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ROLES OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF-A) IN MEDIATION OF DIOXIN (TCDD)-INDUCED DELAYS IN DEVELOPMENT OF THE MOUSE MAMMARY GLAND
Citation:
Fenton, S E., B D. Abbott, P. L. Bryant, AND A R. Buckalew. ROLES OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF-A) IN MEDIATION OF DIOXIN (TCDD)-INDUCED DELAYS IN DEVELOPMENT OF THE MOUSE MAMMARY GLAND. Presented at Endocrine 2000 Meeting, Denver, CO, June 20-23, 2001.
Description:
Roles of Epidermal Growth Factor (EGF) and Transforming Growth Factor-alpha (TGF-a) in Mediation of Dioxin (TCDD)-Induced Delays in Development of the Mouse Mammary Gland.
Suzanne E. Fenton, Barbara Abbott, Lamont Bryant, and Angela Buckalew. U.S. EPA, NHEERL, Reproductive Toxicology Division, Research Triangle Park, NC 27711. Sponsored by Lewis G. Sheffield.
Studies using mice null for the EGF-receptor binding ligand genes, EGF, TGF-a, and
amphiregulin demonstrate an important role of these growth factors in mammary gland (MG)
development, specifically because of lack of epithelial migration through the mammary fat pad
and persistent terminal end buds in mature glands. Our recent studies revealed developmental
MG delays in female rats exposed to TCDD on gestation day (GD)15 suggestive of altered
growth factor expression. Furthermore, studies in other laboratories demonstrated in utero
dioxin exposure decreased amounts of EGF-R protein in male reproductive tract. In light of these
findings, we utilized combinations of EGF and TGF-a null mice and TCDD (as
an example compound) to test the hypothesis that these growth factors play a key role in MG
development. Timed-pregnant wild-type (WT), EGF, EGF/TGF-a (double-knockout, provided
by David Lee, UNC-CH), and TGF-a (Jackson Labs) null mice were dosed by oral gavage on
GD12 with 24 ug/kg TCDD. Mammary tissue was removed on GD17.5 and whole mounts
analyzed. TCDD caused a suppression of overall MG development in WT glands
and altered the morphology of lobuloalveoli (LA) from grape-like to spiked, leaf-like
structures. Glands from control TGF-a dams were similar in morphology to TCDD-treated
WT tissue, but with fewer lateral ductal branches. TCDD exposure in the TGF-a dams
reduced branching further and produced a more spindly appearance of the LA. Control
EGF-null glands were characterized by a dramatic increase in the number of lateral branches
of the main and secondary ducts. The LA were small and also increased in number. EGF-null
dams dosed with TCDD completely lacked the hyperprolific lateral branches, yet the LA
were spiked more severely than that seen in TCDD-exposed TGF-a or WT dams.
Interestingly, in the untreated animals lacking both EGF/TGF-a, there is dense LA formation
and no discernable effect of TCDD in the MG. These results imply that EGF and TGF-a are
both critical components in the signaling pathway of TCDD-induced disruption of mammary
epithelial proliferation. This abstract has been reviewed in accordance with U.S. EPA policy
and approved for publication.