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Annual report : National Institute of Environmental Health Sciences (Volume 1984 pt.2) online

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epithelial cell cultures grown on collagen gels appear to provide us with a good
model system. Cells were radiolabelled with ^H-glucosamine and/or 35s_sulfate and
their secretory products were characterized. Mucins were identified on the basis
of their high molecular weight and complete resistance to proteoglycan-degrading
enzymes, ruling out proteoglycans. Labelling with several monosaccharide
precursors and analysis of the high molecular weight products by strong acid
hydrolysis or neuraminidase treatment showed the presence of sialic acid but not
mannose. B-Elimination released oligosaccharides with the conversion of most of
the N-acetylgalactosamine into N-acetylgalactosaminitol , indicating that the
oligosaccharides are 0-glycosidically linked with protein. This mucin has been
further characterized via B-endogalactosidase treatment and it was shown that
R-GlcNacBl-3GalBl-R linkages are present. This finding is supported by lectin
affinity chromatography on DSA-agarose gels. Studies on the action of retinoids
and monensin on mucin secretion are in progress. For the study of the regulation
of differentiation rabbit tracheal epithelial cell cultures are used as a model
system. These cells undergo terminal differentiation into squamous, cornifying
cells when reaching confluency. This process is inhibited by retinoids and
promoted by calcium and serum. Several biochemical changes accompany this
change in phenotype. Undifferentiated cells produce large amounts of hyaluronic
acid whereas in keratinizing cells the synthesis of hyaluronic acid is very much
reduced. Cells undergo quantitative as well as qualitative changes in keratin
proteins as shown by 2-D electrophoresis and by immunoblot analysis using mono-
clonal antibodies. A 48 kd keratin appears to be a good marker for this dif-
ferentiation. Differentiation into mucin secretory cells can be induced when
cells are grown on collagen gels in the presence of retinoic acid. Retinoic
acid appears to have a key role in the control of differentiation.



PHS 6040 (Rev. 1/84)



119



GPO 904-917



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLir; HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl ES-25022-01



PERIOD COVERED

October 1, 1983 to September 30, 1984



TITLE OF PROJECT (80 characters or less. Title musf fit on one line between the borders)

Study of the Molecular Mechanisms of Action of Retinoids



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator ) (Name, title, laboratory, and institute affiliation)

PI: A. M. Jetten Senior Staff Fellow LPFT, NIEHS
Others: J. E. Shirley Biological Lab. Tech. LPFT, NIEHS



COOPERATING UNITS (if any)



LAB/BRANCH

Laboratory of Pulmonary Function and Toxicology



Cell Biology Group



INSTITUTE AND LOCATION



NIEHS. NIH. Research Triangle Park. North Carolina 27709



TOTAL MAN-YEARS;



1.5



PROFESSIONAL:



0.5



1.0



CHECK APPROPRIATE BOX(ES)

n (a) Human subjects
n (a1) Minors
D (a2) Interviews



n (b) Human tissues



(c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the space provided.)

Retinoids affect many biological and biochemical properties of eukaryotic cells.
Their mechanism of action is unclear. One possibility is that they alter gene
expression either indirectly or directly via the mediation of the binding protein
and interaction with the chromatin. The induction of ornithine decarboxylase
(ODC) activity by the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA)
appears to be a good tool to study the mechanism of action of retinoids.
Retinoids can affect the induction of this enzyme at several levels. We have no
evidence that ODC activity is affected by retinoids at a post-translational
level. Transglutaminase appears not to be involved and no evidence of an inhib-
itory substance activated or induced by retinoic acid was detected. Retinoids
could prevent ODC induction by blocking the interaction of TPA with its receptor.
We have ruled out this possibility since retinoic acid does not compete with the
binding of -^H-PDBu. We have demonstrated that this receptor, which appears to be
the protein kinase C, is causal in inducing ODC, since diacyl glycerols are able
to induce its activity. Retinoic acid does not interfere with the protein kinase
C activity. These resultsindicate that retinoic acid acts at a step after the
activation of protein kinase C. This could be by interfering with the process of
transmitting the signal from protein kinase C to the nucleus or by blocking
transcription directly via binding to specific sites on the chromatin. The
structure-function relationships of the ability of retinoids to inhibit ODC
induction and the capacity to bind to the binding protein suggest a role for
these proteins.



