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Phthalates and Cumulative Risk Assessment: The Tasks Ahead
MALE SEXUAL DIFFERENTIATION IN MAMMALS
Sexual differentiation in males follows complex interconnected pathways during embryo and fetal development that have been reviewed extensively elsewhere (see, for example, Capel 2000; Hughes 2001; Tilmann and Capel 2002; Brennan and Capel 2004).
Critical to the development of male mammals is the development of the testis in embryonic life from a bipotential gonad (a tissue that could develop into a testis or an ovary). The “selection” is genetically controlled in most mammals by a gene on the Y chromosome. The sex-determining gene (sry in mice and SRY in humans) acts as a switch to control multiple downstream pathways that lead to the male phenotype. Male differentiation after gonad determination is exclusively hormone-dependent and requires the presence at the correct time and tissue location of specific concentrations of fetal testis hormones—Mullerian inhibiting substance (MIS), insulin-like factors, and androgens. Although a female phenotype is produced independently of the presence of an ovary, the male phenotype depends greatly on development of the testis. Under the influence of hormones and cell products from the early testis, the Mullerian duct regresses, and the mesonephric duct (or Wolffian duct) gives rise to the epididymis and vas deferens. In the absence of MIS and testosterone, the Mullerian ductal system develops further into the oviduct, uterus, and upper vagina, and the Wolffian duct system regresses. Those early events occur before the establishment of a hypothalamic-pituitary-gonadal axis and depend on local control and production of hormones (that is, the process is gonadotropin-independent). Normal development and differentiation of the prostate from the urogenital sinus and of the external genitalia from the genital tubercle are also under androgen control. More recent studies of conditional knockout mice that have alterations of the luteinizing-hormone receptor have shown normal differentiation of the genitalia, although they are significantly smaller.
Testis descent (see Figure 3-1) appears to require androgens and the hormone insulin-like factor 3 (insl3; Adham et al. 2000) to proceed normally. The testis in early fetal life is near the kidney and attached to the abdominal wall by the cranial suspensory ligament (CSL) and gubernaculum. The gubernaculum contracts, thickens, and develops a bulbous outgrowth; this results in the location of the testis in the lower abdomen (transabdominal descent). The CSL regresses through an androgen-dependent process. In the female, the CSL is retained with a thin gubernaculum to maintain ovarian position. Descent of the testes through the inguinal ring into the scrotum (inguinoscrotal descent) is under androgen control.
Because the majority of studies discussed below were conducted in rats, it is helpful to compare the rat and human developmental periods for male sexual differentiation (see Figure 3-2). Production of fetal testosterone occurs over a broader window in humans (gestation weeks 8-37) than in rats (gestation days [GD] 15-21). The critical period for sexual differentiation in humans is late in