Mammalian germ cell development begins in the form of PGCs which are the embryonic precursors of gametes [1,2] which on later stages becomes male or female gametes often termed as sperm and oocyte, respectively. Here in this review we will mainly discuss both the human and mouse female germ cell development in vivo and in vitro. A number of developmental changes initiated from proximal epiblast cells, later accompanied by attainment of various markers expression under different pathway activations are held responsible for developing a mature sperm or oocyte with functional ability. The developmental route mainly comprised of following steps: gastrulation → epiblast cells formation → primordial germ cell → gonocyte → oogonium → primary oocyte → secondary oocyte → antral follicle → mature oocyte. Earlier developmental processes are under the control of both of the WNT3 and bone morphogenic protein (BMP) family transcription factors and activation of pathways associated with them. In the mouse at around E5.75, PGCs formation is governed by WNT3 secretion by posterior visceral endoderm (VE) and posterior epiblast cells which is further followed by secretion of BMP family member proteins such as BMP4 and BMP8b by extraembryonic ectoderm (ExE) at around E6.0 [1]. WNT3 signaling regulates PGC induction by its downstream target Brachyury, a mesodermal marker which promotes the expression of both somatic as well as germ cell markers, whereas BMP4 governs the suppression of somatic genes while up regulating germline determinant genes Blimp1 and Prdm14 [5]. BMP8b also plays important role in mouse PGC generation. In a mouse study, null mutations in BMP8b were shown to cause complete lack of PGCs whereas reduced number of PGCs were observed in BMP8b heterozygotes [6]. Many other reports have also shown severe reduction in the number of PGCs from mice embryos in which targeted deletion of either BMP2, BMP4, and BMP8b or their downstream signaling components including Smad1, 4, 5 was performed [7,8,9,10,11]. Similarly, no PRDM1 positive PGCs were observed in mutant mouse embryos which undergo targeted deletion of Wnt3 [5]. The Wnt signaling pathway involving Wnt5a and its receptor Ror2 has also been associated with successful migration and functionality of PGCs [12]. These findings strongly advocate the utility and role of BMP and Wnt signaling pathways in development, migration and proper functioning of the developing PGCs which further determines the specification and development of gametes. It is worthy to notice the indispensable role of Fragilis, Smad1, and Stella which helps in the specification of PGCs and also provides distinction from somatic cells [13,14,15]. Any deformity or suppression of these valuable factors results into impaired PGC/gamete production and hampers their functional ability. Beginning with a small number of ~30–40 cells, PGCs proliferate and finally migrates towards genital ridges where they undergo genome wide DNA demethylation, histone modification, imprinting erasure and reactivation of X chromosome [16,17]. Until this stage, sex specification is not achieved as PGCs are bipotent in nature and express common germ cell markers shared by both male and female gametes. In humans, PGC specification begins at around the third gestational week during which erasure of DNA methylation takes place [18,19,20,21]. Differences have been observed among transcription factors requirement for PGCs specification and maintenance among humans and mice [22,23,24]. During progressive stages, cells undergo a transitional shift from pluripotency associated marker expression to germ cell specificity in a gradual manner and attain expression of early PGC makers, late PGC markers, meiosis markers, undergo epigenetic reprograming and finally attains mature germ cell markers [19]. While analyzing the transcriptome of human PGCs, Guo and colleagues [19] found that both pluripotency and germ cell specific genes are simultaneously expressed from their migrating to the gonadal stage. Diagrammatical outflow of the PGC development and specification has been given in Figure 1.

Once the PGCs are formed, their migration to gonadal ridges constitutes an important developmental step towards gamete specification and their proper functioning. It is worth noticing that the concept of signaling guidance for PGCs towards the gonads was first of all described in zebrafish [25]. Both intrinsic motility factors and external guidance cues are required by the PGCs to successfully migrate and maintain their survivability [26]. In the beginning, BMP signaling from ExE governs PGC formation from epiblast cells, which are further mediated by BLIMP1 or PRDM1 transcriptional regulators which not only stimulate PGC specific gene such as Stella but also suppresses the expression of somatic cell genes cascade [27,28]. Like BLIMP1, PRDM14 also regulates mouse PGC specification, lacking or knockdown of both the factors either resulted into improper PGC differentiation and defected migration or induced sterility in mice models [29,30]. Along with BLIMP1 and PRDM14, AP2γ has also been found essential in regulating mammalian PGC specification [31]. AP2γ is expressed by mouse PGCs from E7.25 to E12.5 and its targeted disruption has resulted into male and female sterility. It was also believed that PGC migration in mouse is also coordinated by interferon induced transmembrane protein 1 (IFITM1), as RNA interference induced IFITM1 knockdown in the primitive streak resulted into PGC migration failure towards endoderm, indicating possible role of IFITM1 in PGC migration from mesoderm to endoderm [32]. However, contradicting results were shown by Lange UC et al. (2008), where embryonal deletion of the IFITM1 gene family could not cause impaired PGC migration [33]. During the period of migration and arrival of PGCs towards hindgut, Nanos3 plays multiple vital roles by maintaining germ cell’s undifferentiated state, protecting PGCs against apoptosis by suppressing Bax-dependent and independent pathways and thereby helps in germ cell development [34]. Nanos3 is expressed by migrating PGCs at various germ cell specific developmental stages in both testis and ovaries. Moreover, without its expression, germ cell detection in the ovary and testis is not possible [15,34]. Failure in migration can cause developmental issues and infertility, and also may cause teratoma formation in extra gonadal regions [12]. At around E11.5, most PGCs are migrated towards genital ridges and become populated there at around E12.5. During later stages, establishment of sexually dimorphic sex cords takes place between E13.5–17.5 and birth and most of the ectopic PGCs die due to apoptotic pathways and rest of them transforms into male and female gametes in their respective sex gonads [15]. Researchers believed that PGCs lose their migration properties once they associate with somatic cells and reach gonads [26]. One possible reason for their ceasing behavior may be due to the cell-to-cell interactions between PGCs and somatic cells. Proper mechanism behind this stoppage is not known and need in depth elucidation. Diagrammatical outflow of the PGC migration has been given in Figure 2.

