Biology Reference
In-Depth Information
some (i.e., dichlorodiphenyltrichloroethane (DDT), diethylstilbesterol (DES), and
the PCBs (polychlorinated biphenyls)) which are no longer used in the USA because
of their well-documented impacts on wildlife and human health. These compounds
remain a health concern, however, because they are still present in the environment
and in our bodies. Once bound to a nuclear ER (ER
; Esr2), each
EDC induces a unique conformational change which ultimately determines the
activity of the complex (agonist or antagonist).
One feature of ER
α
; Esr1 or ER
β
which allows for such a diverse range of EDCs to
impact their function is a relatively large and promiscuous ligand-binding pocket.
Although they are highly selective for estradiol (E2), other endogenous and exoge-
nous ligands have been shown to bind with relatively high affi nity. ER
α
and ER
β
, for exam-
ple, is activated by E2 in the sub-nanomolar range, but the binding affi nity for the
androgen metabolite 5alpha-androstane-3beta,17beta-diol (3
β
β
-diol) is similar, sug-
gesting 3
β
-diol can also act as a potent endogenous ligand [
26
,
38
]. Structurally,
3
-diol and estrogenic EDCs share several properties with E2, most importantly
phenolic rings with hydroxyls that can readily undergo hydrogen binding with the
amino acids lining the interior of the ligand-binding pocket [
39
,
40
]. In general, the
relative binding affi nities of environmental EDCs are at least 1,000-fold lower than
E2, with the exception of some phytoestrogens (100-fold lower than E2) [
26
,
41
].
Their transcriptional activity is also typically orders of magnitude lower than for E2.
Thus, historically, estrogenic EDCs have been considered “weak” estrogens.
Although it has rapidly become apparent that this defi nition is too narrow and that
their activity is more complex, context specifi c, and dose dependent (for a detailed
review, see [
16
]), it is their estrogenic properties that make them capable of interact-
ing with the kisspeptin system. Exposures during development are hypothesized to
be particularly adverse because disrupted sex-specifi c organization of kisspeptin
pathways could confer lifelong consequences including altered pubertal timing,
infertility, and metabolic disorders. To date, only three compounds have been stud-
ied for their capacity to interfere with kisspeptin signaling pathways: BPA, PCB
mixtures, and the phytoestrogen GEN (Fig.
21.1
).
BPA was initially developed as a synthetic estrogen [
42
] and entered commercial
production in the 1950s. It is now a high-volume production chemical incorporated
in numerous products from which it readily leaches, including polycarbonate plas-
tics, the epoxy resins that line the interior of food cans, dental sealants, thermal
paper receipts, and plastic water pipes [
43
-
47
]. Human exposure is nearly ubiqui-
tous, with urinary levels higher in children than adults [
48
]. Although long consid-
ered weakly estrogenic, the specifi c mechanisms by which BPA interacts with
molecular and cellular targets within the hypothalamus and elsewhere are not yet
clearly established [
49
]. Classically, BPA is thought to disrupt nuclear ER activity,
but it has also been shown to have rapid actions via membrane ERs [
49
,
50
].
PCBs are organochlorides of which there are 209 congeners with different degrees
of chlorination. Although their physical and chemical properties vary across conge-
ners, in general, their low fl ammability, high thermal conductivity, and exceptional
solubility in organic solvents and oils made them suitable for a wide range of applica-
tions. They were used in a variety of combinations as coolant fl uids in electric motors,
β
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