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Key Event Title
Increased, Differentiation to Testis
|Level of Biological Organization|
Key Event Components
|male gonad development||immature gonad||increased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Aromatase inhibition leads to male-biased sex ratio via impacts on gonad differentiation||KeyEvent||Kelvin Santana Rodriguez (send email)||Under Development: Contributions and Comments Welcome|
|AR agonism leading to male-biased sex ratio||KeyEvent||Dan Villeneuve (send email)||Open for citation & comment|
Key Event Description
Prior to gonadal sex determination in vertebrates, the developing organism has a primordial bipotential gonad that can be fated to either sex depending on the genetic makeup of the embryo (genetic sex determination) or environmental conditions (environmental sex determination) or a combination of both factors.
During male development, the embryonic stem cells can differentiate to primordial germ cells, which in turn proliferate and differentiate into precursor spermatogonia stem cells. Sertoli cells are the first to differentiate into the different fetal gonad seminiferous cords surrounded by peritubular myoid cells enclosing fetal germ cells. Sertoli cells can also differentiate into Leydig cells. Successively, the interstitial Leydig cells differentiate and produce sex steroids such as testosterone to maintain the testis and control aspects of masculinization including secondary sex characteristics (McLaren 1998; DeFalco and Capel 2009; Trukina et al. 2013).
Although the timing and location of gene expression leading to the morphological development of the testis may differ among vertebrate taxa, the basic molecular machinery and pathways involved are well conserved (Cutting et al. 2013). Similarly, the cell types and basic morphological structure of the testis across vertebrates are well-conserved (McLaren 1998; DeFalco and Capel 2009).
How It Is Measured or Detected
Depending upon the size of the test organism and life stage it may be possible to identify the presence of developed testes versus ovaries visually or with low-power magnification without a need for gonad removal, fixation and processing. This would require, of course, experienced personnel well-versed in the biology of the species of interest.
In instances where organisms are small, at early life-stages and/or have poorly differentiated gonads, it will be necessary to employ histological examination by light microscopy to identify nature of the gonad. In all vertebrates, the gonads of phenotypic males in early development have three main differentiating cell types; the gamete forming germ cells (spermatogonia), support cells (Sertoli cells), and hormone-secreting Leydig or interstitial cells (DeFalco and Capel 2009; McLaren 1998).
There are many standardized techniques available for fixation, processing and staining of tissues of concern, including gonads (e.g., Carson and Cappellano 2014). There also are species-specific resources available to aid interpretation of histological images; for example, the National Toxicology Program maintains an on-line Atlas of Non-Neoplastic lesions for a variety of organs, including gonads, in rodents (https://ntp.niehs.nih.gov/nnl/index.htm).
Although there are fewer publicly-accessible resources available for interpretation of histological images in other vertebrate classes, there is often published reference material suitable for this purpose (e.g., Spitsbergen et al. 2009).
Domain of Applicability
The primordial bipotential gonad and basic molecular machinery/pathways responsible for differentiation of testis and ovary are well conserved across all vertebrates (Cutting et al. 2013; DeFalco and Capel 2009). Although timing/expression of key genes controlling pathways involved in male versus female gonadal differentiation can vary across taxa (Cutting et al. 2013), actual structural morphology of the testes is similar across vertebrates (DeFalco and Capel 2009; McLaren 1998). Consequentially, this KE is applicable to most vertebrate taxa.
Carson, F. and C.H. Cappellano. 2014. Histotechnology: A Self-Instructional Text. 4th Ed., ASCP.
Cutting, A., Chue, J., & Smith, C. A. (2013). Just how conserved is vertebrate sex determination?. Developmental dynamics : an official publication of the American Association of Anatomists, 242(4), 380–387.
DeFalco T, Capel B. Gonad morphogenesis in vertebrates: divergent means to a convergent end. Annu Rev Cell Dev Biol. 2009;25:457-482. doi:10.1146/annurev.cellbio.042308.13350
McLaren A. (1998). Gonad development: assembling the mammalian testis. Current biology : CB, 8(5), R175–R177. https://doi.org/10.1016/s0960-9822(98)70104-6
Spitsbergen JM, Blazer VS, Bowser PR, Cheng KC, Cooper KR, Cooper TK, Frasca Jr S, Groman DB, Harper CM, Lawk JM, Marty GD, Smolowitz RM, Leger J, Wolf DC, Wolf JC. 2009. Finfish and aquatic invertebrate pathology resources for now and the future. Comparative Biochemistry and Physiology 149C, 249-257.
Trukhina, A. V., Lukina, N. A., Wackerow-Kouzova, N. D., & Smirnov, A. F. (2013). The variety of vertebrate mechanisms of sex determination. BioMed research international, 2013, 587460. https://doi.org/10.1155/2013/587460