Guest Editorial: Phthalate Exposure during Pregnancy and Lower Anogenital Index in Boys: Wider Implications for the General Population?

Perspectives reignites the issue of the role that phthalate exposure during pregnancy may play in the etiology of reproductive disorders in human males. It does so by providing the first evidence of an association between phthalate exposure of mothers during pregnancy and attenuation of androgen action in their male babies. If this association is indicative of cause and effect, it will join together three key areas of research, namely, testicular dysgenesis syndrome (TDS) disorders in human males, induction of TDS-like disorders by phthalate administration to laboratory animals during pregnancy (experimental studies), and the widespread exposure of humans to various phthalates. TDS refers to a collection of disorders of newborn or young adult males thought to have a common origin in fetal life as a result of tes-ticular dysgenesis (Skakkebaek et al. 2001). These disorders include cryptorchidism (testis maldescent) and hypospadias, the two most common congenital malformations in newborns (2–4% and 0.3–0.7% incidence, respectively), testicular germ cell cancer, and low sperm counts. Low sperm count affects approximately 20% of young men in many European countries (Jorgensen et al. 2002), whereas testicular cancer is the most frequent cancer of young men, and its incidence has been increasing progressively in Caucasian men for the past 50 years or more (Richiardi et al. 2004). An integral feature of the TDS hypothesis is hormonal dysfunction of the fetal testis, in particular , reduced production of testosterone (Sharpe and Skakkebaek 2003). Because testosterone is largely responsible for transforming the fetus into a male, TDS can be viewed as a sexual differentiation (i.e., masculinization) disorder. But where do phthalates come in? Studies by several groups have shown that exposing pregnant rats to certain phthalates (din -butyl, diethylhexyl phthalate or butyl benzyl phthalate) during the period of sexual differentiation of the pups results in a collection of disorders in the male offspring similar to TDS disorders in men (Fisher et al. 2003; Mylchreest et al. 1998). More tellingly, the phthalate exposure results in focal testicu-lar dysgenesis (Barlow et al. 2004; Fisher et al. 2003; Mahood et al. 2005) and associated suppression of hormone production (testos-terone, insulin-like factor 3) by the fetal testis (Parks et al. 2000; Thompson et al. 2004; Wilson et al. 2004). One indication that the phthalate-exposed pups are " undermasculinized " is that they exhibit a reduction in anogenital distance (AGD) (Ema and Miyawaki 2001; Gray et al. 2000; Mylchreest et al. 2000; Zhang et …