Classical toxicity endpoints in female rats are insensitive to the human endocrine disruptors diethylstilbestrol and ketoconazole

Johansson, Hanna Katarina Lilith; Christiansen, Sofie; Draskau, Monica Kam; Svingen, Terje; Boberg, Julie

doi:10.1016/j.reprotox.2021.01.003

Cited by 17 publications

(27 citation statements)

References 53 publications

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“…In one study, developmental exposure to 12-50 mg/kg ketoconazole did not induce any effects on AGD or NR (Wolf et al, 1999). In contrast, a second study using doses between 3 and 12 mg/kg observed statistically significant reduced AGD (∼2% at all doses) and increased NR (mean for NR ranging from 0.3 to 1 nipple) in male offspring (Johansson et al, 2021). With the effects in the second study being very small, albeit statistically significant, some caution should be made when interpreting data, especially across studies.…”

Section: Compounds With Miscellaneous Effects On Nrmentioning

confidence: 85%

“…DDE, DDT metabolite, dichlorodiphenyl- dichloroethylene; HBM, 2-Hydroxy-4-Methoxybenzone; OMC, Octyl Methoxycinnamate; DMP, dimethyl phthalate; DEP, diethyl phthalate; DBP, dibutyl phthalate; MBuP, monobutyl phthalate; DiBP, di-isobutyl phthalate; DEHP, diethylhexyl phthalate; DHP, di-n-hexyl phthalate; DCHP, dicyclohexyl phthalate; BBP, benzyl butyl phthalate; DnHP, di-n-hexyl phthalate; DHPP, di-n-heptyl phthalate; DiHP, di-isoheptyl phthalate; DnOP, di-n-octyl phthalate; DOTP, dioctyl terephthalate; DiNP, di-isononyl phthalate; DUDP, diundecyl phthalate; DTDP, ditridecyl phthalate; DES, diethylstilbestrol. 1: Andrade et al (2006) , 2: Axelstad et al (2011) , 3: Axelstad et al (2014) , 4: Barlow et al (2004) , 5: Beverly et al (2019) , 6: Boberg et al (2011) , 7: Boberg et al (2016) , 8: Bowman et al (2003) , 9: Carruthers and Foster (2005) , 10: Casanova et al (1999) , 11: Christiansen et al (2009) , 12: Christiansen et al (2010) , 13: Christiansen et al (2014) , 14: Clark et al (1990) , 15: Clark et al (1993) , 16: Clewell et al (2013) , 17: Colbert et al (2005) , 18: Delclos et al (2014) , 19: Ferguson et al (2011) , 20: Flick et al (2017) , 21: Foster and Harris (2005) , 22: Fussell et al (2015) , 23: Gray (2001) , 24: Gray et al (2000) , 25: Gray et al (2009) , 26: Gray et al (2019) , 27: Hass et al (2007) , 28: Hass et al (2012) , 29: Hellwig et al (2000) , 30: Hotchkiss et al (2004) , 31: Howdeshell et al (2007) , 32: Howdeshell et al (2008) , 33: Imperato-McGinley et al (1992) , 34: Jarfelt et al (2005) , 35: Johansson et al (2021) , 36: Kim et al (2010) , 37: Laier et al (2006) , 38: Lawson and Luderer (2004) , 39: Lee et al (2004) , 40: Lent et al (2016) , 41: Loeffler and Peterson (1999) , 42: Mandrup et al (2013) <...>…”

Section: Nipple Retention In Rat Toxicity Studiesmentioning

confidence: 99%

“…This might suggest that AGD is a more sensitive endpoint than NR for chemicals with an estrogenic mode of action. However, the much more potent diethylstilbestrol (DES) has been shown to induce some effects on both NR and AGD ( Johansson et al, 2021 ). In this latter study, rats exposed to DES at doses ranging from 0.003 to 0.0012 mg/kg resulted in a mean of 0.4–0.5 retained nipples.…”

Section: Nipple Retention In Rat Toxicity Studiesmentioning

confidence: 99%

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On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies

et al. 2021

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Areola/nipple retention (NR) is an established biomarker for an anti-androgenic mode of action in rat toxicity studies. It is a mandatory measurement under several OECD test guidelines and is typically assessed in combination with anogenital distance (AGD). Both NR and AGD are considered retrospective biomarkers of insufficient androgen signaling during the masculinization programming window in male fetuses. However, there are still aspects concerning NR as a biomarker for endocrine disruption that remains to be clarified. For instance, can NR be regarded a permanent adverse effect? Is it a redundant measurement if AGD is assessed in the same study? Is NR equally sensitive and specific to anti-androgenic chemical substances as a shortening of male AGD? In this review we discuss these and other aspects concerning the use of NR as a biomarker in toxicity studies. We have collected available literature from rat toxicity studies that have reported on NR and synthesized the data in order to draw a clearer picture about the sensitivity and specificity of NR as an effect biomarker for an anti-androgenic mode of action, including comparisons to AGD measurements. We carefully conclude that NR and AGD in rats for the most part display similar sensitivity and specificity, but that there are clear exceptions which support the continued assessment of both endpoints in relevant reproductive toxicity studies. Available literature also support the view that NR in infant male rats signifies a high risk for permanent nipples in adulthood. Finally, the literature suggests that the mechanisms of action leading from a chemical stressor event to either NR or short AGD in male offspring are overlapping with respect to canonical androgen signaling, yet differ with respect to other mechanisms of action.

