Shinichi Miyagawa (Assis. Prof.)Yukiko Ogino (Assis. Prof.)
Synthetic chemicals found in the environment have the capacity to disrupt the development and function of the endocrine system in both wildlife and humans. Early evidence that exposure to estrogenic chemicals during development could pose a threat to human health came from studies of a synthetic estrogen, diethylstilbestrol (DES), which was used to prevent premature birth and spontaneous abortion. Laboratory experiments showed that exposure of animals to estrogens during critical windows of perinatal life caused irreversible alterations to the endocrine and reproductive systems of both sexes. Although many of environmental chemicals can bind to estrogen receptors (ERs) in wildlife and humans, therefore, understanding the molecular mechanisms through which these chemicals act during critical developmental windows is essential.
I. Developmental origin of adult disease: Perinatal estrogen exposure induces persistent changes in reproductive tracts
The emerging paradigm of the gembryonic/fetal origins of adult disease・ｽh provides a powerful new framework for considering the effects of endocrine disrupters on human and animal health. We found that the persistent changes in the vagina in mice exposed neonatally to estrogens result from the persistent phosphorylation of growth factor receptors and ER?, sustained expression of growth factors and phosphorylation of signaling cascade proteins. We are analyzing the methylation status of genes showing altered expression in the mouse vagina and genes induced by environmental chemicals in the mouse reproductive organs during the critical developmental exposure window, and molecular mechanisms of actions of some environmental chemicals.
II. Environmental sex determination: Daphnids and crocodilians
Daphnia magna reproduce asexually (parthenogenesis) when they are in an optimal environment for food, photoperiod and population density. Once environmental conditions become sub-optimal, they alter their reproductive strategy from asexual to sexual reproduction. We found that juvenile hormone agonists (pesticides) induce the production of male offspring. The molecular basis of environmental sex determination is largely unknown in these organisms, however, we recently identified genes expressed in the testis and working on gene function in more detail in this species. Crocodilians show temperature-dependent sex determination (TSD); eggs incubated at 33C develop to male and 30C to female. We are studying molecular mechanism of TSD using American alligator embryos.
III. Evolution of steroid hormone receptors
We have cloned steroid hormone receptors and steroid and xenobiotic receptors (SXR) from various animal species (fish, amphibian, reptiles, birds and mammals) and demonstrated species-specific differences in their responses to various environmental and endogenous chemicals (receptor gene zoo). Thus, simple predictions of chemical effects based on data from a few established model species are not sufficient to develop real world risk assessments. We are currently working on the evolution of receptor genes.
- H. Watanabe, N. Tatarazako, S. Oda, H. Nishide, I. Uchiyama, M. Morita & T. IGUCHI: "Analysis of expressed sequence tags of the waterbfrea Daphnia magna." Genome, 48, 606-609 (2005)
- S. Miyagawa, Y. Katsu, H. Watanabe & T. IGUCHI: "Estrogen-independent activation of ErbBs signaling and estrogen receptor ・ｽ・ｽ in the mouse vagina exposed neonatally to diethylstilbestrol." Oncogene, 23, 340-349 (2004)
- Y. Katsu, D.S. Bermudez, E.L. Braun, C. Helbing, S. Miyagawa, M.P. Gunderson, S. Kohno, T.A. Bryan, LJ. Guillette, Jr. & T. IGUCHI: "Molecular cloning of the estrogen and progesterone receptors of the American alligator." Gen. Comp. Endocr., 136, 122-133 (2004)
- H. Watanabe, A. Suzuki, M. Kobayashi, D. Lubahn, H. Handa & T. IGUCHI: "Analysis of temporal changes in the expression of estrogen regulated genes in the uterus." J. Mol. Endocr., 30, 347-358, (2003)
- Y. Katsu, D. Lubahn & T. IGUCHI: "Expression of novel C-type lectin in the mouse vagina." Endocrinology, 144, 2597-2605 (2003)