The comparison of animal models for premature ovarian failure established by several different source of inducers

Highlights

• Several animal models for premature ovarian failure were compared.

• Some agents caused body weight increasing slowly following administration.

• Serum LH level had a rising trend with a declining serum E2 level.

• Mild or moderate ovotoxicity with the potential infertility was presented.

• Such inducers presented their respective features in animal models.

Abstract

The objective of this study was to compare premature ovarian failure animal models established by several different source of inducers. Female ICR mice, KM mice, and SD rats were treated by cyclophosphamide at 120 mg/kg, busulfan at 12 mg/kg, cisplatin at 3 or 4 mg/kg, 4-vinylcyclohexene diepoxide at 160 mg/kg, 35% galactose food pellet, and tripterygium glycosides at 50 mg/kg, respectively. Parameters were analyzed by body weight, serum concentration level of related hormones, ovarian and uterine pathological examination. The results indicated the body weight of mice increased very slowly following single dose of cyclophosphamide (p < 0.05) with damaged ovary; repeated doses of cisplatin could induce body weight significantly decreased (p < 0.01) with a rising trend of serum LH concentration, declining tendency of serum E2 concentration and injured ovary and uterus; 4-vinylcyclohexene diepoxide also hindered the mice growing (p < 0.05) with damaged ovary and uterus; the body weight of mice feed by 35% galactose food pellet increased slowly (p < 0.05) with dramatically higher serum concentration level of galactose, albumin, and total protein (p < 0.001) and injured ovary. Busulfan and tripterygium glycosides did not present obvious evidences. In conclusion, the inducers presented their respective features in such animal models and should be appropriately applied in preventive methods.

Introduction

Nearly 1% of women under the age of 40 years are suffered from premature menopause, which is defined as premature ovarian failure (POF) before the age of 40 years or ovarian failure occurring two standard deviations in years before the mean menopausal age of the study population. The main concern for such nonfatal disease is that it can lead to a decline in fertility and in some serious cases, it is the main cause of infertility in females. (Mashchak et al., 1981, Coulam et al., 1986, Nelson, 2009, Ikeme et al., 2011). The causes of premature ovary failure are very complex and regarded they may be related with the influence of endogenous gene, abnormal autoimmune, mental factors, exogenous substances, infections, medical therapeutics such as chemotherapy or surgical interventions just like bilateral oophorectomy (Alper and Garner, 1985; Hoek et al., 1997, Sklar, 2005).

Generally speaking, POF is characterized by marked heterogeneity, but with a significant genetic contribution. The major scientific progress in the recent year is the discovery of multiple genes involved in POF occurrence both in man and mice such as meiosis (Powell et al., 1994, Zinn, 2001, Zahed et al., 2002, Northup et al., 2007, Vujovic, 2009, Kim et al., 2014, Zeng et al., 2014), Foxl2 (Uda et al., 2004, De Baere et al., 2005, Fassnacht et al., 2006, De Baere et al., 2009, Laissue et al., 2009, Corrêa et al., 2010, Ni et al., 2010), Anti-Müllerian hormone (AMH) (Park et al., 2014), bone morphogenetic protein 15 (BMP15) (Tiotiu et al., 2010), progesterone receptor membrane component 1 (PGRMC1) (Wang et al., 2014), fragile X mental retardation 1 (FMR1) permutation on the X chromosome (Pastore and Johnson, 2014), growth differentiation factor 9 (GDF9) (Fassnacht et al., 2006), folliculogenesis specific bHLH transcription factor (FIGLA) (Tosh et al., 2015), newborn ovary homeobox gene (NOBOX) (Qin et al., 2007, Qin et al., 2009, Lechowska et al., 2011), nuclear receptor subfamily 5, group A, member 1 (NR5A1) (Jiao et al., 2013, Harrison et al., 2013, Tšuiko et al., 2016), synaptonemal complex central element 1 (SYCE1) (McGuire et al., 2011, Tšuiko et al., 2016), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) (Tenenbaum-Rakover et al., 2015), ATP-dependent DNA helicase homolog (HFM1) genes, LIM homeobox protein 8 (Ren et al., 2015), liver kinase b1 (LKB1/STK11) (Jiang et al., 2016), brain muscle ant-like 1 (Bmal1) (Liu et al., 2014), neurotrophic receptor tyrosine kinase 2 (NTRK2), and kisspeptin receptor (KISS1R) (Dorfman et al., 2014). Chromosomal abnormalities have long been recognized as a frequent cause of POF, with a currently estimated prevalence of 10–13%. Single gene perturbations unequivocally have a deleterious effect in at least one population (Qin et al., 2015). Recently, molecular evidence on the regulatory role of small noncoding RNAs in folliculogenesis and oocyte development began to emerge such as miR-146a in POF patients, miR-23a and miR-27a in the granulosa cells of women undergoing in vitro fertilization/embryo transfer (Bilgin and Kovanci, 2015; Chen et al., 2015, Nie et al., 2015). miR-27b, miR-190, miR-151, miR-672, miR-29a and miR-144 were also identified their function in 4-vinylcyclohexene diepoxide (VCD)-induced rat POF model (Kuang et al., 2014).