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Section: Compounds With Miscellaneous Effects On Nrmentioning

confidence: 85%

Section: Nipple Retention In Rat Toxicity Studiesmentioning

confidence: 99%

Section: Nipple Retention In Rat Toxicity Studiesmentioning

confidence: 99%

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On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies

et al. 2021

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“…Numerous studies using rats or mice have investigated the endocrine disrupting potentials of azole fungicides from both agriculture and medicine, and the observed adverse reproductive outcomes are many and diverse ( Figure 1 ). Several azoles induce anti-androgenic effects such as short male AGD following developmental exposure ( Vinggaard et al, 2005 ; Laier et al, 2006 ; Taxvig et al, 2007 ; Taxvig et al, 2008 ; Hass et al, 2012 ; Johansson et al, 2021a ), but surprisingly also longer AGDs in both male and female offspring with certain azole fungicides ( Noriega et al, 2005 ; Laier et al, 2006 ; Goetz et al, 2007 ; Taxvig et al, 2007 ; Christiansen et al, 2009 ; Hass et al, 2012 ; Melching-Kollmuss et al, 2017 ). Developmental exposure to azoles have also been shown to cause nipple retention in male rat offspring ( Noriega et al, 2005 ; Vinggaard et al, 2005 ; Laier et al, 2006 ; Taxvig et al, 2007 ; Hass et al, 2012 ), which is a biomarker for compromised androgen action ( Schwartz et al, 2021 ).…”

Section: Adverse Reproductive Effects Of Azole Fungicidesmentioning

confidence: 99%

“…Developmental exposure to azoles have also been shown to cause nipple retention in male rat offspring ( Noriega et al, 2005 ; Vinggaard et al, 2005 ; Laier et al, 2006 ; Taxvig et al, 2007 ; Hass et al, 2012 ), which is a biomarker for compromised androgen action ( Schwartz et al, 2021 ). Azoles can also cause increased incidents of malformed external genitalia and hypospadias ( Noriega et al, 2005 ; Laier et al, 2006 ), as well as delayed pubertal onset ( Melching-Kollmuss et al, 2017 ; Johansson et al, 2021a ), and fewer motile sperm ( Taxvig et al, 2007 ; Melching-Kollmuss et al, 2017 ).…”

Section: Adverse Reproductive Effects Of Azole Fungicidesmentioning

confidence: 99%

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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Transcriptional profiling of the developing rat ovary following intrauterine exposure to the endocrine disruptors diethylstilbestrol and ketoconazole

et al. 2023

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Exposure to endocrine-disrupting chemicals (EDCs) during development may cause reproductive disorders in women. Although female reproductive endpoints are assessed in rodent toxicity studies, a concern is that typical endpoints are not sensitive enough to detect chemicals of concern to human health. If so, measured endpoints must be improved or new biomarkers of effects included. Herein, we have characterized the dynamic transcriptional landscape of developing rat ovaries exposed to two well-known EDCs, diethylstilbestrol (DES) and ketoconazole (KTZ), by 3’ RNA sequencing. Rats were orally exposed from day 7 of gestation until birth, and from postnatal day 1 until days 6, 14 or 22. Three exposure doses for each chemical were used: 3, 6 and 12 µg/kg bw/day of DES; 3, 6, 12 mg/kg bw/day of KTZ. The transcriptome changed dynamically during perinatal development in control ovaries, with 1137 differentially expressed genes (DEGs) partitioned into 3 broad expression patterns. A cross-species deconvolution strategy based on a mouse ovary developmental cell atlas was used to map any changes to ovarian cellularity across the perinatal period to allow for characterization of actual changes to gene transcript levels. A total of 184 DEGs were observed across dose groups and developmental stages in DES-exposed ovaries, and 111 DEGs in KTZ-exposed ovaries across dose groups and developmental stages. Based on our analyses, we have identified new candidate biomarkers for female reproductive toxicity induced by EDC, including Kcne2, Calb2 and Insl3.

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Classical toxicity endpoints in female rats are insensitive to the human endocrine disruptors diethylstilbestrol and ketoconazole

Cited by 17 publications

References 53 publications

On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies

On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies

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

Transcriptional profiling of the developing rat ovary following intrauterine exposure to the endocrine disruptors diethylstilbestrol and ketoconazole

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