; Zhao, Yanbin [in: Environmental Pollution]
    Chlormadinone acetate (CMA) is a frequently used progestin with antiandrogenic activity in humans. Residues may enter the aquatic environment but potential adverse effects in fish are unknown. While our previous work focused on effects of CMA in vitro and in zebrafish eleuthero-embryos, the present study reports on reproductive and transcriptional effects in adult female and male zebrafish (Danio rerio). We performed a reproductive study using breeding groups of zebrafish. After 15 days of pre-exposure, we exposed zebrafish to different measured concentrations between 6.4 and 53,745 ng/L CMA for 21 days and counted produced eggs daily to determine fecundity. Additionally, transcriptional effects of CMA in brains, livers, and gonads were analyzed. CMA induced a slight but statistically significant reduction in fecundity at 65 ng/L and 53,745 ng/L compared to pre-exposure. Furthermore, we observed differential expression for gene transcripts of steroid hormone receptors, genes related to the hypothalamic-pituitary-gonadal axis, and steroidogenesis. In particular, we found a significant decrease of transcript levels of vitellogenin (vtg1) in ovaries and liver, and of cyp2k7 in the liver of males, as well as a significant increase of transcripts of the progesterone receptor (pgr) in testes, and cyp2k1 in the liver of females. The observed effects were weaker than those of other very potent progestins, which is probably related to the lack of interaction of CMA with the zebrafish progesterone receptor.
    01A - Beitrag in wissenschaftlicher Zeitschrift