Human-relevant concentrations of the antifungal drug clotrimazole disrupt maternal and fetal steroid hormone profiles in rats

Draskau, Monica Kam; Rosenmai, Anna Kjerstine; Scholze, Martin; Pedersen, Michael; Boberg, Julie; Christiansen, Sofie; Svingen, Terje

doi:10.1016/j.taap.2021.115554

Cited by 6 publications

(5 citation statements)

References 44 publications

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“…We first used the humanized C. elegans GMC101 strain, where full-length human Aβ 1-42 is expressed in muscles. This strain generates amyloid aggregates when incubated at 25 • C, which correlates with paralysis [20][21][22][23]. NS1643 resulted in worm developmental problems and was discarded from the study.…”

Section: Resultsmentioning

confidence: 99%

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Esteban-Martos,

Brokate-Llanos,

Real

et al. 2023

IJMS

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Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

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Section: Resultsmentioning

confidence: 99%

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Esteban-Martos,

Brokate-Llanos,

Real

et al. 2023

IJMS

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“…Another frequently observed effect in rats is changes to steroid hormone levels in both serum and reproductive organs, specifically the testes. Common observations include decreased testosterone levels and increased progesterone ( Vinggaard et al, 2005 ; Vinggaard et al, 2006 ; Laier et al, 2006 ; Taxvig et al, 2007 ; Taxvig et al, 2008 ; Draskau et al, 2021 ), but also decreased estrogen in plasma ( Taxvig et al, 2008 ; Draskau et al, 2019 ; Draskau et al, 2021 ). These in vivo effects fit with what we know about the affinity towards CYP enzymes for many azoles, as revealed by numerous in vitro studies ( Loose et al, 1983 ; Mason et al, 1985 ; Mason et al, 1987 ; Ayub and Levell, 1989a ; Kragie et al, 2002 ; Zarn et al, 2003 ; Trösken et al, 2006 ; Kjærstad et al, 2010 ; Ohlsson et al, 2010 ; Van der Pas et al, 2012 ; Gal and Orly, 2014 ; Munkboel et al, 2019 ).…”

Section: Adverse Reproductive Effects Of Azole Fungicidesmentioning

confidence: 99%

“…Then, despite the fact that many azole fungicides are not readily absorbed (for instance from vaginal applicators) and are often rapidly metabolized, concerns still remain regarding indiscriminate use of azole fungicides, especially during pregnancy. For instance, an OTC azole fungicide such as clotrimazole has shown strong endocrine disrupting effects in vitro and in vivo at very low concentrations, even below human therapeutically used concentrations ( Munkboel et al, 2019 ; Draskau et al, 2021 ). A second example, fluconazole, also displays endocrine disrupting potential ( Mogensen et al, 2017 ; Munkboel et al, 2019 ), almost completely avoids metabolization ( Bury et al, 2021 ), and can rapidly penetrate from plasma into female genital organs including uterus, ovary, and oviduct ( Mikamo et al, 1999 ).…”

Section: Adverse Reproductive Effects Of Azole Fungicidesmentioning

confidence: 99%

“…Many azole fungicides are potent endocrine disruptors, but these also include both prescription drugs and agricultural pesticides. With regard to OTC drugs containing azoles as the active ingredient, they are considered safe for the user; however, recent studies have questioned this, at least for certain vulnerable individuals such as the unborn child ( Mogensen et al, 2017 ; Draskau et al, 2021 ). Herein, we will briefly discuss the endocrine disrupting potential of azoles and possible detrimental effects on sexual development.…”

Section: Introductionmentioning

confidence: 99%

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Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development

Draskau

Svingen

2022

Front. Toxicol.

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Azoles are antifungal agents used in both agriculture and medicine. They typically target the CYP51 enzyme in fungi and, by so doing, disrupt cell membrane integrity. However, azoles can also target various CYP enzymes in mammals, including humans, which can disrupt hormone synthesis and signaling. For instance, several azoles can inhibit enzymes of the steroidogenic pathway and disrupt steroid hormone biosynthesis. This is of particular concern during pregnancy, since sex hormones are integral to reproductive development. In other words, exposure to azole fungicides during fetal life can potentially lead to reproductive disease in the offspring. In addition, some azoles can act as androgen receptor antagonists, which can further add to the disrupting potential following exposure. When used as pharmaceuticals, systemic concentrations of the azole compounds can become significant as combatting fungal infections can be very challenging and require prolonged exposure to high doses. Although most medicinal azoles are tightly regulated and used as prescription drugs after consultations with medical professionals, some are sold as over-the-counter drugs. In this review, we discuss various azole fungicides known to disrupt steroid sex hormone biosynthesis or action with a focus on what potential consequences exposure during pregnancy can have on the life-long reproductive health of the offspring.

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“…This includes analgesics; the most commonly used pharmaceutical agents during pregnancy, many of which are available over the counter [40]. Also, there are increasing concern about anti-fungal medication (the azole fungicides), as they can be potent inhibitors of steroidogenic enzymes critical for testosterone production in the human foetal testis [41, 42]. A challenge with both non-prescription analgesics and fungicides is that their use is poorly monitored, with potential high exposure doses if used excessively during pregnancy.…”

Section: Environmental Factorsmentioning

confidence: 99%

Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models

Jørgensen¹,

Svingen²,

Miles³

et al. 2021

Horm Res Paediatr

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Background: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. Summary: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. Key Messages: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

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Human-relevant concentrations of the antifungal drug clotrimazole disrupt maternal and fetal steroid hormone profiles in rats

Cited by 6 publications

References 44 publications

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Azole Fungicides and Their Endocrine Disrupting Properties: Perspectives on Sex Hormone-Dependent Reproductive Development

Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models

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