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Advisory Committee on Health Effects of Endocrine Disruptors
The Supplement II to the Intermediary Report
1.3.2 |
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(2) New findings on the mechanisms of action
Studies of various effects of suspected endocrine disruptors on
the homeostatic regulatory systems from the viewpoint of systems
biology25 have recently
attracting attention. Significant results obtained in this area
include properties of endocrine stimulating substances that have
been shown by receptor tests to bind to estrogen receptors but
to have different mechanisms of action, and the interactions of
effects of dioxins (TCDD) and estrogen receptor (ER) signals via
allyl hydrocarbon receptors26,27.
These results are believed to be associated with the low-dose
effects, synergistic effects, and mechanisms of action mentioned
above.
(3) Findings related to the homeostatic regulatory systems
In the area of genesis and reproduction, BPA was found to
accelerate significantly the dilation of the vagina of pregnant
mice. Administration of BPA to adult mice had no effect on the
pregnancy rate, litter size and sex ratio, at least for the
first delivery28. A high-dose
administration of BPA to a neonatal female mouse resulted in
anovulia after maturation, which is a noticeable example of
delayed anovulia.
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25
Systems biology is an approach to the essence of biological
phenomena through study of mechanisms of cellular processes
(temporal development, expression of response gene to
stimulation, etc.) by means of simulation, modeled after
reaction kinetics.
26 It has been proposed that the
endocrine disruption associated with dioxin receptors (AhR)
depends on the balance between estrogen-independent binding to
ERs and activation of transcription on the one hand, and the
ubiquitination of estrogen-dependently activated ERs on the
other: ligand-activated AhRs activates estrogen-independent
transcription of ER, while suppressing transcription by
estrogen-activated ER. This supports the previously suggested
association of dioxins with endocrine disruption. Similar
mechanisms may operate with other nuclear receptors, though
relevant experimental data are still scanty. This will be an
important subject in future.
27 Ohtake F, Takeyama K, Matsumoto T, et al. Modulation
of estrogen receptor signaling by an association with the
activated dioxin receptor. Nature 423, 545-550, 2003.
28 Honma S, Suzuki A, Buchanan DL,
Katsu Y, Watanabe H, Iguchi T.: Low dose effect of in utero
exposure to bisphenol A and diethylstilbestrol on female mouse
reproduction. Reprod. Toxicol., 16: 117-122,2002. (No
multigeneration experiment has been performed.) |
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