Transcriptome analysis of fetal rat testis following intrauterine exposure to the azole fungicides triticonazole and flusilazole reveals subtle changes despite adverse endocrine effects

Draskau, Monica Kam; Lardenois, Aurélie; Evrard, Bertrand; Boberg, Julie; Chalmel, Frédéric; Svingen, Terje

doi:10.1016/j.chemosphere.2020.128468

Cited by 21 publications

(10 citation statements)

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“…The 3’ Bulk RNA Barcoding and sequencing (BRB-seq) (Alpern et al 2019 ) experiments were performed as previously described (Draskau et al 2021 ; Giacosa et al 2021 ). Briefly, RNAs from ovaries for all treatment groups were distributed onto two 96-well plates, referred to as plate #1 and plate #2.…”

Section: Methodsmentioning

confidence: 99%

“…There are obvious temporal differences in ovarian development between the species, which also means that there are differences in susceptible windows of chemical exposure (Johansson et al 2017 ). With regard to chemical safety assessments, a prevailing challenge is that current rodent test guidelines may not be sensitive enough to reveal endocrine-disrupting effects that could pose a risk to women’s reproductive health (Draskau et al 2021 ; Johansson et al 2021 ; OECD 2018 ). This is not necessarily because there is a lack of effects, but could instead be that the endpoints being assessed are not sensitive or specific enough for their intended purposes (Johansson et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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“…For instance, the fungicide triticonazole can both inhibit steroidogenesis and AR activity, and fetal exposure leads to a short male AGD (Draskau et al, 2019). However, when analyzing the transcriptome of the fetal testes, very few changes are observed (Draskau et al, 2021) and thus triticonazole would not have been flagged as potentially harmful if relying on transcriptional changes to the fetal testis. When analyzing the transcriptome of the androgen-sensitive genital tissues, however, marked changes to the transcriptome is observed (Draskau et al, in preparation) This is just a single case to exemplify the importance of looking at the right place at the right time when elucidating mechanisms-of-action for apical in vivo endpoints and using that knowledge to develop simplified alternative methods.…”

Section: Tg 455mentioning

confidence: 99%

Using alternative test methods to predict endocrine disruption and reproductive adverse outcomes: do we have enough knowledge?

Svingen

Schwartz

Rosenmai

et al. 2022

Environmental Pollution

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“…Reads mapping to several positions in the genome were filtered out from the analysis. The pipeline is described in Draskau (2021). After quality control and data preprocessing, a gene count matrix was generated by counting the number of unique UMIs associated with each gene (lines) for each sample (columns).…”

Section: Brb-seq Raw Data Preprocessingmentioning

confidence: 99%

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Bancet

Frem

Jeanneret

et al. 2022

Preprint

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Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric αD pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 αD pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

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Transcriptome analysis of fetal rat testis following intrauterine exposure to the azole fungicides triticonazole and flusilazole reveals subtle changes despite adverse endocrine effects

Cited by 21 publications

References 50 publications

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

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

Using alternative test methods to predict endocrine disruption and reproductive adverse outcomes: do we have enough knowledge?

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

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