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Relationship: 2481
Title
Oocyte meiosis, disrupted leads to Ovarian follicle pool, reduced
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Inhibition of ALDH1A (RALDH) leading to impaired fertility via disrupted meiotic initiation of fetal oogonia of the ovary | adjacent | Moderate | Moderate | Cataia Ives (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
Foetal | High |
Key Event Relationship Description
The establishment of the primordial follicle pool is a multistep process that spans from early fetal life to reproductive maturity. This period of time varies greatly between species, lasting only a few weeks in mice and rats, but years in humans (Tingen et al, 2009). One important process is for the mitotic primordial germs cells to enter meiosis prior to cyst formation (Findlay et al, 2015; Tingen et al, 2009). Notably, in females there is a massive loss of oocytes between cyst formation and time of maturity, and the exact mechanisms behind this oocyte degradation is not well understood (Findlay et al, 2015; Sun et al, 2017).
Evidence Collection Strategy
Evidence Supporting this KER
It is well established that disruption to meiosis during oocyte development can lead to sub-/infertility in females at reproductive age. There are numerous gene mutation in mice showing links between meiotic defects and fertility phenotypes, as well as associations to female fertility phenotypes in humans (Adelfalk et al, 2011).
Biological Plausibility
Although the entry into meiosis is required for oocyte development, the relationship between meiotic entry and final oocyte reserve remains unclear. However, there are strong correlations between disrupted meiosis and infertility (or aneuploidy) in females (Handel & Schimenti, 2010). For instance, in mice, ablation of Stra8 prevents oocytes from entering meiosis in the fetal ovaries and mature females are infertile (Baltus et al, 2006; Zhou et al, 2008). Mutation in Atm, a gene involved in recombination during meiosis, results in complete loss of primary oocytes in mice, and greatly reduced follicle pool in humans (Adelfalk et al, 2011; Agamanolis & Greenstein, 1979; Aguilar et al, 1968; Xu et al, 1996). Other examples include Fanca and Fancd2 genes that are involved in recombination. Mutations to these genes lead to oocyte degeneration and subfertility in mice (Cheng et al, 2000; Houghtaling et al, 2003; Wong et al, 2003).
Mice with Lhx8 ablation display total loss of oocytes. Lhx8-/- mice maintain oocytes during fetal development, but loose the oocytes shortly after birth by autophagy, likely because the oocytes have failed to enter meiosis in utero (Choi et al, 2008; D'Ignazio et al, 2018). Fzr1 is a regulator of mitotic cell division. When conditionally ablated from the germ cells, female mice display premature ovarian failure by 5 months of age and are subfertile; oocytes are lost in utero during early meiotic prophase I (Holt et al, 2014).
CYP51 (lanosterol 14 α-demethylase) is expressed by fetal oocytes and is involved in meiotic regulation (Mu et al, 2018). Inhibition of CYP51 activity reduces the formation of primordial follicles (Zhang et al, 2009) by disrupting entry into diplotene stage (Mu et al, 2018). Importantly, retinoic acid induces nuclear translocation of CYP51 in oocytes at the onset of meiosis (Mu et al, 2018).
Empirical Evidence
Study type |
Species |
Compound |
Effect Dose |
Duration |
Results |
Reference |
In vivo |
Mouse |
di(2-ethylhexyl) phthalate (DEHP) |
Delayed meiotic progression at 17.5 dpc (reduced Stra8 expression at time of initiation, 13.5 dpc) |
|||
In vivo |
Mouse |
Bisphenol A (BPA) |
0.08 mg/kg/d |
12.5-17.5 dpc |
Delayed meiotic progression at 17.5 dpc (incl. decreased Stra8 expression) |
|
In vivo |
Mouse |
Paracetamol |
350 mg/kg/d |
13.5-21.5 dpc |
Delayed meiotic entry and reduced fertility |
|
In vivo |
Mouse |
Indomethacin |
0.8 mg/kg/d |
15.5-18.5 dpc |
Delayed meiotic entry and reduced fertility |
|
fetal ovary culture |
Mouse |
RS21745 (CYP51 inhibitor) |
10 µM |
3 days |
Oocytes arrest at zygote stage (delayed meiotic progression). |
|
fetal ovary culture |
Mouse |
RS21745 (CYP51 inhibitor) |
1, 25, 50 µM |
2 days exposure + 5 days no exposure |
Dose dependent reduction in follicle numbers; significant in 25 and 50 µM groups |
Uncertainties and Inconsistencies
Known modulating factors
atRA is synthesized from vitamin A in a two-step enzymatic pathway. Vitamin A is required from the diet; hence, dietary changes to vitamin A can greatly affect the level of available atRA and thus modulate atRA-regulated responses.
Quantitative Understanding of the Linkage
The quantitative understanding of this KER remains poorly understood, not least because the quantification of actual oocyte numbers at various stages of development are very difficult perform.
Response-response Relationship
The ovarian follicle pool (ovarian reserve) refers to the final number of primordial follicles in the mature ovary and is established through a series of events. In most mammals, it is determined during gestation or just after birth and relies on i) how many germ cells were established during embryogenesis, ii) their proliferation during migration and early ovary development, iii) death rate during oogenesis and iv) formation of primordial follicles at nest breakdown (Findlay et al, 2015). The last two stages, which includes nest formation and breakdown, is largely influenced by the mitotic-meiotic transition, in that oocytes that have failed to enter meiosis may contribute to the cysts population, but only high quality oocytes in meiotic prophase are spared during cyst breakdown (Findlay et al, 2015). Thus, there is a response-response relationship between meiotic entry and final follicle pool, albeit the quantitative relationship is not that well understood.
Time-scale
The time-scale for oocyte mitotic-meiotic transition and subsequent nest breakdown varies between species, but generally takes place from mid gestation to around the time of birth. In mice, meiosis and nest formation is initiated from around E13, whereas in humans it initiates at around GW12-14 (Childs et al, 2012; Findlay et al, 2015; Grive & Freiman, 2015; Pepling, 2006; Tingen et al, 2009). Nest breakdown starts just before birth in mice and completes around postnatal day 5 (Grive & Freiman, 2015; Pepling, 2006). In humans, nest breakdown takes place during second trimester (Grive & Freiman, 2015; Tingen et al, 2009).