Chromosomal aberrations correspond to insertion, deletion or translocation of some or the whole part (arms) of a chromosome. These abnormalities have been associated with the occurrence of impaired functioning of the various body parts and hence are the causatives of many complications including ovarian germ cell tumors (OGSTs). According to Matyakhina et al., all malignant human tumors occur due to chromosomal aberrations induced chromosomal instability [40]. These disturbances happen due to abnormal segregation of chromosomes at the time of cell division. While observing abnormal karyotypes from the patients with OGSTs, comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) techniques revealed that gains or loss from the chromosomal arms or some of the whole chromosomes resulted into dysgerminomas (DGs), endodermal sinus tumors (ESTs) and immature teratomas [41,42,43]. The gain and loss of different chromosome numbers such as loss of 1p, gain of 1q or whole chromosomal gains chromosome numbers including 3, 8, 14 and 21 have been observed in female patients with malignant OGCTs. Among OGCTs, dysgerminomas were associated with abnormalities in 12p chromosome [41]. While performing dual color fluorescence in situ hybridization (FISH), Paolo Cossu-Rocca and colleagues observed that aberrations in the 12p chromosome were associated with 81% of total dysgerminomas [43] and seminomas (testicular germ cell tumor). Chromosomal abnormalities have also been correlated with ovarian granulosa cell tumors [44,45]. Comparative genomic hybridization and FISH techniques revealed that gains of chromosomes 12 and 14 and losses of chromosomes 22 and X were causatives of ovarian granulosa cell tumors [44]. In a similar study, patients with stage 1 granulosa cell tumors were shown to have chromosomal abnormalities in the form of losses from 1p33 to p36, 16p13.1, 16q and 22q chromosomes whereas gains were observed in chromosomes including 7p15 to p21, 12 and 14 [45]. Among these chromosomes, losses from chromosome 22 and gains in chromosome 14 were more prevalent. However, none of the conditions exhibited alarming degree of metastasis. In general, due to low prevalence rate (comparatively less than testicular germ cell tumors) in comparison to other extra-gonadal tumors, not many reports are available. However, it is equally important to draw attention on the role of chromosomal aberrations in the occurrence of diseases especially OGCTs as they can be diagnosed and can be proved helpful in avoiding future complications. Therefore, techniques like karyotyping, CGH and FISH should also be given preferences so that anomalies against normal behavior can be diagnosed and eradicated in time.

Epigenetics plays an important role in regulating overall transformation and functional activity of germ cells which upon fertilization can transmit proper information to the next generation [46,47]. A series of gradual events including PGC specification, meiotic entry, epigenetic imprinting of PGCs, histone modification and X-chromosome inactivation, DNA methylation erasure and its resumption during gamete formation, are highly important during gametogenesis [48]. The actual reason behind epigenetic information erasure in germ cells is not known but it may be attributed to the restricted transmission of unwanted acquired epimutations during life [20]. Although, except ESCs and iPSCs (only few reports), other stem cell sources derived gamete-like cells could either failed to initiate meiosis, or failed to prove their functionality by producing healthy viable offsprings upon fertilization. This may be perhaps due to developmental issues related to improper epigenetic modifications [48]. During migration period, PGCs go through genome wide DNA demethylation, histone modification by means of downregulation of H3 lysine 9 dimethylation (H3K9me2), upregulation of H3 lysine 27 trimethylation (H3K27me3), imprinting erasure and reactivation of X chromosome [16,17]. By the end of E12.5, H3K9me3 and H3K64me3 are gradually lost from PGCs and all these events are vital for efficient differentiation into gametes [49,50].

A healthy life with proper functionality of all the organs depends a lot on many factors including surrounding environment, lifestyle, routine activities (exercising, food and drinking habits), and opted occupation. All these factors have also been associated with the reproductive life of an individual especially during female pregnancies. Here below is the detailed description about these factors in relation to female reproductive health.