Page 307 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

274 SECTION | II Organ Toxicity

VetBooks.ir the survival of a given species of animal (Senger, 2003). defects induced by toxicant exposures occurring between
conception and birth (Hodgson et al., 2000; Eaton and
The physiological processes involved in reproduction gen-
Klaassen, 2001; Rogers and Kavlock, 2008). The types of
erally include the following: (1) gametogenesis (produc-
tion of sperm or ova) and the pre- and peri-pubertal abnormalities that are typically associated with teratogen-
changes leading up to its onset; (2) release of gametes esis include embryonic or fetal death; morphological,
(i.e., sperm transport and maturation, penile erection and functional and/or neurobehavioral abnormalities; and
ejaculation of sperm (mammals), copulation between a decreased growth rate and/or birth weight (Panter, 2002;
male and a female of the same species (several vertebrate Rogers and Kavlock, 2008).
classes) and ovulation of oocytes); (3) formation of the
zygote (i.e., sperm storage, capacitation and other pro-
Wilson’s General Principles of Teratology
cesses leading to fertilization, or union, of a single sperm
with an egg); (4) embryonic and fetal development during With respect to teratogenesis, there are six basic tenets of
teratology, first defined by Wilson in 1959, which need to
the incubation process in egg-bearing vertebrates or,
be kept in mind whenever gestational exposure to a tera-
especially in the case of mammals, during pregnancy
togenic xenobiotic is suspected or when a chemical is
(gestation) (i.e., activities related to the initiation and
being evaluated for its teratogenic potential. As stated by
progression of zygote cleavage, blastocyst formation, sep-
Wilson in the Handbook of Teratology (Wilson, 1977),
aration of the germ layers, placentation (mammalian spe-
the general principles of teratology are as follows:
cies), neurulation and organogenesis (including sexual
differentiation)); and finally (5) “birth” of a single or mul- 1. Susceptibility to teratogenesis depends on the geno-type
tiple offspring (hatching in oviparous vertebrates). In the of the conceptus and the manner in which it interacts
conventional sense, the reproductive process culminates with environmental factors.
with birth or parturition (mammals); however, the initia- 2. Susceptibility to teratogenic agents varies with the
tion and maintenance of milk production (lactation) for developmental stage at the time of exposure.
the postpartum nutrition of offspring can also be consid- 3. Teratogenic agents act in specific ways (mechanisms)
ered a critical aspect of mammalian reproduction (Evans on developing cells and tissues to initiate abnormal
et al., 2007; Evans and Ganjam, 2017). embryogenesis.
4. The final manifestations of abnormal development are
death, malformation, growth retardation and functional
Reproductive Toxicity
disorder.
For the purposes of this chapter, “reproductive toxicity” 5. The access of adverse environmental influences to
will refer to any manifestations of xenobiotic exposure developing tissues depends on the nature of the influ-
reflecting adverse effects on the physiological processes ences (agent).
and associated behaviors and/or anatomical structures 6. Manifestations of deviant development increase in
involved in animal reproduction or development. This is a degree as dosage increases from no effect to the
fairly broad definition which encompasses developmental totally lethal level.
toxicity, as well as any toxic effects of post-pubertal
exposures to xenobiotics on either male or female repro- Mechanisms of Reproductive Toxicity
duction. “Developmental toxicity” refers to any adverse and Teratogenesis
effect on the developing organism associated with either
There are a wide range of specific mechanisms of action
pre-conception parental exposures to toxicants or post-
by which xenobiotics can adversely affect reproductive
conception xenobiotic exposures to the embryo, fetus or
function, including embryonic and fetal development. In
pre-pubertal offspring (Hodgson et al., 2000; Eaton and
general, many of these mechanisms are the same as those
Klaassen, 2001; Foster and Gray, 2008). Adverse effects
for toxicants affecting other organ systems and essentially
associated with developmental toxicity of xenobiotics
involve some sort of toxicant-induced cellular dysregula-
might not necessarily be observed until after the affected
tion and alterations in cellular maintenance which, when
individuals have reached sexual maturity (Foster and
Gray, 2008; Rogers and Kavlock, 2008). possible, the body attempts to repair, either successfully
or unsuccessfully (Gregus, 2008). Oxidative damage and
interference with normal enzymatic reactions are two
Teratogenesis common mechanisms by which xenobiotics can cause the
The term “teratogenesis” is derived from the Greek word dysregulation and altered maintenance of cells within var-
for monster (“teras”) and is a form of developmental ious organs and tissues.
toxicity (Panter, 2002; Rogers and Kavlock, 2008). Normal reproduction and development require, by
“Teratogenesis” refers specifically to developmental their very nature (see review in this chapter), signaling