Developmental effects of imatinib mesylate on follicle assembly and early activation of primordial follicle pool in postnatal rat ovary

Asadi-Azarbaijani, Babak; Santos, Regiane R.; Jahnukainen, Kirsi; Braber, Saskia; Duursen, Majorie B.M. van; Toppari, Jorma; Saugstad, Ola Didrik; Nurmio, Mirja; Oskam, Irma C.

doi:10.1016/j.repbio.2016.11.003

Cited by 17 publications

(12 citation statements)

References 55 publications

(75 reference statements)

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“…One case of primary ovarian insufficiency was reported in a 28-year-old woman treated with imatinib ( 3 ), but the cause-and-effect relationship of this case was speculative ( 4 ). Two mouse models yielded conflicting results on the impact of imatinib on folliculogenesis ( 5 , 6 ). Thus, more research is needed on the reproductive toxicity of TKIs in women.…”

Section: Introductionmentioning

confidence: 99%

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Liao

Xue

et al. 2020

Oncol Rep

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The present study was designed to ascertain whether lapatinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), affects ovarian reserve and fertility potential in a mouse model. Female C57BL/6 mice were treated with either vehicle or lapatinib (100 or 200 mg/kg/day orally) for 4 weeks, after which body weight, vaginal smears, follicle numbers, serum anti-Müllerian hormone (AMH) levels and mating outcomes were analyzed to assess the ovarian reserve and reproductive function. Slices from the ovaries of 4-week-old mice were cultured with lapatinib (0, 5 or 10 µM) for 24 and 48 h, and protein expression levels were assessed to validate the changes in signaling pathways. The results indicated that mice treated with 200 mg/kg lapatinib showed a slight decrease in body weight compared to those treated with vehicle or 100 mg/kg lapatinib. There was no statistical difference in estrous cyclicity among the three groups. No significant difference was observed in follicle numbers, AMH levels, histological morphologies of the ovaries or mating outcomes in the three groups of mice. Western blotting and immunohistochemical staining of the EGF receptor and its main downstream signaling pathways showed decreased phosphorylation of EGFR and mitogen-activated protein kinase (MAPK)3/1 and increased phosphorylation of signal transducers and activators of transcription (STAT)3 in the lapatinib-treated groups compared to the control group. Our study suggests that lapatinib has little effect on ovarian reserve and reproductive function in a mouse model. This lack of effect of lapatinib on ovarian function may be due to the activation of the STAT3 signaling pathway that counteracts the inhibitory effects of lapatinib on EGF receptors.

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Section: Introductionmentioning

confidence: 99%

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Liao

Xue

et al. 2020

Oncol Rep

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“…Area measurements were obtained using ImageJ (National Institutes of Health, MD, USA). Follicle counts were adjusted per total section volume, calculated as area multiplied by section thickness, according to Bernal et al (44), Aiken et al (45, 46), Tsoulis et al (47), Asadi-Azarbaijani et al (48), and Chan et al (49), and presented as counts per mm 3 ( n = 4–6 animals per group). Follicles were classified as atretic if they presented with one or more of the following criteria: oocyte degeneration; granulosa cell degeneration, disorganization and retraction from the oocyte; appearance of pyknosis in more than 10% of granulosa cells (49–51).…”

Section: Methodsmentioning

confidence: 99%

Acylated Ghrelin Supports the Ovarian Transcriptome and Follicles in the Mouse: Implications for Fertility

et al. 2019

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Ghrelin, an orexigenic gut-derived peptide, is gaining increasing attention due to its multifaceted role in a number of physiological functions, including reproduction. Ghrelin exists in circulation primarily as des-acylated and acylated ghrelin. Des-acyl ghrelin, until recently considered to be an inactive form of ghrelin, is now known to have independent physiological functionality. However, the relative contribution of acyl and des-acyl ghrelin to reproductive development and function is currently unknown. Here we used ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no measurable levels of endogenous acyl ghrelin and chronically high levels of des-acyl ghrelin, to characterize how the developmental and life-long absence of acyl ghrelin affects ovarian development and reproductive capacity. We combined the assessment of markers of reproductive maturity and the capacity to breed with measures of ovarian morphometry, as well as with ovarian RNA sequencing analysis. Our data show that while GOAT KO mice retain the capacity to breed in young adulthood, there is a diminished number of ovarian follicles (per mm3) in the juvenile and adult ovaries, due to a significant reduction in the number of small follicles, particularly the primordial follicles. We also show pronounced specific changes in the ovarian transcriptome in the juvenile GOAT KO ovary, indicative of a potential for premature ovarian development. Collectively, these findings indicate that an absence of acyl ghrelin does not prevent reproductive success but that appropriate levels of acyl and des-acyl ghrelin may be necessary for optimal ovarian maturation.

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“…The density of preantral follicles, per development group or as total, was calculated as the total number of follicles, per class, divided by the total tissue volume and expressed as the number of follicles/mm 3 of ovarian tissue [62]. The volume of the analysed ovarian sections was calculated by summing the number of sections of area multiplied by the thickness of each section.…”

Section: Methodsmentioning

confidence: 99%

Equol: A Microbiota Metabolite Able to Alleviate the Negative Effects of Zearalenone during In Vitro Culture of Ovine Preantral Follicles

Silva

Brito

Sá

et al. 2019

Toxins

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The impact of zearalenone (ZEN) on female reproduction remains an issue, since its effects may differ among exposed cell types. Besides the use of decontaminants in animal diet, other approaches should be considered to minimise ZEN effects after exposure. Since the first organ in contact with ZEN is the gastrointestinal tract, we hypothesise that products of microbiota metabolism may play a role in ZEN detoxification. We aimed to evaluate the effect of 1 µmol/L ZEN and 1 µmol/L equol (a microbial metabolite), alone or in combination, on the survival and morphology of in vitro cultured ovarian preantral follicles. Ovaries from 12 sheep were collected at a local abattoir and fragmented, and the ovarian pieces were submitted to in vitro culture for three days in the presence or absence of the test compounds. The follicular morphology was impaired by ZEN, but equol could alleviate the observed degeneration rates. While ZEN decreased cell proliferation in primary and secondary follicles, as well as induced DNA double-strand breaks in primordial follicles, all these observations disappeared when equol was added to a culture medium containing ZEN. In the present culture conditions, equol was able to counteract the negative effects of ZEN on ovarian preantral follicles.

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Developmental effects of imatinib mesylate on follicle assembly and early activation of primordial follicle pool in postnatal rat ovary

Cited by 17 publications

References 55 publications

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Lapatinib‑induced inhibition of ovarian function is counteracted by the STAT3 pathway both in vivo and in vitro

Acylated Ghrelin Supports the Ovarian Transcriptome and Follicles in the Mouse: Implications for Fertility

Equol: A Microbiota Metabolite Able to Alleviate the Negative Effects of Zearalenone during In Vitro Culture of Ovine Preantral Follicles

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