Download James, Margaret, PhD - Reproductive and Perinatal Biology

BIOGRAPHICAL SKETCH
Provide the following information for the Senior/key personnel and other significant contributors.
Follow this format for each person. DO NOT EXCEED FOUR PAGES.
NAME
POSITION TITLE
Margaret O. James
Professor
eRA COMMONS USER NAME (credential, e.g., agency login)
mojames
EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and
residency training if applicable.)
DEGREE
INSTITUTION AND LOCATION
MM/YY
FIELD OF STUDY
(if applicable)
University College London, United Kingdom
St. Mary’s Medical School, London, UK
National Institute of Environmental Health
Sciences, North Carolina, USA
B.Sc.(Hons)
Ph.D.
06/69
07/72
Chemistry
Bio-organic chemistry
Post-doc
06/75
Pharmacology
A. Personal Statement
The goal of this research is to investigate, for the first time, the in vivo consequences of inhibition of placental
estrogen sulfotransferase by a common environmental chemical, Triclosan. I have extensive experience in
studying xenobiotic biotransformation in vivo and in vitro and a particular interest in the sulfonation pathway. I
am experienced in using tools of analytical chemistry, including LC/MS/MS, enzymology, toxicology, organic
chemistry and molecular biology. I have served as PI of NIH-funded RO1, RO3 and P42 grants and have
experience in leading research teams. I have also served as Co-I of NIH-funded RO1 grants and work well as
a member of an interdisciplinary research group such as proposed herein.
The idea for this application began with my observation that Triclosan was structurally related to hydroxylated
PCBs, which are known sulfotransferase inhibitors. I showed that Triclosan inhibited sulfonation of xenobiotic
substrates in human liver cytosol and with several sulfotransferase enzymes that are expressed in human liver
(SULT1A1, SULT1B1, SULT1E1), and then showed that Triclosan was a much more potent inhibitor of
hSULT1E1 with estradiol as substrate. In considering the in vivo implications of the potent inhibition of
estrogen sulfotransferase by Triclosan, a common environmental pollutant, I entered discussions with Charles
Wood in the College of Medicine, University of Florida. Dr. Wood is an endocrine physiologist who has
developed the fetal sheep model for exquisitely sensitive measurements of fetal physiology during prenatal
development. He is interested in the role of estrogen in fetal maturation and parturition, and in the secretion of
estradiol and estrone sulfates from placenta as a source of estrogen to the fetus. Working together, we found
that Triclosan was an extraordinarily potent in vitro inhibitor of sheep placental estrogen sulfotransferase. We
think that the sheep model, well established in fetal endocrinology as an animal model relevant to human
pregnancy, will permit us to determine the in vivo relevance of our finding that Triclosan is a potential
endocrine disruptor through the as yet unexplored mechanism of inhibition of estrogen sulfonation. Dr Wood
and I will each serve as PI. My role in this application will be to analyze plasma and tissue samples from
treated sheep (maternal and fetal components) for Triclosan and its glucuronide and sulfate conjugates.
B. Positions and Honors
Positions and Employment
1975 - 1980 Research Associate (1975-76) and Senior Staff Fellow (1976-80), NIEHS at Whitney Marine
Research Lab., St. Augustine, FL.
1980 - date Assistant Professor (80-85), Associate Professor (85-90), Professor (1990 - date), Department of
Medicinal Chemistry, University of Florida, Gainesville, FL.
1991 - date Department Chair, Medicinal Chemistry.
Honors and other experience
1987-88
Lucille B. Markey fellowship, Mount Desert Island Biological Laboratory, Maine
1991 - 1995 Member, NIEHS Review Committee, NIH, PHS, U.S. Dept Health and Human Services.
1993
Awarded D.Sc. University of London.
1995-date Reviewers reserve, NIH and NCRR, service on ad hoc study sections for NIH, NSF.
1992 - 1994 Member, Toxic Chemical Contaminants Technical Advisory Committee, National Oceanic and
Atmospheric Administration, US Dept. of Commerce.
1991 - date Editorial Board, Aquatic Toxicology
1992 – 1998 & 2004 to date Editorial Board, Chemico-Biological Interactions.
