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Reproductive Toxicity and Endocrine Disruption Chapter | 17 295

VetBooks.ir endocrine-induced morphological changes take place, are maintained within the hypothalamus of the female
fetus in this low-estradiol environment (Ford and
resulting in both a genotypically and a phenotypically male
D’Occhio, 1989; Senger, 2003). Testosterone produced by
fetus (Figure 17.5a). The sequence of signaling and devel-
opmental changes, which result in male sexual differentia- the fetal testes crosses the blood brain barrier and is con-
tion, include the following: (1) Sertoli cell development and verted to estradiol within the brain, and, as a result of this
secretion of anti-Mu ¨llerian hormone (AMH) or Mu ¨llerian estradiol synthesis, the hypothalamic GnRH surge center
inhibiting substance (MIS); (2) AMH-induced regression of in the male fetus is minimized (Senger, 2003).
the paramesonephric (Mu ¨llerian) ducts and differentiation While the differentiation of male sexual behavior in
of Leydig cells capable of producing testosterone; (3) large domestic animals generally involves prenatal defem-
testosterone-facilitated development of the mesonephric or inization, especially in species having longer gestations, it
Wolffian ducts; (4) differentiation of the mesonephric ducts should be noted that postnatal defeminization of the brain
into the rete testes, efferent ductules, epididymidies and is occurs in male swine and rodents (Ford and D’Occhio,
ducti deferens; (5) development of primordial accessory sex 1989). There is also evidence to suggest that the males of
glands and the formation of external genitalia from primor- some species with prenatal defeminization of the brain
dia and, finally, in most species (some exceptions in wild- might also require postnatal exposure to androgens for
life species); (6) testicular descent of the intra-abdominal maximum masculinization of the brain (Senger, 2003).
testes into their extra-abdominal position in the scrotum, Depending on the timing of exposure, xenoestrogens and
prior to or very shortly after birth (some species) (Senger, exogenously administered testosterone and, possibly,
2003; Genuth, 2004b; Basrur, 2006; Edwards et al., 2006). some xenoandrogens, which cross the placenta and the
blood brain barrier have the potential to have profound
Development of the Female Phenotype effects on sexual differentiation of the brain and future
reproductive function.
If the previously undifferentiated gonads do not commit
to testes development (TDF absent), ovaries are formed
and a cascade of morphological changes occurs in the
absence of AMH and testosterone stimulation, resulting in Parturition and Lactation
a genotypically and phenotypically female fetus Physiology of Parturition
(Figure 17.5b). This sequence of “default” or “constitu-
Parturition constitutes transport of the fetus and its associ-
tive” morphological and endocrine alterations results
ated membranes from the maternal to the external
in the following sequence of developmental events:
environment, and represents transition of the fetus to a
(1) regression of mesonephric (Wolffian ducts); (2) differ-
neonate. Maturation of the fetal hypothalamic pituitary
entiation of the paramesonephric (Mu ¨llerian) ducts into
adrenal axis plays an important role in the cascade of neu-
the oviducts, uterine horns, uterine body, cervix and ante-
ral and endocrine events which lead to parturition in most
rior vagina; (3) remodeling of the ovary into its typical
mammals (Senger, 2003; Evans et al., 2007). As most
parenchymal and cortical structure; (4) cortical develop-
clearly demonstrated in ruminants, fetal CRF stimulates
ment of primordial follicles, with primary oocytes
the release of ACTH from the fetal pituitary, and ACTH,
arrested in meiosis and surrounded by future granulosa
in turn, stimulates fetal secretion of cortisol by the adrenal
and theca interna cells; and (5) development of the caudal
glands (Senger, 2003). Elevations in fetal cortisol (fetal
vagina and vulva from the urogenital sinus (external geni-
LH may be involved as well) activate placental steroido-
talia primordia) (Senger, 2003; Genuth, 2004b; Basrur,
genic enzyme systems, resulting in decreased progesta-
2006; Edwards et al., 2006; Evans et al., 2007).
gens and elevated estrogens prior to parturition (Ginther,
1992; Evans et al., 2007). The resulting increase in the
Sexual Differentiation of the Brain estrogen:progestagen ratio facilitates several important
Sex-specific endocrine patterns and the resulting gender processes (e.g., cervical softening, up-regulation of myo-
appropriate sexual behaviors in animals are necessary for metrial oxytocin receptors, uterine synthesis of PGF 2α
fertile copulations to occur and require that the brain also and increased blood flow to the gravid uterus and pla-
undergo prenatal (postnatal in some species) sexual differ- centa) which prepare the uterus for parturition (Evans
entiation. Although large amounts of estradiol defeminize et al., 2007). Teratogen-induced congenital defects in the
the brain, alpha-fetoprotein prevents most of the endoge- fetal pituitary gland can result in prolonged gestation
nous estrogens in the female fetus from crossing the (e.g., Veratrum californicum), and any xenobiotic expo-
blood brain barrier (Senger, 2003). The brain remains sure causing maternal and/or fetal stress can be associated
inherently female under the influence of minimal amounts with abortion or premature parturition (e.g., nitrates and
of estradiol, and both the GnRH tonic and surge centers pine needle abortion).