LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

Rossi, Valerio; Lispi, Monica; Longobardi, Salvatore; Mattei, Maurizio; Rella, Francesca Di; Salustri, Antonietta; Felici, Massimo De; Klinger, Francesca Gioia

doi:10.1038/cdd.2016.97

Cited by 93 publications

(93 citation statements)

References 61 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Some scholars found that sildenafil inhibited the loss of antral follicles induced by cisplatin and increased the level of AMH (Taskin, Yay, Adali, Balcioglu, & Inceboz, 2015). A study by Rossi et al (2017) has shown the rescue of the number of primordial follicles in prepubescent mice treated with luteinizing hormone, which increased the chance of pregnancy and number of offspring. Jang et al (2017) found that melatonin and ghrelin could promote the binding of Foxo3a to the p27Kip1 promoter to inhibit the phosphorylation of Foxo3a, thus reducing the activation of primordial follicles induced by cisplatin.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo

Xie

Zhou

et al. 2020

Molecular Reproduction Devel

View full text Add to dashboard Cite

Rapamycin has been proven to effectively inhibit the activation of primordial follicles while cisplatin-induced the loss of primordial follicles due to the overactivation of the primordial follicle stockpile. Whether rapamycin could inhibit the loss of primordial follicles induced by cisplatin is still unknown. The ovaries of neonatal Sprague Dawley rats were cultured in vitro in different doses of rapamycin (0.08, 0.16, and 0.32 μg/ml) and cisplatin (0.1, 0.4, and 0.8 μg/ml). The immature BALB/c mice were administered cisplatin with or without rapamycin by intraperitoneal injection. Ovaries were collected to analyze the histomorphology, the messenger RNA (mRNA) expression of anti-Mullerian hormone (AMH), growth differentiation factor 9 (GDF9), and bone morphogenetic protein 15 (BMP15) and the expression of key proteins of mammalian target of rapamycin (mTOR) pathway.Growing follicle counts of ovaries cultured in vitro in the R0.16 and R0.32 groups were decreased and the ratio of growing to primordial follicles was also decreased in a dose-dependent manner. In the C0.8 group, growing follicles were decreased compared with the other groups while the ratio was substantially increased in the C0.4 and C0.8 group. Co-treatment attenuated primordial follicle loss and reduced the upregulated ratio induced by cisplatin. Ovarian follicle dynamics in vivo was consistent with the in vitro results. Primordial follicles counts were statistically increased and the ratio was reduced in the rapamycin group compared with the control group. Primordial follicle counts were dramatically reduced in the cisplatin group whereas co-treatment with rapamycin slightly recovered its counts. There was no obvious difference in the number of growing follicles between the cisplatin group and other groups. The ratio was significantly increased in cisplatin-treated mice whereas decreased in the co-treatment group. The apoptosis rate of antral follicles in cisplatin-treated mice was higher than the other groups while the apoptosis rate was decreased in the co-treatment group in vivo. Compared with the control and rapamycin group, the mRNA expression of AMH, GDF9, and BMP15 were Abbreviations: AMH, anti-Mullerian hormone; BMP15, bone morphogenetic protein 15; CCK-8, cell counting kit-8; con, control group; FBS, fetal bovine serum; GDF9, growth differentiation factor 9; HE, hematoxylin and eosin; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; PBS, phosphate-buffered solution; PFA, paraformaldehyde; POI, premature ovarian insufficiency; PTEN, phosphate and tension homology deleted on chromosome ten; qPCR, quantitative polymerase chain reaction; TSC1/TSC2, tuberous sclerosis complex; TUNEL, terminal deoxynucleotidyl transferase-mediated nick end labeling assay. downregulated in the cisplatin group. The co-treatment group recovered the mRNA expression of BMP15. In addition, the expression of key protein of mTOR pathway rpS6 and its phosphorylated forms were increased in the cisplatin-treated group while co-treatme...

show abstract

Section: Discussionmentioning

confidence: 99%

Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo

Xie

Zhou

et al. 2020

Molecular Reproduction Devel

View full text Add to dashboard Cite

show abstract

“…Eight-day-old (P8) female CD-1 mice were purchased from Charles River Laboratories. Ovaries were harvested, transferred to sterile 96-well plates with 50 µl α-MEM (+L-Glu, Gibco) supplemented with 10% FBS (Gibco), 1x penicillin/ streptomycin (Gibco), 0.2 mg/ml Na-pyruvate (Gibco), 2 mg/ml N -acetyl-l-cysteine (Sigma) and ITS liquid media supplement (100x) (Sigma) cultured at 37°C with 5% CO 2 overnight 32 . The final concentrations of the kinase inhibitors targeting ATM (KU55399, Selleckchem), CHK2 (BML-277, Merck) and CK1 (PF 670462, Sigma Aldrich) were 25 µM.…”

Section: Methodsmentioning

confidence: 99%

p63 sets the threshold for induction of apoptosis using a kinetically encoded ‘doorbell-like’ mechanism

