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Key Event Title
Reduced size of the ovarian follicle pool
|Level of Biological Organization|
|ovary sex cord|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Inhibition of ALDH1A leading to reduced fertility||KeyEvent||Terje Svingen (send email)||Under development: Not open for comment. Do not cite||Under Development|
Key Event Description
Formation of the follicle pool (follicle assembly)
During fetal life, primordial germ cells migrate to the genital ridges where they arrange into germ cell nests and proceed through to meiosis prophase I (Pepling & Spradling, 2001). Assembly into individual follicles occurs via mechanisms that are not well known, but involves germ cell nest break down and a reduction in oocyte numbers via programmed cell death. Somatic pre-granulosa cells infiltrate between the oocytes, arrange around them in a single layer, and establish what is called the primordial follicles (Escobar et al, 2008; Gawriluk et al, 2011; Pepling & Spradling, 2001). The primordial follicles constitute the follicle pool - a limited stock of oocytes that are available for maturation and potential fertilization determining the length of a female’s reproductive life span (Grive & Freiman, 2015).
The timing of follicle assembly differs between mammalian species, but the processes involved seem to be relatively well conserved (Grive & Freiman, 2015). In humans, follicle assembly occurs during mid-gestation whereas in mice and rats it is initiated around the time of birth and continues until approximately six days post partum.
Reduced follicle pool as Key Event
An intact follicle pool is critical for female fertility. Any disruption to the formation of the final pool can have adverse consequences for reproductive capacity, leading to sub- or infertility. Loss of oocytes/follicles can occur during any of the abovementioned stages during the process of follicle assembly – oocyte nest breakdown, programmed cell death or somatic pre-granulosa cell intrusion. Follicle assembly and establishment of the functional follicle pool is also dependent on the stages occurring before this process, e.g. migration of primordial germ cells to the genital ridges, sex determination and meiosis.
How It Is Measured or Detected
In animal studies, counting of follicles of different sizes is included in OECD guidelines: TG 416 (Two-Generation Reproductive Toxicity Study) and TG 443 (Extended One-Generation Reproductive Toxicity Study). It is a time-consuming and labor-intensive method and it is not recommended to compare values between studies (Tilly, 2003).
In humans, there is no direct way to count the follicle pool in vivo. Instead, surrogate markers are used. The most established biomarker for estimation of the follicle pool is anti-Müllerian hormone (AMH). It is readily measured in a blood sample and the levels are rather stable throughout the menstrual cycle (Broer et al, 2014).
The size of the pool can also be measured indirectly by mRNA and protein expression of meiotic markers, or by assessing overall ovary histology by histological assessments (Zhang et al, 2012).
Domain of Applicability
Follicle assembly occur in females during fetal life (humans) or around and after birth (rodents). Many of the mechanisms involved are preserved between mice, rats and humans.
Broer SL, Broekmans FJM, Laven JSE, Fauser BCJM (2014) Anti-Müllerian hormone: ovarian reserve testing and its potential clinical implications. Hum Reprod Update 20: 688-701
Escobar ML, Echeverría OM, Ortíz R, Vázquez-Nin GH (2008) Combined apoptosis and autophagy, the process that eliminates the oocytes of atretic follicles in immature rats. Apoptosis 13: 1253-1266
Gawriluk TR, Hale AN, Flaws JA, Dillon CP, Green DR, Rucker 3rd EB (2011) Autophagy is a cell survival program for female germ cells in the murine ovary. Reproduction 141: 759-765
Grive KJ, Freiman RN (2015) The developmental origins of the mammalian ovarian reserve. Development 142: 2554-2563
Jefferson W, Newbold R, Padilla-Banks E, Pepling M (2006) Neonatal genistein treatment alters ovarian differentiation in the mouse: inhibition of oocyte nest breakdown and increased oocyte survival. Biol Reprod 74: 161-168
Mu X, Liao X, Chen X, Li Y, Wang M, Shen C, Zhang X, Wang Y, Liu X, He J (2015) DEHP exposure impairs mouse oocyte cyst breakdown and primordial follicle assembly through estrogen receptor-dependent and independent mechanisms. Journal of Hazardous Materials 298: 232-240
Pepling ME, Spradling AC (2001) Mouse ovarian germ cell cysts undergo programmed breakdown to form primordial follicles. Dev Biol 234: 339-351
Rodríguez HA, Santambrosio N, Santamaría CG, Muñoz-de-Toro M, Luque EH (2010) Neonatal exposure to bisphenol A reduces the pool of primordial follicles in the rat ovary. Reprod Toxicol 30: 550-557
Tilly JL (2003) Ovarian follicle counts--not as simple as 1, 2, 3. Reprod Biol Endocrinol 1: 11
Wang W, Hafner KS, Flaws JA (2014) In utero bisphenol A exposure disrupts germ cell nest breakdown and reduces fertility with age in the mouse. Toxicol Appl Pharmacol 276: 157-164
Zhang HQ, Zhang XF, Zhang LJ, Chao HH, Pan B, Feng YM, Li L, Sun XF, Shen W (2012) Fetal exposure to bisphenol A affects the primordial follicle formation by inhibiting the meiotic progression of oocytes. Mol Biol Rep 39: 5651-5657