PHS 6040 (Rev. 1/84)



rzir



GPO 904-917



I PROJECT NUMBER
DEPARTMENT OF HEALTH AND HUMAN SKRVICES - PUBLIC HEALTH SERVICE !

NOTICE OF INTRAMURAL RESEARCH PROJECT [ZOl ES-25023-01 LPFT



PERIOD COVERED

October 1, 1983 to September 30. 1984



TITLE OF PROJECT (SO characters or less. Title must lit on or^e lirte between trie tyoraers.)

Studies on the Mechanism of Neoplastic Development in Airway Epithelial Cells



PRINCIPAL INVESTIGATOR (List ottier professional personnel below trie Principal Investigator ) (Name, title, laboratory, and institute affiliation)

Chief LPFT, NIEHS

Research Chemist LPFT, NIEHS

Visiting Fellow LPFT, NIEHS

Former Postdoctoral Fellow LPFT, NIEHS

Former Postdoctoral Fellow LPFT, NIEHS

Biologist LPFT, NIEHS

Biological Lab. Tech. LPFT, NIEHS



PI:


P.


Nettesheim


Others:


J.


C. Barrett




D.


J. Fitzgerald




M.


J. Mass




D.


G. Thomassen




T.


E. Gray




M.


P. Smith



COOPERATING UNITS (if any)



LAB/BRANCH



Laboratory of Pulmonary Function and Toxicology



SECTION



Epithelial Carcinogenesis Group



INSTITUTE AND LOCATION

NIEHS, NIH. Research Triangle Park. North Carolina 27709



TOTAL MAN-YEARS;

4.1



PROFESSIONAL: , OTHER

Ltl \ 2.0



CHECK APPROPRIATE BOX(ES)

n (a) Human subjects D (b) Human tissues x] (c) Neither

D (a1) Minors
D (a2) Interviews



SUMMARY OF WORK (Use standard unreduced type. Do not exceed trie space provided.)

Studies on mechanisms of neoplastic development in airway epithelial cells are
being conducted with the aim to characterize pre-neoplastic epithelial cell
variants on both the cellular and molecular level . By investigating important
modulators of neoplastic progression, we hope to elucidate its cellular and
biochemical basis.

An analysis of cell populations of transformed rat tracheal epithelial (RTE) cells
indicates that transformed stem cells produce large numbers of cells not exhi-
biting transformed growth characteristics.

Studies on the role of the anchorage independent (ag"*") phenotype in neoplastic
transformation of RTE cells indicates that ag"*" cell variants are being generated
in preneoplastic RTE cell populations at a rate of about 10"^ per cell, per cell
generation and that the ag"^ phenotype may not be an obligatory step in neoplastic
transformation of RTE cells.

Chromosomal analyses of RTE cell transformants suggest that spontaneous and
induced transformants have similar qualitative and quantitative chromosomal
changes which might be important in the establishment of the EG-variant phenotype.

The tumor promoter TPA does not increase the frequency of the EG-variant phenotype
but it may enhance the development of the ag"*" phenotype in some but not other pre-
neoplastic RTE cell clones.

Retinoic acid inhibits RTE cell transformation at concentrations which are not
inhibitory for growth of normal RTE cells. Whether RA inhibits the clonal expan-
sion or the expression of RTE cell transformation is under study.



PHS 6040 (Rev. 1/84) ]21



GPO 904-917



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl ES-25024-01 LPFT



PERIOD COVERED

October 1, 1983 to September 30, 1984



TITLE OF PROJECT (80 characters or less. Title must tit on one line tietween the borders.)

