Uterine Development and Endocrine Disruption
The female reproductive tract develops from the seemingly uniform undifferentiated paramesonephric duct. The paramesonephric duct develops into the fallopian tubes, uterus, cervix and upper vagina. The molecular mechanisms that establish differential development along this axis were previously unknown. We determined that Hox genes establish positional developmental identity in the development of the Mullerian tract. Hoxa-9, Hoxa-10, Hoxa-11, and Hoxa-13 are all expressed along the length of the paramesonephric duct in the embryonic mouse. After birth, a spatial Hox axis is established, corresponding to the postnatal differentiation of this organ system in the mouse. Hoxa-9 is expressed in the fallopian tubes, Hoxa-10 in the uterus, Hoxa-11 in the uterus and uterine cervix, and Hoxa-13 in the upper vagina. These genes remain expressed in the adult and are expressed in the same pattern in the mouse and human.
An endocrine disruptor is a synthetic chemical that either mimics or blocks hormones and disrupts normal development or function. Many such compounds are present in the environment or used in drugs and food. A classic example is diethylstilbestrol (DES), a drug formerly used in pregnancy to prevent miscarriage. Instead DES distorted the development of the female reproductive tract; exposure to DES led to an increased risk of miscarriage and cancer in women who were exposed as a fetus. We have identified a common mechanism by which several endocrine disruptors cause these defects. DES alters the action of estrogen- the hormone that normally regulates this gene. We have cloned the HOXA10 ERE and demonstrated differential response to estradiol and DES. We have also found that methoxychlor, a commonly used pesticide, also disrupts the proper development of the uterus by blocking this gene. Finally we have recently found that bisphenol A (BPA) also distorts the normal expression of the HOXA10 gene. BPA is a common component of plastic food and beverage storage containers as well as dental composites. Humans are widely exposed this chemical. Each of these agents acts by disrupting this common gene. Understanding the mechanism of action of these agents may lead to better means of testing new compound for adverse effects, and perhaps prevention of excess exposure.
Current research focuses on understanding the fundamental mechanisms of reproductive tract development as well as the effect of endocrine disruptors on this process.
- Taylor HS, Vanden Heuvel GB and Igarashi P. A Conserved Hox Axis in the Mouse and Human Female Reproductive System: Late Establishment and Persistent Adult Expression of the HOXA Cluster Genes. Biol Reprod 1997, 57(6):1338-1345.
- Block K, Kardana A, Igarashi P and Taylor HS. In Utero Diethylstilbestrol (DES), Exposure Alters Hox Gene Expression in the Developing Müllerian System. FASEB J 14(7):1101-1108, 2000.
- Akbas, GE, Song J and Taylor HS. A HOXA10 estrogen response element (ERE) is differentially regulated by 17ß estradiol and diethylstilbestrol (DES) J Mol Biol 2004, 340(5):1013-1023.
- Fei X, Chung H and Taylor HS. Methoxychlor disrupts uterine Hoxa10 gene expression. Endocrinolgy, 2005, 146(8): 3445-3451.
- Du H and Taylor HS. Molecular regulation of Müllerian development by HOX genes. Ann NY Acad Sci 2004, 1034:152-165.