Page 313 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

280 SECTION | II Organ Toxicity

VetBooks.ir mammals is DNA methylation of CpG nucleotides in the 11β-hydroxysteroid dehydrogenase (11β-HSD) which
play key roles in glucocorticoid metabolism (Gru ¨n and
promoter regions of genes, which results in methylated genes
Blumberg, 2006). Because of increased societal concerns
being “turned off” and unmethylated or demethylated genes
being “turned on” (McLachlan, 2001; Anway and Skinner, about obesity, there is likely to be greater future interest
2006). Patterns of DNA methylation are generally established in organotins and other EDCs with similar “obesogenic”
during development at the gastrulation stage (i.e., lineage- activities.
specific pattern in somatic cells) and after sex determination
(i.e., germ line-specific lineage pattern in the gonad) (Anway NORMAL ANIMAL REPRODUCTION
and Skinner, 2006). DNA methylation can facilitate “geno-
mic imprinting,” a form of epigenetic gene regulation result- Reproduction is a complex and dynamic process involv-
inginthe expression of theallele from only one parent (i.e., ing precise coordination and integration of the functions
monoallelic expression) (McLachlan, 2001; Anway and of multiple organs within the body. The production of
Skinner, 2006). The ability of developmental exposures to viable and functional gametes and their transport and
xenobiotics to provide a basis for adult disease, such as neo- union to form a zygote which develops into a healthy and
plasia, might very likely involve epigenetic changes involv- fertile individual require that many stringent physiological
ing methylation or demethylation of the promoters for and metabolic needs be met. A thorough understanding of
specific genes (Newbold et al., 2006). Epigenetic modifica- the mechanisms involved in reproduction is absolutely
tion by alterations in DNA methylation patterns in the germ essential in order to recognize which steps in the repro-
line might be one mechanism for observed xenobiotic- ductive process are most susceptible to the adverse effects
induced transgenerational (vertically transmitted) effects of potential toxicants. It is critical that one be able to
associated with infertility and tumor susceptibility in rodents understand the pathophysiological basis for reproductive
(Anway and Skinner, 2006; Newbold et al., 2006). abnormalities. In addition, it is necessary, from a clinical
perspective, to identify what constitutes “normal” repro-
duction in order to recognize abnormal reproductive beha-
Disruption of “Non-Reproductive”
viors and morphological changes in both domestic and
Endocrine Systems wild animals. Impaired reproductive function in domestic
Although it can be argued that almost all endocrine sys- animals, which is associated with exposure to toxic
tems are “reproductive” to some extent, there are multiple amounts of xenobiotics, necessitates the use of diagnostic,
systems with primary functions which are not directly prognostic and therapeutic procedures which require a
related to reproduction, and several of these systems have thorough knowledge of normal reproductive anatomy and
also been identified as potential targets of EDCs. In addi- physiology.
tion, gonadal steroids and xenobiotics which mimic these Normal reproduction will be reviewed in this chapter
endogenous hormones can have “non-reproductive” to provide a basis for discussion concerning specific
effects. The synthesis of triiodothyronine (T 3 ) and thyrox- reproductive toxicants. Although the emphasis will be on
ine (T 4 ) by the thyroid gland can be decreased by chemi- mammalian reproduction, many of the principles will be
cals which inhibit the uptake of iodine (e.g., perchlorate applicable to other classes of vertebrates. If additional
and thiocyanate) and also by xenobiotics which inhibit information is needed, textbooks are available which pro-
thyroperoxidase (e.g., thiourea, propylthiourea (PTU), vide a comprehensive overview of animal reproduction
some sulfonamides, methimazole, carbimazole, aminotria- (Hafez and Hafez, 2000; Senger, 2003), as well as general
zole and acetoacetamide) (Capen, 2008). Polybrominated veterinary anatomy (Dyce et al., 2002). Other references
diphenyl ethers (PBDEs) have been shown to have antith- can be consulted for descriptions of various aspects of
yroidal activity (Guillette, 2006), and thyroid hormone normal reproduction in species of domestic or laboratory
secretion can be inhibited by exposure to excessive animals, which might be of particular interest to the
amounts of iodine or lithium (Capen, 2008). Xenobiotics, reader (Johnston et al., 2002; Hedrich and Bullock, 2004;
0
such as the o,p -DDD metabolite of dichlorodiphenyltri- Suckow et al., 2006; Youngquist and Threlfall, 2007).
chloroethane (DDT), can interfere with glucocorticoid
metabolism (Guillette, 2006), and there has been increas- Neuroendocrine Control of Reproduction
ing interest in the relationship between gestational and
neonatal exposures to xenoestrogens and the development In humans and animals alike, visual, olfactory, auditory
of obesity (Cooke and Naz, 2005; Newbold et al., 2005, and other sensory data are integrated within the brain and
2006). Some EDCs (e.g., organotin compounds) have are reflected in endocrine events. The neuroendocrine
recently been described as “obesogens” because of their functions of the pineal gland, hypothalamus and pituitary
ability to affect adipogenesis by several different mechan- gland play an important role in the integration and endo-
isms, including interactions involving the isoforms of crine regulation of the body’s physiological processes and