Pathogenesis of Early Pulmonary Lesions Induced by Inhaled Inorganic Particles



PRINCIPAL INVESTIGATOR (Ust other professional personnel below the Principal Investigator.) (Name, title, laboratory, and institute atiiliation)

PI: A. R. Brody Research Biologist LPFT, NIEHS

Others: L. H. Hill Chemist LPFT, NIEHS

V. Roggli Guest Worker LPFT, NIEHS



COOPERATING UNITS (il any)



LAB/BRANCH

Laboratory of Pulmonary Function and Toxicology



Pulmonary Pathology Group



INSTITUTE AND LOCATION



NIEHS. NIH. Research Triangle Park. North Carolina 27709



TOTAL MAN-YEARS:

3^0



PROFESSIONAL:



1.0



_2^



CHECK APPROPRIATE BOX{ES)

D (a) Human subjects
n (a1) Minors
D (a2) Interviews



n (b) Human tissues ixl (c) Neither



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided.)

Interstitial fibrotic lung disease is commonly found in humans exposed occupa-
tionally and environmentally to certain inorganic particles. We have established
animal models to elucidate the initial cellular events associated with inhalation
of the toxic dusts, asbestos and silica, and we have determined that a variety of
inorganic particles, regardless of shape or concentration, deposits initially
at bifurcations of alveolar ducts. It is at these sites of particle deposition
that we have documented the earliest anatomic alterations induced by inhalation
of asbestos fibers. These alterations at duct bifurcations include (1) phago-
cytosis of asbestos fibers by the alveolar epithelium, (2) translocation of
fibers through the epithelium to capillary spaces and interstitial connective
tissue, (3) phagocytosis of fibers by interstitial fibroblasts, (4) formation of
interstitial intracellular microcalcifications, and (5) accumulation of alveolar
and interstitial macrophages. Now, we report the following: (1) One month after
a 1-hr exposure to chrysotile asbestos, the alveolar duct bifurcations exhibited
normal epithelial cells, but there were significant increases in the numbers of ■
interstitial fibroblasts and macrophages and in the amount of interstitial
extracellular matrix, some of which was collagen. (2) Autoradiographic studies
demonstrated that increased numbers of epithelial cells lining terminal
bronchioles as well as epithelial and interstitial cells of alveolar duct bi-
furcations incorporated tritiated thymidine into DNA. (3) One month after the
1-hr exposure to asbestos, 19% of the fibers which had originally been deposited
after inhalation was still present in the interstitium of the rats' lungs.
Further studies are ongoing to establish the role of interstitial fibers and the
mechanisms through which the fibers induce fibroblast proliferation and collagen
production.



PHS 6040 (Rev 1/84)



122



GPO 904-917



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE

NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl ES-25025-01 LPFT



PERIOD COVERED

October 1, 1983 to September 30, 1984



TITLE OF PROJECT (80 characters or less. Title must lit on one line Ijetween the borders.)

Asbestos Activation of Complement-Dependent Chemotactic Factors for Macrophages



PRINCIPAL INVESTIGATOR (Ust other professional personnel below the Principal Investigator ) iName. title, laboratory, ana institute attiliationi



PI: Arnold R. Brody
Others: D. B. Warheit
L. H. Hill
G. George



Research Biologist
Postdoctoral Fellow
Chemist
Visiting Fellow



LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS



COOPERATING UNITS (il any)



LAB/BRANCH

Laboratory of Pulmonary Function and Toxicology



SECTION

Pulmonary Pathology Group



INSTITUTE AND LOCATION

NIEHS. NIH, Research Triangle Park, North Carolina 27709



TOTAL MAN-YEARS:

3.0



PROFESSIONAL.



