Origin of Testicular Dysgenesis Syndrome Disorders in the Masculinization Programming Window: Relevance to Final Testis Size (=Sperm Production)

Abstract

Testicular dysgenesis syndrome (TDS) disorders are common and/or increasing in incidence in human males, implicating lifestyle/environmental causes. Our studies in rats suggest that TDS disorders originate in fetal life because of deficient testosterone production by the fetal testis within a specific masculinization programming window (MPW). Administration of dibutyl phthalate (DBP) to pregnant rats suppresses testosterone levels in the fetal testis more dramatically after the MPW than during the MPW, but only suppression in the MPW affects anogenital distance (AGD), confirming that this simple measure provides a life-long readout of androgen action just within the MPW. Using maternal treatments (DBP, linuron, prochloraz, alone or in combination) that can impair testosterone production by the fetal testis, we show that suppression of androgen action within the MPW, as inferred from AGD, is highly correlated (P < 0.0001) with testis size at e21.5 (when Sertoli cells are still proliferating), at postnatal day 25 (early puberty, when final Sertoli cell number has been determined) and in adulthood (when it equates to the level of sperm production). As a similar correlation was found between AGD and final Sertoli cell number, effects on this parameter probably explain the AGD:testis size correlation. Low sperm count is the commonest TDS disorder, affecting ~20% of young men. Emerging evidence suggests it may originate in fetal life in the MPW, consistent with the present rat studies.