Does sphingosine-1-phosphate have a protective effect on cyclophosphamide- and irradiation-induced ovarian damage in the rat model?

doi:10.1016/j.fertnstert.2007.03.065

Fertility and Sterility

Volume 89, Issue 3, March 2008, Pages 732-735

https://doi.org/10.1016/j.fertnstert.2007.03.065 Get rights and content

The aim of this study was to assess the possible protective effect of sphingosine-1-phosphate (S1P), a polar sphingoid metabolite that seemingly promotes cell survival, on cytotoxin- and irradiation-induced ovarian injury in the rat model. Administration of S1P into ovarian bursa before whole-body irradiation led to decreased percentage of apoptotic cells, mostly in primordial follicles; however, S1P was not effective against apoptosis in rats that were given intraperitoneal cyclophosphamide.

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2. CYP group received a single dose of CYP (100 mg/kg) (C0768; Sigma, St. Louis, MO) (Ataya et al., 1989; Hassan et al., 2011; Kaya et al., 2008). 3.
Cyclophosphamide (CYP) is one of the alkylating chemotherapeutic agents and its adverse effects on folliculogenesis in the ovary are well-known due to the previous scientific research on this topic. Magnesium has various effects in organisms, including catalytic functions on the activation and inhibition of many enzymes, and regulatory functions on cell proliferation, cell cycle, and differentiation. In this study, the effects of magnesium sulfate (MgSO₄) on CYP induced ovarian damage were investigated. Immature Wistar-Albino female rats of 28-days were treated with pregnant mare serum gonadotrophin (PMSG) to develop the first generation of preovulatory follicles. Rats of the experimental groups were then treated with either CYP (100 mg/kg, i.p) and MgSO₄ (270 mg/kg loading dose; 27 mg/kg maintenance doseX12, i.p) solely or in combination. Following in-vivo 5-bromo-2-deoxyuridine (BrdU) labeling, animals were sacrificed and ovaries were embedded in paraffin and Epon. In the ovaries, added to the evaluation of general morphology and follicle count; BrdU and TUNEL-labeling, cleaved caspase-3 and p27 (cyclin-dependent kinase inhibitor) staining was also performed immunohistochemically and an ultrastructural evaluation was performed by transmission electron microscopy (TEM). The number of primordial follicles were decreased and multilaminar primary and atretic follicles were increased in CYP group. After MgSO₄ treatment, while primordial follicle pool were elevated, the number of atretic follicles were decreased. Additionally, decreased BrdU-labeling, increased cleaved caspase 3 immunoreactivity and increased TUNEL labeling were observed in CYP group. In CYP treated animals, observations showed that while MgSO₄ administration caused no alterations in BrdU proliferation index and caspase-3 immunoreactivity, it significantly reduced the TUNEL labeling. It was also observed that, while p27 immunoreactivity significantly increased in the nuclei of granulosa and theca cells in the CYP group; MgSO₄ treatment significantly reduced these immunoreactivities. The ultrastructural observations showed frequent apoptotic profiles in granulosa and theca cells in both early and advanced stages of follicles in the CYP group and the MgSO₄ treatment before the CYP application led to ultrastructural alleviation of the apoptotic process. In conclusion, our data suggest that MgSO₄ may provide an option of pharmacologic treatment for fertility preservation owing to the beneficial effects of on chemotherapy-induced accelerated follicular apoptotic process, and the protection of the primordial follicle pool.
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Oocytes treated with S1P had higher rates of cleavage and blastocyst development than control oocytes when they were exposed to a heat shock in vitro (Roth and Hansen, 2004). Likewise, S1P treatment into the bursal sac surrounding the ovary prevent the massive loss of oocytes caused by radiation therapy in mice (Morita et al., 2000; Jurisicova et al., 2006; Kaya et al., 2008). Non-human primates treated with S1P, or its analogue FTY720, for 1 week prior to ovarian irradiation retained ovarian follicles and resumed menstrual cycles post treatment (Zelinski et al., 2011).
