Division of Nephrology-Hypertension

Michael E. Baker, Ph.D.

Researcher
Curriculum Vitae

Phone : (858) 534-8317
E-mail : mbaker@ucsd.edu
Location : Pharmaceutical Sci Bldg
Room : 2111
Mail Code : 0693
Mailing Address :9500 Gilman Drive # 0693
La Jolla, CA 92093-0693

Research Interests

  1. Mechanism of steroid binding to receptors and steroid dehydrogenases.
  2. Evolution of steroid hormone signaling
  3. Hormonal activities of environmental compounds [endocrine disruptors].
  4. Effects of plant-derived compounds on hormone action and the evolutionary basis for this activity.
  5. History of herbal medicines and their mechanisms of action

The general theme of our research is to understand how steroids bind to receptors and steroid dehydrogenases, and the effects of plant-derived compounds and environmental pollutants on steroid hormone action.  We use Dobzhansky’s insight “Nothing in biology makes sense except in the light of evolution” to investigate these aspects of steroid hormone action.

We have used sequence analysis to identify conserved amino acids in receptors and dehydrogenases from organisms that diverged from a common ancestor over 500 million years ago.  Conserved amino acids are likely to be functionally important, as well as provide information about the evolution of steroid receptors and dehydrogenases.  For example, our phylogenetic analysis of steroid receptor sequences reveals that steroid hormone action is a "recent" event in life on earth.  That is, steroid receptors for estrogens, androgens, progestins, glucocorticoids, and mineralocorticoids arose about 600 million years ago, prior to the Cambrian explosion.

We have modeled the 3D structures of steroid receptors in lamprey, sharks and amphioxus to investigate the evolution of structure and function in steroid receptors.  Using docking algorithms, we screened chemical databases to identify chemicals that bind to steroid receptors and disrupt normal endocrine responses.  These chemicals are endocrine disruptors.  In silico screening is a powerful tool to find chemicals that are likely to be endocrine disruptors.  3D models of endocrine disruptors in the hormone-binding domain of steroid receptors provide important information about the molecular interaction between these compounds and steroid receptors.

Some pesticides that are designed to interfere with insect physiology have structures that resemble steroids and other lipophilic hormones that bind to human proteins.  These pesticides can have profound effects on human physiology.  Indeed, many pesticides, plastics and other synthetic chemicals that have entered our food supply have been found to have hormonal activity and act as endocrine disruptors.  Many of these compounds bind to the estrogen receptor.  The effects of these compounds on human health and especially on fetal health are of great concern.  Using microarrays and qRT-PCR, we are studying the effects of bisphenol A [BPA] on gene expression in zebrafish embryos, as a model for the effects of BPA on fetal physiology

Plants have hormonal activity in humans.  In fact, herbals have long been used to treat problems associated with endocrine physiology.  For example, licorice root has glucocorticoid and mineralocorticoid activities in humans.  Licorice inhibits a steroid dehydrogenase that converts cortisol to cortisone, an inactive steroid.  By inhibiting this steroid dehydrogenase, licorice increases cortisol levels, which leads to a glucocorticoid response, as well as a mineralocorticoid response in the kidney.

The hormone-like activities of flavonoids in soy, flax, citrus, etc. have made these compounds of interest for controlling various hormone-dependent cancers, including breast and prostate cancer.  We are studying the binding of phytochemicals to steroid receptors.  There is an evolutionary basis for the endocrine activities of phytochemicals in humans.  Plants synthesize compounds that interfere with animal physiology as a defense against consumption by animals.  Some phytochemicals have cyclic structures similar to that of steroids.  The use of chemicals by plants as a defense against animals is ancient, originating well before the origin of humans.  Because many human proteins, including steroid receptors and steroid dehydrogenases, retain structures at their active sites that resemble their ancestral proteins in fish, amphibians, etc., plant-derived compounds that evolved to act in these animals also have activity in humans.