1.0



2.0



CHECK APPROPRIATE BOX(ES)

n (a) Human subjects
n (a1) Minors
n (a2) Interviews



n (b) Human tissues 0(j (c) Neither



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided I

In earlier studies, we showed that pulmonary macrophages migrate to the sites
where inhaled chrysotile asbestos fibers initially are deposited (i.e., surfaces
of alveolar duct bifurcations). These macrophages form a major component of an
early asbestos-induced interstitial lesion in rats. Thus, in order to establish
the basic cellular mechanisms of asbestos-induced lung disease, it is essential
to determine the chemical mediators which attract macrophages to these sites of
fiber deposition. Chrysotile asbestos fibers used in vitro activate complement
proteins in peripheral blood serum and in lavaged cell-free lung proteins. After
brief inhalation of chrysotile asbestos, fluids lavaged from the lungs of exposed
rats contain substantial chemotactic activity for macrophages compared to fluids
from sham-exposed animals (pX.Ol). We hypothesize that this chemotactic activity
is derived from complement activated by inhaled asbestos on alveolar surfaces.
This contention is supported by the following observations: (1) Production in
vitro of chemotactic activity by asbestos in serum or in lung lavageates was
blocked by complement inhibitors. (2) Fractionation, by molecular sieve chromato-
graphy, of serum proteins and concentrated proteins lavaged from the lungs of
asbestos-exposed rats showed that chemotactic activity was detected in the 14-
18,000 MW range. This fractionation profile is similar to C5a, the chemotactic
product of complement activation. In addition, (3) rats treated with cobra venom
factor to deplete circulating complement as well as complement-deficient mice
demonstrated significantly depressed macrophage accumulation at sites of asbestos
deposition. Pulmonary macrophages are the cells which form the initial inflam-
matory response to asbestos inhalation. Our findings support the hypothesis
that macrophages are attracted to the anatomic sites where inhaled asbestos fibers
activate complement-derived chemotactic activity.



PHS 6040 (Rev. 1/84)



123



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl ES-25026-01 LPFT



PERIOD COVERED

October 1, 1983 to September 30. 1984



TITLE OF PROJECT (80 characters or less. Title rr)ust fit on one line between the borders.)

I nteractions of Inorganic Particles with Pulmonary Cell Membranes



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator ) (Name, title, laboratory, and institute affiliation)

PI: Arnold R. Brody Research Biologist LPFT, NIEHS

Others: L. H. Hill Chemist LPFT, NIEHS

J. E. Gallagher Graduate Student LPFT, NIEHS

G. George Visiting Fellow LPFT, NIEHS



COOPERATING UNITS (if any)



LAB/BRANCH

Laboratory of Pulmonary Function and Toxicology



SECTION

Pulmonary Pathology Group



INSTITUTE AND LOCATION

NIEHS, NIH. Research Triangle Park, North Carolina 27709



TOTAL MAN-YEARS;



3.0



PROFESSIONAL.



1.0



_E^



CHECK APPROPRIATE BOX(ES)

D (a) Human subjects
n (a1) Minors
n (a2) Interviews



n (b) Human tissues



[x] (c) Neither



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided )

Inhaled particles such as asbestos and silica are toxic to pulmonary cells. In
recent studies on mechanisms of membrane injury, we have shown that chrysotile
asbestos causes damage to erythrocyte membranes through binding to terminal sialic
acid (SA) residues. The hemolytic events involved (1) binding of the positively-
charged chrysotile fibers to negatively-charged SA groups, (2) rapid (within 5
min) distortion of the cells, (3) redistribution of SA groups, and (4) alterations
of intracellular Na"*", K"*" ratios. Negatively-charged crocidolite asbestos bound to
and distorted red cells but had no effect on SA groups or ion flux. To establish
whether or not similar mechanisms of membrane injury play a role in particle-
induced toxicity of pulmonary cells, we have extended our studies to pulmonary
macrophages. Our hypothesis is that non-specific (i.e., non-receptor mediated)
binding and subsequent uptake of positively-charged particles are mediated by
negatively-charged cell surface sialic acid groups. In support of this hypothesis
we have shown the following: (1) Wheat germ agglutinin (WGA), a lectin which
binds to sialic acid, is distributed evenly across macrophage surfaces. (2)
Positively-charged carbonyl iron (Fe) spheres and chrysotile asbestos fibers bind
to macrophage membranes at 4° C and the binding is blocked by a dose-dependent
pretreatment of the cells with WGA. Other lectins such as Ricin and ConA do not
inhibit binding at comparable doses. (3) Removal of cell-surface glycoproteins
with neuraminidase and periodate inhibit binding of the positively-charged
particles. (4) Fe-spheres normally are readily phagocytized by macrophages at
37 C. In the presence of WGA, over 90% of the phagocytic activity is blocked,
but other lectins have no effect. These studies support our hypothesis that
charged surface sialic acid groups play a role in particle binding and phago-
cytosis. Further studies are ongoing to substantiate our findings using
negatively-charged particles and membrane markers of receptor turnover.