The clinical examination presents ovarian histology that lads to the distinction of two phenotypes, such as small-sized ovaries with deprivation of follicles and normal-sized ovaries with partial follicular maturation (Massin et al., 2004, Massin et al., 2008). It is also clinically marked by amenorrhea, oligomenorrhoea, increased gonadotrophin levels and oestrogen deficiency. It may be confirmed by the detection of an elevated serum concentration level of follicle stimulating hormone (FSH) with the levels above 40 mIU/ml. Therefore, the clinical diagnostic criteria of POF is mainly concluded by the basic hormone detection and echographers such as ovarian ultrasonic testing. In recent years, some new clinical marks to identify POF are also actively explored, including thiol/disulfide homeostasis (Isik et al., 2016) and AMH (Massin et al., 2008, Knauff et al., 2009, Detti et al., 2013). AMH is produced by growing follicles and studies in women indicate that serum AMH levels decrease with age and correlate with antral follicle count (Kevenaar et al., 2006, La Marca et al., 2006, Méduri et al., 2007, van Houten et al., 2010). It has been used as an ovarian reserve marker since 2002, which can be considered as an indicator of fertility in late reproductive age women (Meczekalski et al., 2016). It is also treated as a marker of ovarian function in women after chemotherapy and radiotherapy for haematological malignancies (Lie Fong et al., 2008, Visser et al., 2012). It seemed AMH serum level is more sensitive than FSH serum level (Alipour et al., 2015).

In the past, little was known about premature ovary failure until quite recently. With the improvement of cognition for POF, many therapeutic methods were applied to prevent or ameliorate POF symptoms (Ting and Petroff, 2010, Roti Roti and Salih, 2012, Fu et al., 2012, Yener et al., 2013, Li et al., 2013, Takehara et al., 2013, Altuner et al., 2013, Ge et al., 2014, Piasecka-Srader et al., 2015, Salih et al., 2015, Khedr, 2015; Zhao et al., 2015, Kropp et al., 2015) and several different types of POF animal models were established as the auxiliary tools (Hoyer et al., 2001, 2007; Ben-Aharon et al., 2010, Kappeler and Hoyer, 2012; Li et al., 2013, Chen et al., 2014). The success of the animal model establishment is based on the standards such as the hormone changes, ovarian follicle maturation and damaged ovary. The ideal animal model could simulate POF clinical symptoms quickly. Some mutant mouse models are conducted to help scientists to gain a better understanding of the molecular mechanisms underlying POF in humans, which exhibit phenotypes which are comparable to human POF (Jagarlamudi et al., 2010). Considering there are numerous candidate genes in the literature, maybe several mutant POF animal models could not reach the requirements of extensive use of animals and have not been widely used in the exploration of preventive methods. However, the mutant mouse models based on the knowledge of genomics of POF are new, important and promising mouse POF models in near future. Another issue is that inducers such as alkylating agents, methotrexate, 6 mercaptopurine, and adriamycin may produce the respective characteristics of POF occurrence. Even for POF animal model induced by cyclophosphamide, it has much difference both in administrative doses and the different duration time (Liu et al., 2012, Jiang et al., 2013, Sun et al., 2013, Liu et al., 2013, Liu et al., 2014, Li et al., 2013, Xiao et al., 2014). There is no standard to mimic the POF animal models. So, it may be difficult to choose the appropriate animal models in the exploration of therapeutic methods for POF. Here, several inducers were selected to build POF animal models according to the references and the comparison was conducted to figure out the difference between them.