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Event: 1688
Key Event Title
anogenital distance (AGD), decreased
Short name
Exploration Options for Key Events
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Biological Context
| Level of Biological Organization |
|---|
| Tissue |
Organ term
| Organ term |
|---|
| perineum |
Key Event Components
| Process | Object | Action |
|---|---|---|
| androgen receptor signaling pathway | Musculature of male perineum | disrupted |
Key Event Overview
AOPs Including This Key Event
| AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|
| 5α-reductase inhibition leading to short AGD | AdverseOutcome | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
| AR antagonism leading to short AGD | AdverseOutcome | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
| Decreased testosterone synthesis leading to short AGD | AdverseOutcome | Terje Svingen (send email) | Under development: Not open for comment. Do not cite | Under Development |
| Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicity | AdverseOutcome | Yue Zhang (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Life Stages
| Life stage | Evidence |
|---|---|
| Foetal | High |
Sex Applicability
| Term | Evidence |
|---|---|
| Male | High |
Key Event Description
The anogenital distance (AGD) refers to the distance between anus and the external genitalia. In rodents and humans, the male AGD is approximately twice the length as the female AGD (Salazar-Martinez et al, 2004; Schwartz et al, 2019). This sexual dimorphisms is a consequence of sex hormone-dependent development of secondary sexual characteristics (Schwartz et al, 2019). In males, it is believed that androgens (primarily DHT) activate AR-positive cells in non-myotic cells in the fetal perineum region to initiate differentiation of the perineal levator ani and bulbocavernosus (LABC) muscle complex (Ipulan et al, 2014). This AR-dependent process occurs within a critical window of development, around gestational days 15-18 in rats (MacLeod et al, 2010). In females, the absence of DHT prevents this masculinization effect from occurring.
The involvement of androgens in masculinization of the male fetus, including the perineum, has been known for a very long time (Jost, 1953), and AGD has historically been used to, for instance, sex newborn kittens. It is now well established that the AGD in newborns is a proxy readout for the intrauterine sex hormone milieu the fetus was developing. Too low androgen levels in XY fetuses makes the male AGD shorter, whereas excess (ectopic) androgen levels in XX fetuses makes the female AGD longer, in humans and rodents (Schwartz et al, 2019).
How It Is Measured or Detected
The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans).
In rodent studies AGD is assessed as the distance between the genital papilla and the anus, and measured using a stereomicroscope with a micrometer eyepiece. The AGD index (AGDi) is often calculated by dividing AGD by the cube root of the body weight. It is important in statistical analysis to use litter as the statistical unit. This is done when more than one pup from each litter is examined. Statistical analyses is adjusted using litter as an independent, random and nested factor. AGD are analysed using body weight as covariate as recommended in Guidance Document 151 (OECD, 2013).
Domain of Applicability
A short AGD in male offspring is a marker of insufficient androgen action during critical fetal developmental stages (Schwartz et al, 2019; Welsh et al, 2008). A short AGD is thus a sign of undervirilization, which is also associated with a series of male reproductive disorders, including genital malformations and infertility in humans (Juul et al, 2014; Skakkebaek et al, 2001).
There are numerous human epidemiological studies showing associations with intrauterine exposure to anti-androgenic chemicals and short AGD in newborn boys alongside other reproductive disorders (Schwartz et al, 2019). This underscores the human relevance of this AO. However, in reproductive toxicity studies and chemical risk assessment, rodents (rats and mice) are what is tested on. The list of chemicals inducing short male AGD in male rat offspring is extensive, as evidenced by the ‘stressor’ list and reviewed by (Schwartz et al, 2019).
Regulatory Significance of the Adverse Outcome
In regulatory toxicology, the AGD is mandatory inclusions in OECD test guidelines used to test for developmental and reproductive toxicity of chemicals. Guidelines include ‘TG 443 extended one-generation study’, ‘TG 421/422 reproductive toxicity screening studies’ and ‘TG 414 developmental toxicity study’.