Endocrine-Disrupting Chemicals and Their Environmental Impacts - Organic Pollutants: An Ecotoxicological Perspective - page 269

able to inhibit aromatase activity, both in mammals and fish (reviewed in Kazeto
et al. 2004 and Cheshenko et al . 2008). Another enzyme in the sex steroid biosyn-
thesis pathway that can be disrupted by EDC exposure effects is cytochrome P450
17 alpha-hydroxylase/C17-20-lyase (P450c17), which catalyzes the biosynthesis of
dehydroepiandrosterone (DHEA) and androstenedione in the adrenals (Canton et
al . 2006) and testosterone in the Leydig cells within the testis (Majdic et al. 1996).
Maternal treatment with diethylstilbestrol (DES) or the environmental estrogen,
4-octylphenol (OP), has been shown to reduce expression of P450c17 in fetal Leydig
cells (Majdic et al . 1996), which can have subsequent adverse affects on fetal steroid
synthesis and the masculinization process. PAHs and Di ( n -butyl) phthalate (DBP)
also cause dose-dependent reductions in P450c17 expression in fetal testis of rats
(Lehmann et al . 2004).
Some EDCs have been shown to have multiple hormonal activities (Sohoni and
Sumpter 1998). Examples of this include bisphenol A, o , p ′-DDT, and butyl benzyl
phthalate, which possess both estrogenic and antiandrogenic activity, acting both as
an agonist at the estrogen and antagonist at the androgen receptor. Other examples
include the PCBs that can alter the estrogenic pathway, interfere with thyroid func-
tion, and disrupt corticosteroid function via the Ah receptor pathway. Some estro-
gens are even agonists in one tissue yet antagonists in another (Cooper and Kavlock
1997). Adding further to this complexity, disruptions to the endocrine system can
affect the functioning of the nervous and immune systems and the processes they
control (and vice versa). Examples of this include increases in autoimmune diseases
in women that result from exposure to the clinical estrogen DES, and suppression
in the expression of a gene associated with immune function (Williams et al . 2007),
modifications in phagocyte cells to the point of suppressing phagocytosis (Watanuki
et al . 2002), and decreases in IgM antibody concentrations (Hou et al. 1999) in fish
exposed to the steroid estrogen 17β-oestradiol (E 2 ).
In an attempt to unravel the pathways of effect of some EDCs and the biological
systems affected, toxicogenomics, most notably transcriptomics, are being increas-
ingly explored. Different mechanisms of toxicity can generate specific patterns
of gene expression indicative of the mode of action (and the biological processes
affected; Tyler et al . 2008). Expanded PCR-based methodologies have been used
to highlight the complex nature of the estrogenic effect of the pesticides p,p ′-DDE
and dieldrin in fish (Garcia-Reyero et al. 2006a, 2006b; Garcia-Reyero and Denslow
2006; Barber et al. 2007). In the Garcia-Reyero et al. 2006a study, three different
modes of action were identified, namely, direct interactions with sex steroid recep-
tors, alteration of sex steroid biosynthesis, and alterations in sex steroid metabo-
lism. Expanded PCR-based methodologies have similarly been applied to illustrate
the multiple mechanisms of action of environmental steroidal estrogens (E 2 and the
pharmaceutical estrogen ethinyloestradiol, EE 2 ) and the antiandrogen flutamide in
fish (Filby et al . 2006; Filby et al . 2007b). In that work E 2 was shown to trigger
a cascade of genes regulating growth, development, thyroid, and interrenal func-
tion. Responses were noted across six different tissues, with implications of more
wide-ranging effects of these chemicals beyond their well-documented effects on
reproduction. Santos et al. (2007), employing an oligonucleotide gene array (with
16,400 identified gene targets), recently discovered alterations in the expression of