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

Kugathas, Indusha; Johansson, Hanna Katarina Lilith; Peng, Edith Chan Sock; Toupin, Maryne; Evrard, Bertrand; Darde, Thomas Alain; Boberg, Julie; Draskau, Monica Kam; Rolland, Antoine; Mazaud-Guittot, Séverine; Chalmel, Frédéric; Svingen, Terje

doi:10.1007/s00204-023-03442-2

Cited by 5 publications

(2 citation statements)

References 67 publications

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“…For this reason, any compound which interferes with estrogen-dependent processes, as estrogenic or anti-androgenic compounds, in the developing brain can disrupt the sexual differentiation and consequently also the programming of puberty and reproductive function. Thus, we cannot exclude that the hypothalamic disruption is indirect and due to an altered release of peripheral steroids as KTZ can inhibit steroidogenic P450 enzymes in the adrenal cortex ( 104 , 105 ) and gonads ( 105 , 106 ). A recent review also reported that azole fungicides may affect all levels of the hypothalamo-pituitary-adrenal & gonadal axes in fish ( 107 ).…”

Section: Discussionmentioning

confidence: 99%

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats

et al. 2023

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IntroductionEstrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats.DesignFemale rats were exposed to KTZ or DES during perinatal (DES 3-6-12μg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48μg/kg.d; KTZ 3-12-48mg/kg.d).ResultsEx vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted “Creb signaling in Neurons” and “IGF-1 signaling” among the most downregulated pathways by all doses of KTZ and DES before puberty, and “PPARg” as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood.ConclusionnRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation.

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Section: Discussionmentioning

confidence: 99%

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats

et al. 2023

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“…Using two compounds that we know have endocrine disrupting effects in humans enables comparison of the two exposure windows, as well as endpoint sensitivity using an established OECD test guideline ( 3 ). Perinatal exposure to these endocrine disruptors has been shown to affect reproductive development ( 1 , 2 , 16 , 17 ) and they are expected to display different effect patterns depending on age at exposure start.…”

Section: Introductionmentioning

confidence: 99%

Comparison of female rat reproductive effects of pubertal versus adult exposure to known endocrine disruptors

Boberg,

Li,

Christiansen

et al. 2023

Front. Endocrinol.

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A prevailing challenge when testing chemicals for their potential to cause female reproductive toxicity is the lack of appropriate toxicological test methods. We hypothesized that starting a 28-day in vivo toxicity study already at weaning, instead of in adulthood, would increase the sensitivity to detect endocrine disruptors due to the possibility of including assessment of pubertal onset. We compared the sensitivity of two rat studies using pubertal or adult exposure. We exposed the rats to two well-known human endocrine disruptors, the estrogen diethylstilbestrol (DES; 0.003, 0.012, 0.048 mg/kg bw/day) and the steroid synthesis inhibitor ketoconazole (KTZ; 3, 12, 48 mg/kg bw/day). Specifically, we addressed the impact on established endocrine-sensitive endpoints including day of vaginal opening (VO), estrous cyclicity, weights of reproductive organs and ovarian histology. After 28 days of exposure, starting either at weaning or at 9 weeks of age, DES exposure altered estrous cyclicity, reduced ovary weight as well as number of antral follicles and corpora lutea. By starting exposure at weaning, we could detect advanced day of VO in DES-exposed animals despite a lower body weight. Some endpoints were affected mainly with adult exposure, as DES increased liver weights in adulthood only. For KTZ, no effects were seen on time of VO, but adrenal and liver weights were increased in both exposure scenarios, and adult KTZ exposure also stimulated ovarian follicle growth. At first glance, this would indicate that a pubertal exposure scenario would be preferrable as timing of VO may serve as sensitive indicator of endocrine disruption by estrogenic mode of action. However, a higher sensitivity for other endocrine targets may be seen starting exposure in adulthood. Overall, starting a 28-day study at weaning with inclusion of VO assessment would mainly be recommended for substances showing estrogenic potential e.g., in vitro, whereas for other substances an adult exposure scenario may be recommended.

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Ketoconazole blocks progesterone production without affecting other parameters of cumulus-oocyte complex maturation

Asimaki,

Vazakidou,

van Tol

et al. 2024

Reproductive Toxicology

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

Cited by 5 publications

References 67 publications

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats

Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats

Comparison of female rat reproductive effects of pubertal versus adult exposure to known endocrine disruptors

Ketoconazole blocks progesterone production without affecting other parameters of cumulus-oocyte complex maturation

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