Page 312 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Reproductive Toxicity and Endocrine Disruption Chapter | 17 279

VetBooks.ir hydro-carbons” (HAHs or PAHs, respectively) and development (Petersen et al., 2006). AhR-mediated
effects of TCDD can interfere with the biosynthesis of
includes many highly stable and lipophilic organo-
testosterone by a mechanism which alters the regulation
chlorine industrial chemicals (e.g., polycyclic aromatic
hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), of the synthesis and release of LH (Sikka et al., 2005). It
polychlorinated dibenzo-p-dioxins (PCDDs) and poly- has also been shown in cell cultures that TCDD can dis-
chlorinated dibenzodifurans (PCDFs)), as well as their rupt testosterone signal transduction pathways (Jana et al.,
metabolites (Safe, 2005). In addition, other organic 1999). The liganded AhR/Arnt heterodimer appears to be
compounds, such as polycyclic aromatic hydrocarbons able to interact with inhibitory DREs (iDREs) in selected
(PAHs) (e.g., 3-methylcholanthrene and benzo[a]pyr- tissues to suppress the expression of some genes induced
ene) (BaP)) and flavones (e.g., β-naphthoflavone), have by estrogens (Safe, 2005), as well as be able to actually
also been shown to be AhR agonists (Parkinson and block the ability of estrogen ER complexes to bind to
Ogilvie, 2008). their HREs (Kharat and Saatcioglu, 1996; Thomas and
Khan, 2005). It is likely that a variety of other means of
crosstalk between TCDD- and estrogen-mediated signal-
Mechanisms of Aryl Hydrocarbon ing pathways exist, and, in fact, TCDD has actually been
Receptor-Mediated Endocrine Disruption shown to have the potential for estrogenic activity through
Many of the mechanisms of action mediated by interactions between liganded AhR/Arnt heterodimers and
AhR ligand interactions have been elucidated using unliganded ERs (both ERα and ERβ)(Ohtake et al.,
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a proto- 2003; Bigsby et al., 2005; Thomas and Khan, 2005).
typical AhR agonist (Safe, 2005; Parkinson and Ogilvie, Ohtake et al. (2003) have reported that these novel inter-
2008). TCDD is considered by many to be the most toxic actions resulted in the recruitment of unliganded ERs and
of all of the HAHs, and it is reported to have the highest p300 co-activator to gene promoters which are responsive
AhR-binding affinity of any of the xenobiotics in that to estrogens. Based on the results of the various experi-
class of chemicals (Safe, 2005). The AhR, also referred to ments performed with TCDD, it is important to remember
as the “dioxin receptor,” is located in the cytoplasm that the effects observed following exposure to HAHs and
bound to heat shock proteins (Parkinson and Ogilvie, EDCs, in general, can be dependent on animal species
2008). Following ligand (i.e., TCDD) binding and the involved, as well as the type of tissue, organ or physiolog-
subsequent disassociation of the heat shock proteins, ical response being evaluated.
the AhR is activated by phosphorylation (Parkinson and
Ogilvie, 2008) and the activated ligand AhR complex
undergoes a rapid sequence of events involving interac- Epigenetic Mechanisms of Action
tions with the AhR nuclear translocator protein (Arnt) and of Endocrine Disrupting Chemicals
relocation of the ligand AhR Arnt complex into the In recent years there has been increasing interest in the
nucleus (Safe, 2005). association between prenatal exposures to some reproduc-
Within the nucleus, the liganded AhR/Arnt heterodi- tive toxicants and the postnatal development of neoplasia
mer can facilitate a variety of endocrine disrupting (cancer) involving the reproductive tract, as well as the
mechanisms. This activated heterodimer complex can occurrence of transgenerational or vertically transmitted
interact with dioxin/xenobiotic-response elements (DREs/ adverse reproductive effects (Crews and McLachlan,
XREs), which function in much the same way as the pre- 2006). These two phenomena are not mutually exclusive
viously discussed HREs, and with various co-activators to of one another, and, in fact, there is increasing evidence
increase the expression of selected genes (Safe, 2005; of vertically transmitted neoplasia involving reproductive
Parkinson and Ogilvie, 2008). Depending on the animal organs (McLachlan et al., 2006). Both tumor formation
species and the tissue, multiple-phase I drug-metabolizing and transgenerational reproductive abnormalities can
enzymes (e.g., cytochrome P450 (CYP) enzymes (CYP1A1, occur because of “genetic” mutations or alterations in the
CYP1A2 and CYP1B1)) and enzymes involved in phase II genotype (i.e., DNA sequence) or as a result of “epige-
drug-biotransformation reactions (e.g., glutathione-S-trans- netic” changes where there are heritable modifications in
ferase and glucuronosyl transferase), are induced by TCDD the properties of a cell which do not represent genetic
(Safe, 2005). changes (inherited phenotypic alteration without geno-
Although the antiandrogenic and antiestrogenic prop- typic change) (Lewin, 1998; McLachlan, 2001; Crews
erties of TCDD have been associated with the ability of and McLachlan, 2006).
HAHs to induce enzymes involved in androgen and estro- Epigenetic changes are a normal part of development and
gen metabolism, TCDD can interact with androgen-, most likely represent one means for heritable environmental
estrogen- and progestagen-modulated pathways in a num- adaptation (Crews and McLachlan, 2006). One of the
ber of ways, including interference with neuroendocrine more common mechanisms of epigenetic modification in