1993 - date Editorial Board, Drug Metabolism and Disposition.
1997-1999 Selected as a University of Florida Research Foundation Professor
1998
Selected for Professorial Excellence Program at University of Florida
2001-2003 Elected as Secretary, International Society for the Study of Xenobiotics
2003-4
Guest Editor, special issue of Marine Environmental Research
2006
Elected as Chair, American Association for the Advancement of Science, section on
pharmaceutical sciences: Term 2007-9 (chair-elect, chair, past chair)
2006-2011 Selected as the Jack C. Massey professor, University of Florida College of Pharmacy
C. Selected Peer-reviewed Publications (Selected from 140 peer-reviewed publications)
Most relevant to this application
Wang, L.Q., Falany, C.N. and James, M.O. Triclosan as a substrate and inhibitor of 3’-phosphoadenosine-5’phosphosulfate sulfotransferase and UDP-glucuronosyl transferase in human liver fractions. Drug
Metabolism and Disposition, 32: 1162-1169, 2004.
Wang, L-Q. Lehmler, H-J. Robertson, L.W., Falany, C.N. and James, M.O. In vitro inhibition of human hepatic
and cDNA-expressed sulfotransferase activity with 3-hydroxybenzo[a]pyrene by polychlorobiphenylols.
Environmental Health Perspective, 113: 680-687, 2005
Wang, L.Q. and James, M.O. Inhibition of sulfotransferases by xenobiotics. Current Drug Metabolism. 7: 83104, 2006
Wang, L.Q., Lehmler, H.J., Robertson L.W. and James, M.O. Polychlorobiphenylols are selective inhibitors
of human phenol sulfotransferase 1A1 with p-nitrophenol as substrate. Chemico-Biological Interactions,
159: 235-246, 2006
James, MO, Li, W, Summerlot, D, Rowland-Faux, L. and Wood CE. Triclosan is a potent inhibitor of estradiol
and estrone sulfonation in sheep placenta.. Environment International, 36: 942-949, 2010.
Other relevant publications
Lou, Z., Johnson, J.V. and James, M.O. Intestinal and hepatic metabolism of testosterone and progesterone
by a 3-alpha hydroxysteroid dehydrogenase to the 3-alpha hydroxy derivatives in the channel catfish,
Ictalurus punctatus. J. Steroid Biochem. Mol. Biol. 82: 413-424, 2002
Felitsyn N.M., Henderson G.N., James M.O., Stacpoole P.W. Liquid chromatography-tandem mass
spectrometry method for the simultaneous determination of delta-ALA, tyrosine and creatinine in biological
fluids. Clin Chim Acta. 350:219-30, 2004.
Sacco, J.C. and James, M.O. Sulfonation of environmental chemicals and their metabolites in the polar bear,
Ursus maritimus. Drug Metab. Disp. 33(9): 1341-1348, 2005
Wang, L.Q. and James, M.O. Sulfotransferase 2A1 forms estradiol-17-sulfate and celecoxib switches the
dominant product from estradiol-3-sulfate to estradiol-17-sulfate. J. Steroid Biochem. Mol. Biol. 96: 367374, 2005
Wang, L.Q. and James, M.O. Sulfonation of 17-estradiol and inhibition of sulfotransferase activity by
polychlorobiphenylols and celecoxib in Channel catfish, Ictalurus punctatus. Aquatic Toxicology, 81:
286-292, 2007
Blum, J.L., James, M.O., Stuchal, L.D. and Denslow, N.D. Stimulation of transactivation of the largemouth
bass estrogen receptors alpha, beta-a and beta-b by methoxychlor and its mono- and bis- demethylated
metabolites in HepG2 cells. Journal of Steroid Biochemistry and Molecular Biology, 108: 55-63, 2008
James MO Stuchal LD, and Nyagode BA. Glucuronidation and sulfonation in vitro of the major endocrineactive metabolites of methoxychlor in the channel catfish, Ictalurus punctatus, and induction following
treatment with 3-methylcholanthrene. Aquatic Toxicology 86: 227-238, 2008
Sacco, J. Robertson, L.W., Lehmler, H.J., Li, W. and James, M.O. Glucuronidation of polychlorobiphenylols
and UDPGA concentrations in channel catfish liver and intestine. Drug Metab Disp. 36: 623-630, 2008
Shroads, A.L., Guo, X., Dixit, V., Liu, H.P., James, M.O. and Stacpoole, P.W. Age-Dependent Kinetics and
Metabolism of Dichloroacetate: Possible Relevance to Toxicity . J. Pharmacol. Exp. Therap. 324: 11631171, 2008
Nyagode, B.A., Kleinow, K.M. and James, M.O. Influence of co-exposure to benzo(a)pyrene on the
biotransformation and elimination of 14C-methoxychlor in the channel catfish, Ictalurus punctatus.
