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Reproductive Toxicity and Endocrine Disruption Chapter | 17 293

VetBooks.ir differentiation and organization must take place. Gonadal Sex Determination
and Phenotypic Sexual Differentiation
Embryonic and fetal survival requires that these various
steps take place in a precise order and at set times dur-
ingthe gestationofeachspecies. Within 24 h following Development of a phenotypically male or female mam-
malian fetus occurs during the first trimester of pregnancy
fertilization, the zygote located in the oviduct begins to in most species and consists of the determination of
divide, within the confines of the zona pellucida, into gonadal sex followed by the further development and dif-
multiple blastomeres, which ultimately form a ball of ferentiation of either the mesonephric or the parameso-
cells referred to as the morula (Ginther, 1992; Senger, nephric ducts and regression of the other duct system.
2003). A fluid-filled cavity (blastocoele) develops, and The selection of the mesonephric or paramesonephric
the newly formed blastocyst, which is divided into ducts for retention and further differentiation results in
cells forming either the inner cell mass (future embryo the formation of genitalia (phenotypic sex) appropriate
proper) or the trophoblast (future chorion), enters the for either the male or female gonads, respectively
uterus (Senger, 2003). The blastocyst undergoes rapid (Genuth, 2004b). Gonadal sex determination and pheno-
growth and “hatches” from the zona pellucida. The sub- typic sexual differentiation are dependent on complex and
sequent cellular division and differentiation results in carefully timed signaling events and are extremely sus-
the formation of the three germ layers (i.e., endoderm, ceptible to disruption by xenobiotics. Toxicants which
mesoderm and ectoderm), which are destined to develop alter epigenetic programming or mimic or inhibit endoge-
into the embryonic tissues forming the various organs nous hormones can have potentially deleterious effects on
and body systems, as well as the extraembryonic mem- sexual development (Basrur, 2006). Xenobiotic-induced
branes involved in placental formation and attachment abnormalities in phenotypic sexual differentiation can
(Ginther, 1992; Senger, 2003). Germ layer differentia- arise from defects in testicular formation, defects in
tion leads to organogenesis and the transformation of an androgen production and defects in androgenic action
embryo into the fetus which continues to grow and (Basrur, 2006; Hughes et al., 2006). While some toxicant-
develop for the remainder of pregnancy. With respect to induced abnormalities in sexual differentiation can be
reproductive toxicity in non-rodent mammals, the orga- very obvious (e.g., hermaphroditism (presence of ovo-
nogenic and other developmental processes occurring testes), pseudohermaphroditism (differences in gonadal
during the first trimester of pregnancy are especially and phenotypic sex), hypospadias (feminized external
susceptible to the teratogenic effects of xenobiotics. The genitalia; failure of urethral fold fusion) and cryptorchi-
abnormalities induced by a teratogen are dependent on dism (failure of testicular descent)), other more subtle
the specific developmental processes or signaling path- effects can be related to functional rather than structural
ways targeted by that toxicant and the timing of the abnormalities. In order to identify the steps in gonadal sex
exposure. determination and phenotypic sexual differentiation most
likely to be targeted by the effects of EDCs and other
reproductive toxicants, it is important to understand how
Sex Determination and Sexual Differentiation these processes are initiated within the fetus and how they
of Reproductive Function impact subsequent fetal development.
Genotypic Sex and Development For the last several decades, the model for gonadal
of the Primitive Sex Cords sex determination and phenotypic sexual differentiation
has been based on the premise that a “testis determining
The genotypic sex of a mammalian conceptus is deter-
factor” (TDF) on the Y chromosome dictates that a gonad
mined at fertilization by the sex chromosome (X or Y)
differentiates into a testis and initiates the cascade of
contributed by the sperm, which, in combination with the
endocrine changes (Figure 17.5)which resultsina
X chromosome in the ovum, denotes either a geno-
pheno-typically male fetus (developed mesonephric duct
typically female (XX) or a male (XY) zygote. During
system; regressed paramesonephric ducts) (Senger, 2003;
early gestation in most species, the primordial germ cells
Genuth, 2004b; Basrur, 2006; Evans and Ganjam, 2017).
arise from the epithelium of the embryonic yolk sac and
Without the determination that the gonads will develop
migrate through the developing mesentery to the gonadal
into testes, the “default” or “constitutive” pathway is fol-
(genital) ridge (testicular or ovarian anlage) in its position
lowed and ovarian gonads are formed in association with
contiguous with the mesonephros (Senger, 2003; Evans
a developed paramesonephric duct system and regressed
et al., 2007). Germ cells and stimulated somatic cells pro-
mesonephric ducts (Senger, 2003; Genuth, 2004b;
liferate and organize into primitive sex cords within
Basrur, 2006). While this model is useful to explain
undifferentiated (bipotential) gonads, which have the
rather complex developmental processes, it should be
potential to develop into either ovaries or testes (Senger,
kept in mind that other toxicant-susceptible mechanisms
2003; Basrur, 2006).