Sphingosine-1-phosphate (S1P) is a bioactive polar sphingolipid which stimulates proliferation, growth and survival in various cell types. In the ovary S1P has been shown protect the granulosa cells and oocytes from insults such as oxidative stress and radiotherapy, and S1P concentrations are greater in healthy than atretic large follicles. Hence, we postulate that S1P is fundamental in follicle development and that it is activated in ovarian granulosa cells in response to FSH and VEGF. To test this hypothesis we set out: i) to evaluate the effect of FSH and VEGF on S1P synthesis in cultured bovine granulosa cells and ii) to analyse the effect of S1P on proliferation and survival of bovine granulosa cells in vitro. Seventy five thousand bovine granulosa cells from healthy medium-sized (4–7 mm) follicles were cultured in 96-well plates in McCoy’s 5a medium containing 10 ng/mL of insulin and 1 ng/mL of LR-IGF-I at 37 °C in a 5% CO₂/air atmosphere at 37 °C. Granulosa cell production of S1P was tested in response to treatment with FSH (0, 0.1, 1 and 10 ng/mL) and VEGF (0, 0.01, 0.1, 1, 10 and 100 ng/mL) and measured by HPLC. Granulosa cells produced S1P at 48 and 96 h, with the maximum production observed with 1 ng/mL of FSH. Likewise, 0.01 ng/mL of VEGF stimulated S1P production at 48, but not 96 h of culture. Further, the granulosa cell expression of sphingosine kinase-1 (SK1), responsible for S1P synthesis, was demonstrated by Western blot after 48 h of culture. FSH increased the expression of phosphorylated SK1 (P < 0.05) and the addition of a SK1 inhibitor reduced the constitutive and FSH-stimulated S1P synthesis (P < 0.05). Sphingosine-1-phosphate had a biphasic effect on granulosa cell number after culture. At low concentration S1P (0.1 μM) increased granulosa cell number after 48 h of culture (P < 0.05) and the proportion of cells in the G2 and M phase of the cell cycle (P < 0.05), whereas higher concentrations decreased cell number (10 μM; P < 0.05) by an increase (P < 0.05) in the proportion of cells in apoptosis (hypodiploid cells). In addition, treatment with SK-178 suppressed the FSH- and VEGF-stimulated rise of the granulosa cells number (P < 0.05). Interestingly, the effect of 0.1 μM S1P on granulosa cell number and their proportion in G2/M phases is similar to that observed with 1 ng/mL FSH. The results of this study are the first to demonstrate sphingosine-1-phosphate (S1P) synthesis in granulosa cells under the control of FSH and VEGF. The later achieved through the regulation of sphingosine kinase 1 expression. This S1P augments the proportion of cells in the G2/M phase of the cell cycle that translates in increased granulosa cell proliferation.
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Ex vivo, S1P treatment of mouse oocytes conferred resistance to DXR-induced apoptosis (34). However, results have not been uniformly positive, with one study reporting no reduction in Cy-induced follicle loss in S1P treated rats (56). Due to its very short plasma half-life S1P cannot be administered by systemic injection, and would either require continuous administration (studies used mini-osmotic pumps), or injections directly into the ovary.
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Recent advances in our understanding of the mechanisms underlying the impact of cytotoxic drugs on the ovary have opened up new directions for the protection of ovarian function from chemotherapy-induced damage. There has been parallel effort towards the development of pharmacological agents that may prevent ovarian damage at the time of treatment, which would provide significant advantages over existing fertility-preservation techniques. This chapter will review preclinical developments for the protection of the ovary during ovotoxic treatment, including agents that act on relevant apoptotic pathways, the PI3K/PTEN/Akt follicle activation pathway, the vascular system, and other potential methods of reducing chemotherapy-induced ovotoxicity. These preclinical studies continue to advance our understanding of the mechanisms and pathways involved in cytotoxic ovarian damage, thus bringing us closer to preventing chemotherapy-induced infertility.
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: Supported in part by the Department of Scientific Research Management, Suleyman Demirel University, Isparta, Turkey.

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CorrespondenceDoes sphingosine-1-phosphate have a protective effect on cyclophosphamide- and irradiation-induced ovarian damage in the rat model?

Mol Cell Endocrinol

Fertil Steril

DNA Repair (Amst)

Free Radic Biol Med

Fertil Steril

Fertil Steril

Am J Pathol

Fertil Steril

J Biol Chem

Biochim Biophys Acta

Germ cell proliferation and apoptosis in the developing human ovary

J Clin Endocrinol Metab

Survival of human ovarian follicles from fetal to adult life: apoptosis, apoptosis-related proteins, and transcription factor GATA-4

J Clin Endocrinol Metab

Programmed cell death in human ovary is a function of follicle and corpus luteum status

J Clin Endocrinol Metab

In situ localization of apoptosis in the rat ovary during follicular atresia

Biol Reprod

Survival factors regulating ovarian apoptosis—dependence on follicle differentiation

Reproduction

Correspondence
Does sphingosine-1-phosphate have a protective effect on cyclophosphamide- and irradiation-induced ovarian damage in the rat model?