Toxicological Sciences, 108:320-329, 2009
D. Research Support
Ongoing Research Support
R21 ES 020545 James, M.O. and Wood, C.E. co-PIs. 8/1/2011 – 6/30/2013
NIH
Fetal endocrine disruption by Triclosan
Studies showed that the antibacterial compound triclosan was a potent inhibitor of estrogen
sulfotransferase in the placenta. The goals of this project are to investigate the biological implications of
this finding by treating pregnant sheep with triclosan and examining changes in gene expression through
microarray technology.
1 U19 ES020683-01. Morris, J.G., PI. 6/30/2011 to 5/31/2016
NIH
Health Impact of Deepwater Horizon Spill in Eastern Gulf Coast Communities
The goals of this cooperative agreement are to determine how the BP oil spill affected communities who live
in the east of the Gulf of Mexico. Part of the project will involve analyzing seafood for PAH and dispersant
contamination. Role: co-investigator
RO1-ES014617
Stacpoole, P.W., PI
4/1/2006 to 3/31/2011 in no-cost ext NIH
Pharmacotoxicology of trichloroethylene metabolites
The goals of this project are to understand the molecular basis for the liver toxicity of two trichloroethylene
metabolites, dichloroacetate (DCA) and chloral hydrate (CH). The aims are 1) to quantify the effects of DCA
and CH on human liver maleylacetoacetate isomerase (MAAI) and tyrosine catabolites, as well as to
examine adducts formed in vivo in human liver following exposure to dichloroacetate; 2) to establish the
relationship between human MAAI haplotype and DCA and tyrosine metabolism; 3) to determine the in vivo
kinetics and biotransformation of CH in healthy adults and the influence of CH and DCA on each other’s
metabolism. Role: co-investigator
Completed Research Support
RO3-CA123575
James, M.O., PI
Modulation of steroid sulfation by celecoxib-like drugs
9/15/2008 to 8/31/2011
NIH
Evidence is mounting that celecoxib has chemo-preventive and chemo-therapeutic effects against breast
cancer. As well as inhibiting COX-2, celecoxib interacts with sulfotransferase (SULT) 2A1 to stimulate the
17-sulfation and inhibits the 3-sulfation of estradiol. (normally a minor pathway). Estradiol-3-sulfate, but not
17-sulfate, is a transport form of estradiol that is taken up by the breast where it is hydrolyzed to estradiol.
Stimulation of 17-sulfation should be beneficial for estrogen sensitive breast cancers by reducing the uptake
of estrogen into the breast. The long-term objective of this research is to ascertain the significance of the
effect of celecoxib in modulating sulfation, with respect to its anticarcinogenic activity. This could lead to the
development of new therapeutic agents for prevention or treatment of cancer. This small grant application is
focused on defining the effect and determining the mechanism. Role: PI
R01-ES07355
Stacpoole, P.W., PI
7/1/2004 to 6/30/2009
NIH
Dichloroacetate Kinetics Metabolism and Toxicology
This project examines the pharmacokinetics and biotransformation of dichloroacetate (DCA) in patients and
normal volunteers. The main human toxicity of DCA is reversible neuropathy. This project tests hypotheses
regarding the mechanism of toxicity of DCA to nerve cells. Role: co-investigator
P42-ES07375
James, M.O., P.I.
4/1/1995 to 5/30/2007
NIH
Health Effects of Chlorinated Compounds
This program-project grant focused on the effects of chlorinated Superfund chemicals on human and animal
health. Role: PI of administrative core and project 6; co-I of project 4