Endocrine-Disrupting Chemicals and Their Environmental Impacts - Organic Pollutants: An Ecotoxicological Perspective - page 268

system are widely reported, and they include malformation of limbs due to excessive
or insufficient retinoic acid (structurally similar to thyroid hormones) in birds and
mammals, the production of small eggs and chicks in birds, and impaired metamor-
phosis in amphibians (reviewed in Rolland 2000). Known thyroid-disrupting chemi-
cals include many members of the polyhalogenated aromatic hydrocarbons (PHAHs)
such as PCBs (polychlorinated biphenyls; see Chapter 6, Section 6.2.4), dioxins,
PAHs, polybrominated dimethylethers (PBDEs, flame retardants), and phthalates
(Brouwer et al . 1998; Zhou et al . 1999; Rolland 2000; Boas et al . 2006).
Other modes of hormonal disruption identified, but for which there is consider-
ably less data, include those acting via the progesterone or Ah receptors, corticos-
teroid axis, and the enzyme systems involved with steroid biosynthesis. Chemicals
interacting with the progesterone receptors can impact both reproductive and behav-
ioral responses, notably in fish in which progesterones can function as pheromones
(Zheng et al. 1997; Hong et al. 2006). Various progesterones are used in contraceptive
pharmaceuticals such as norethisterone, levonorgestrel, desogestrel, and gestodene,
and find their way into the aquatic environment via WWTW discharges. The fungi-
cide vinclozolin and the pyrethroid insecticides fenvalerate and permethrin have also
been shown to interfere with progesterone function (Kim et al. 2005; Buckley et al .
2006; Qu et al. 2008).
It has long been recognized that the Ah receptor (AhR) is a ligand-activated
transcription factor that plays a central role in the induction of drug-metabolizing
enzymes and hence in xenobiotic activation and detoxification (Marlowe and Puga
2005; Okey 2007; see Chapter 6, Section 6.2.4). Much of our understanding of AhR
function derives from analyses of the mechanisms by which its prototypical ligand
2,3,7,8 tetrachlorodibenzo-p-diosin (TCDD) induces the transcription of CYP1A1
(Pocar et al. 2005), which encodes for the microsomal enzyme cytochrome P4501A1
that oxygenates various xenobiotics as part of their step-by-step detoxification
(Conney 1982; see Chapter 6, Section 6.2.4.). Most effects on the endocrine systems
of organisms exposed to halogenated and polycyclic aromatic hydrocarbons such as
benzopyrene, polybrominated dimethylethers (PBDEs), and various PCBs are medi-
ated by the Ah receptor (Pocar et al. 2005).
Interference with corticosteroid function and the stress response has been shown
for a variety of chemicals, including the pharmaceutical salicylate (Gravel and
Vijayan 2006) and the PAH, phenanthrene (Monteiro et al. 2000a, 2000b). Other
classes of chemicals shown to have significant effects on cortisol levels include PCBs
and PAHs (Hontela et al. 1992, 1997). The precise mechanisms for these effects are
poorly understood, but for PCBs, are believed to be via their actions through the Ah
receptor (Aluru and Vijayan 2006).
Studies on the endocrine-disrupting effects of chemicals via enzyme biosynthe-
sis pathways have focused on cytochrome P450 aromatase, encoded by the CYP19
gene, and involved with the production of estrogens from androgens (Cheshenko et
al. 2008). Modulation of aromatase CYP19 expression and function can dramati-
cally alter the rate of estrogen production, disturbing the local and systemic levels of
estrogens that play a critical role in vertebrate developmental sex differentiation and
reproductive cycles (Simpson et al . 1994). Natural and synthetic chemicals, includ-
ing certain xenoestrogens, phytoestrogens, pesticides, and organotin compounds, are