Gebel

Tuppi

Chaikuad

et al. 2019

Preprint

View full text Add to dashboard Cite

27 quality control, ovarian reserve, premature ovarian insufficiency, light sheet microscopy 28 29 Abbreviations: DSBs, DNA double strand breaks; POI, premature ovarian insufficiency; TAD, 30 transactivation domain; DBD, DNA binding domain; TD, tetramerization domain; SAM, sterile 31 alpha motif; PAD, phosphorylation activation domain; TID, transcriptional inhibitory domain; 32 NMR, nuclear magnetic resonance; Dox, doxorubicin; CHK2, checkpoint kinase 2; CK1, 33 casein kinase 1; Cs, Cisplatin; PARP 1, poly(ADP-ribose)-polymerase; DSBs, double strand 34 breaks; 35 36 2 Abstract 37Cell fate decisions such as apoptosis require cells to translate signaling input into a binary 38 yes/no response. A tight control of the process is required to avoid loss of cells by accidental 39 activation of cell death pathways. One particularly critical situation exists in primary oocytes 40 because their finite number determines the reproductive capacity of females. On the one hand 41 a stringent genetic quality control is necessary to maintain the genetic integrity of the entire 42 species; on the other hand an overly stringent mechanism that kills oocytes with even minor 43 DNA damage can deplete the whole primary oocyte pool leading to infertility. The p53 homolog 44 TAp63α is the key regulator of genome integrity in oocytes. After DNA damage TAp63α is 45 activated by multistep phosphorylation involving multiple phosphorylation events by the kinase 46 CK1, which triggers the transition from a dimeric and inactive conformation to an open and 47 active tetramer. By measuring activation kinetics in ovaries and single site phosphorylation 48 kinetics in vitro with peptides and full length protein we show that TAp63α phosphorylation 49 follows a biphasic behavior. While the first two CK1 phosphorylation events are fast, the third 50 one that constitutes the decisive step to form the active conformation is slow. We reveal the 51 structural mechanism for the difference in the kinetic behavior based on an unusual 52 CK1/TAp63α substrate interaction and demonstrate by quantitative simulation that the slow 53 phosphorylation phase determines the threshold of DNA damage required for induction of 54 apoptosis. 55activation mechanism has to be adjusted to a certain level of damage that on the one hand 93 must be sufficiently low to protect the integrity of the genetic pool of a species but on the other 94 hand tolerant enough not to endanger reproductive capacity. This situation requires a 95 mechanism that ideally works similar to a doorbell: an input signal (mechanical pressure) below 96 a certain threshold has no effect. If, however, this threshold is surpassed the output signal is 97 independent of the actual input signal strength (pressing harder does not make the doorbell 98 louder). Indeed, a tight dose-response curve has been measured in four-day old mice: while 99 most oocytes survive irradiation with 0.1 Gy (~three DSBs per cell), virtually all primary oocytes 100 were eliminated by 0.45 Gy irradiation (~ten DSBs per cell) 4 .101 Sw...

show abstract

“…For each analysis of every experimental treatment, all technical replicates from one patient were combined to give a single datapoint. Tissues were exposed to chemotherapy drugs for a short time period, as in previous work by us and others, to mimic the short period of exposure that patients usually experience each drug cycle (Morgan et al 2013, Lopes et al 2014, Lande et al 2017, Rossi et al 2017, Smart et al 2018. On Day 3 of culture, after 24 h of drug exposure, tissue from experimental treatments was moved to drug-free medium for 96 h, with medium changed after 48 h: Control tissue was kept in drug-free medium throughout, with medium changed at the same time as for experimental groups.…”

Section: Human Ovary Tissue Culturementioning

confidence: 99%

Single and combined effects of cisplatin and doxorubicin on the human and mouse ovary in vitro

et al. 2020

View full text Add to dashboard Cite

Chemotherapy drugs are administered to patients using combination regimens, and as such the possibility of multiplicative effects between drugs need to be investigated. This study examines the individual and combined effects of the chemotherapy drugs cisplatin and doxorubicin on the human ovary. Although cisplatin and doxorubicin are known to affect female fertility, there is limited information about their direct effects on the human ovary, and none examining the possibility of combined, multiplicative effects of co-exposure to these drugs. Here, human ovarian biopsies were obtained from 14 women at the time of caesarean section, with 38 mouse ovaries also obtained from neonatal C57Bl/6J mice. Tissue was cultured for 6 days prior to analyses, with chemotherapy drugs added to culture medium on the second day of culture only. Treatment groups of a single (5 μg/mL human; 0.5 μg/mL mouse) or double (10 μg/mL human; 1.0 μg/mL mouse) dose of cisplatin, a single (1 μg/mL human; 0.05 μg/mL mouse) or double (2 μg/mL human; 0.01 μg/mL mouse) dose of doxorubicin or a combination of a single dose of both drugs together were compared to controls without drug exposure. Exposure to cisplatin or doxorubicin significantly decreased follicle health in human and mouse, supporting the suitability of the mouse as a model for the human ovary. There was also a significant reduction of mouse follicle number. Human ovarian stromal tissue exhibited increased apoptosis and decreased cell proliferation. Crucially, there was no evidence indicating the occurrence of multiplicative effects between cisplatin and doxorubicin.

show abstract

LH prevents cisplatin-induced apoptosis in oocytes and preserves female fertility in mouse

Cited by 93 publications

References 61 publications

Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo

Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo

p63 sets the threshold for induction of apoptosis using a kinetically encoded ‘doorbell-like’ mechanism

Single and combined effects of cisplatin and doxorubicin on the human and mouse ovary in vitro

Contact Info

Product

Resources

About