PHS 6040 (Rev 1/84)



124



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl ES-25027-01 LPFT



PERIOD COVERED

October 1, 1983 to September 30. 1984



TITLE OF PROJECT (80 characters or lass. Title must fit on one line Cenveen me boraers.)

Identification and Characterization of Materials Secreted by Pulmonary Clara Cells



PRINCIPAL INVESTIGATOR (List other prolessiona! personnel below the Principal Investigator ) (Name, title, laboraton/. and institute affiliation)



PI:


G.


E. R. Hook


Others:


S.


E. Patton




A.


M. Jetten




P.


Nettesheim




L.


B. Gilmore




L.


A. Dethloff



Research Chemist

Postdoctoral Fellow

Senior Staff Fellow

Chief

Biologist

Biological Lab. Tech.



LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS



COOPERATING UNITS (if any)



LAB/BRANCH

Laboratory of Pulmonary Function and Toxicology



Biochemical Pathology Group



INSTITUTE AND LOCATION

NIEHS. NIH. Research Triangle Park. North Carolina 27709



TOTAL MAN-YEARS:

2.7



PROFESSIONAL



1.7



1.0



CHECK APPROPRIATE BOX(ES)

n (a) Human subjects
D (a1) Minors
D (a2) Interviews



D (b) Human tissues



(c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the space provided )

The functions of the nonciliated bronchiolar epithelial cell (Clara cell) of the
lungs are not known. Numerous morphological investigations in many species have
led to the hypothesis that the Clara cell is secretory although the nature of
those secretions and their function in the airways are not known. The objectives
of this research are to eludicate the secretory nature of the Clara cell, identify
and characterize those secretions and determine their extracellular functions.
We have developed a model system for the study of Clara cell functions and
metabolism using cells isolated from the lungs of rabbits. Cells were dispersed
from lung tissue using a pancreatic protease introduced via the trachea. These
dispersed cells contained approximately 8% Clara cells. The Clara cells were
enriched to about 40% by centrifugation on a continuous density Percoll gradient.
The Clara cells were then subjected to centrifugal elutriation, resulting in
further purification (Clara cells 75-85% pure). These cells were added to
collagen I coated culture dishes and incubated overnight in Ham's F12 medium.
The attached cells consisted of at least 90% Clara cells. The isolated Clara
cells contained abundant endoplasmic reticula and osmiophilic cytoplasmic
granules typical of Clara cells in vivo . These features were maintained when the
cells were incubated for 24 hours. Incubation of the isolated cells with ^^S-
methionine for 4 hours resulted in the radiolabell ing of many intracellular
proteins some of which were released into the incubation medium. The major radio-
labelled protein present in the medium had a molecular weight of about 10,000
daltons as determined by sodium dodecyl sulphate-polyacryl amide gel electrophor-
esis under reducing conditions. Clara cells could be maintained in
in vitro culture for periods up to 2 weeks in Ham's F12 medium supplemented with
insulin, transferrin, EGF, hydrocortisone, bovine hypothalamus extract and anti-
biotics. These studies indicate that the isolated Clara cells may be an approp-
riate model for the study of Clara cell function and metabolism.