Selected Publications
69. Baker M E. Endocrine activity of plant-derived compounds: An evolutionary perspective.  Proc Soc Experimental Biol Med 208, 131-138, 1995.
82. Baker M E. Steroid receptor phylogeny and vertebrate origins. Molec Cell Endocrinol 135, 101-107, 1997.
83. Baker M E et al. Flavonoids inhibit estrogen binding to rat alpha-fetoprotein.  Proc Soc Experimental Biol & Med 217, 317-321, 1998.
100. Baker M E. Evolution of adrenal and sex steroid action in vertebrates: A ligand-based mechanism for complexity.  BioEssays 25, 396-400, 2003.
102. Baker M E. Evolution of glucocorticoid and mineralocorticoid responses: Go fish. Endocrinology 144, 4223-4225, 2003.
115. Baker ME, Chandsawangbhuwana C, Ollikainen N, Structural analysis of the evolution of steroid specificity in the mineralocorticoid and glucocorticoid receptors. BMC Evol Biol 7, 24, 2007.
123. Baker M E. Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution.  Biochem Biophys Res Commun. 375, 623-627, 2008.
124. Gumy et al. Dibutyltin disrupts glucocorticoid receptor function and impairs glucocorticoid-induced suppression of cytokine production.  PLoS ONE 3, e3545, 2008.
126. Baker et al. Analysis of endocrine disruption in Southern California coastal fish using an aquatic multispecies microarray. Environ Health Perspect 117, 223-230, 2009.
128. Baker ME, Chang DJ, Chandsawangbhuwana C. 3D model of lamprey estrogen receptor with estradiol and 15alpha-hydroxy-estradiol.  PLoS ONE 4, e6038, 2009.
131. Baker ME. 11beta-hydroxysteroid dehydrogenase-type 2 evolved from an ancestral 17beta-hydroxysteroid dehydrogenase-type 2. Biochem Biophys Res Commun 399, 215-220, 2010.
132. Baker ME. Origin and diversification of steroids: co-evolution of enzymes and nuclear receptors. Mol Cell Endocrinol 334, 14-20, 2011.
133. Baker ME, Asnaashari P, Chang DJ, McDonnell S. 3D models of lamprey progesterone receptor complexed with progesterone, 7a-hydroxy-progesterone and 17a-hydroxy-progesterone. Steroids 76, 169-176, 2011.
134. Baker ME. Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption. Biochem Pharmacol 82, 1-8, 2011.
137. Baker ME, Uh KY, Asnaashari P. 3D models of lamprey corticoid receptor complexed with 11-deoxycortisol and deoxycorticosterone. Steroids 76, 1451-1457, 2011.
138. Baker ME, Uh KY, Evolutionary analysis of the segment from helix 3 through helix 5 in vertebrate progesterone receptors. J Steroid Biochem Mol Biol 132, 32-40, 2012.
137. Baker ME, Uh KY, Asnaashari P. 3D models of lamprey corticoid receptor complexed with 11-deoxycortisol and deoxycorticosterone. Steroids 76, 1451-1457, 2011.
138. Baker ME, Uh KY, Evolutionary analysis of the segment from helix 3 through helix 5 in vertebrate progesterone receptors. J Steroid Biochem Mol Biol 132, 32-40, 2012.
139. Baker ME, Uh KY, Chandsawangbhuwana C. 3D models of human ERa and ERβ complexed with 5-androsten-3β,17β-diol. Steroids 77, 1192-1197. 2012.
140. Baker ME, Chandsawangbhuwana C. 3D models of MBP, a biologically active metabolite of bisphenol A, in human estrogen receptor a and estrogen receptor β. PLoS One 7, e46078, 2012.
141. Baker ME, What are the physiological estrogens? Steroids 78, 337-340, 2013.

A video describing our research on the evolution of glucocorticoid and mineralocorticoid receptors is found at http://www.scivee.tv/node/5275.