This Adverse Outcome Pathway describes the linkage between a decrease in 7α-hydroxylase/C17,20-lyase (Cyp17a1) activity and a specific reproductive malformation in male newborns : impaired testicular descent also called cryptorchidism.
Cyp17a1 enzyme is known to mediate 17 alpha-hydroxylase and 17,20-lyase activities, the distinction between the two being functional and not genetic or structural. Mainly expressed in Leydig cells, this steroidogenic enzyme catalyzes the conversion of 17-OH-pregnenolone and 17-OH-progesterone to dehydroepiandrosterone (DHEA) and androstenediol, respectively. In that way, a decrease in Cyp17a1 activity would inevitably lead to a decline in both steroid precursors’ levels. As a result, this succession of key events will affect testosterone (T) and dihydrotestosterone (DHT) synthesis and circulating levels. A direct consequence to such a drop in major androgens levels would be a decline in androgen receptor activation, causing potential disturbances in development and maintenance of the male reproductive system such as cryptorchidism. To understand this AOP, it is important to notice that the second stage of the testicular descent process called “inguinoscrotal“ is an androgen-dependent event that can be dramatically affected by variations in androgenic activity.
The present AOP is linked to EU-ToxRisk Case Study 7: Read across evaluation of reproductive toxicity of conazoles. Conazoles are fungicide used in agriculture and as pharmaceuticals for treatment of human fungal diseases. They are known to act through inhibition of CYP51 which can be related to cross-reactivity with human enzymes involved in steroid metabolism, such as CYP17a1. In that respect, the proposed AOP and associated methods can be used as a basis to assess the effects of conazoles on steroidogenesis and reproductive development.