PHS 6040 (Rev. 1/84)



125



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



ZOl ES-25028-01 LPFT



PERIOD COVERED

October 1, 1983 to September 30, 1984



TITLE OF PROJECT (80 characters or less. Title must lit on one line between the Doraers I

Mol ecular Basis for Cellular Changes in Chemical Carcinogenesis



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator ) (Name, title, laboratory, and institute affiliation)



PI:
Others:



J. C. Barrett
T. Gilmer
M. Koi

D. Thomassen
L. Annab



Research Chemist
Senior Staff Fel low
Visiting Fellow
Postdoctoral Fellow
Biological Lab. Tech.



LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS

LPFT, NIEHS



COOPERATING UNITS (if any)



LAB/BHANCH

Laboratory of Pulmonary Function and Toxicology



SECTION

Environmental Carcinogenesis Group



INSTITUTE AND LOCATION

NIEHS. NIH. Research Triangle Park. North Carolina 27709



TOTAL MAN-YEARS:



4.0



PROFESSIONAL:



3.0



JUL



CHECK APPROPRIATE BOX{ES)

n (a) Human subjects
D (a1) Minors
D (a2) Interviews



n (b) Human tissues Xj (c) Neither



SUMMARY OF WORK (Use standard unreduced type. Do not exceed the space provided )

Neoplastic development of Syrian hamster embryo (SHE) cells is a multistep pro-
cess. We have examined the influence of chemical carcinogens and the role of
cellular and viral oncogenes in this process. We have compared the suscep-
tibilities of normal and carcinogen-induced preneoplastic SHE cells to neoplastic
transformation following transfection by the calcium phosphate precipitate tech-
niques with plasmids of genomic clones of four oncogenic viruses: polyoma virus,
Harvey murine sarcoma virus (Ha-MSV), Rous sarcoma virus (RSV) and MC29 virus
(pSVv-myc). Normal SHE cells transfected with polyoma virus DNA formed progressi-
vely growing tumors of hamster origin within 3-4 weeks when injected into nude
mice. In contrast, SHE cells treated with Ha-MSV DNA remained nontumorigenic.
SHE cells treated with RSV DNA formed one tumor (one of six sites) with a latency
period of 15 weeks. SHE cells transfected with either Ha-MSV DNA and pSVv-myc
DNA or RSV DNA and pSVv-myc DNA formed tumors with short latency periods. Polyoma
virus DNA, Ha-MSV DNA or RSV DNA could individually neoplastically transform pre
neoplastic SHE cells which were immortalized following treatment with the car-
cinogen diethylstilbestrol .. These results suggest that multiple changes or
activated oncogenes are required for the neoplastic transformation of SHE cells.
To determine if normal cellular factors or genes can regulate the phenotypic
expression of tumorigenicity and/or oncogenes, cell-cell hybrids between chemi-
cally transformed SHE cells and either normal or preneoplastic SHE cells were pre-
pared. Our results indicate that anchorage independence, which is a good marker
for tumorigenicity of these cells, is suppressed in hybrids between tumorigenic
and normal cells and in hybrids between tumorigenic and most but not all pre-
neoplastic cells. This suggests that this suppressive ability may be lost during
neoplastic progression and represents one step in this process.



PHS 6040 (Rev. t/84)



126



GPO 904-917



LABORATORY OF REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY



127



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE

NOTICE OF INTRAMURAL RESEARCH PROJECT ZOl ES 70010-08 LRDT



PERIOD COVERED

October 1, 1983 to September 30, 1984



TITLE OF PROJECT (80 characters or less Title must tit on one tine between the borders )

Study of Normal and Abnormal Embryonic Development



PRINCIPAL INVESTIGATOR IList other protessionat personnel below the Principal Investigator ) (Name, title laboratory ana institute atiihation)


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Online LibraryNational Institute of Environmental Health ScienceAnnual report : National Institute of Environmental Health Sciences (Volume 1984 pt.2) → online text (page 11 of 19)