Effect of fetal alcohol exposure on mammary gland development and tumorigenesis in offspring
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Crismale-Gann, Catina.
Effect of fetal alcohol exposure on mammary gland development and tumorigenesis in offspring. Retrieved from
https://doi.org/doi:10.7282/T3XP736Z
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TitleEffect of fetal alcohol exposure on mammary gland development and tumorigenesis in offspring
Date Created2014
Other Date2014-05 (degree)
Extentxv, 166 p. : ill.
DescriptionAlcohol exposure in utero increases susceptibility to carcinogen-induced mammary tumorigenesis in adult rats. However, the mechanisms underlying the enhanced susceptibility are not well understood. Pregnant Sprague Dawley rats were fed either a liquid diet containing 6.7% ethanol, an isocaloric liquid control diet, or rat chow ad libitum from gestation day 7 until parturition. At birth, female pups were cross-fostered to control dams. To determine if fetal alcohol alters the insulin-like growth factor (IGF)/estradiol (E2) axis in mammary gland development, we analyzed time points in pre-pubertal, pubertal, and mature F1 offspring. Mammary glands from alcohol-exposed animals displayed increased epithelial cell proliferation and aromatase expression at PND 20 and 40. Animals exposed to alcohol in utero exhibited increased hepatic IGF-I expression at all time points, increased mammary IGF-I expression at PND 20, and decreased mammary IGFBP-5 expression at PND 40. To investigate tumorigenesis, N-nitroso-N-methylurea (NMU) was administered on PND 50 to induce tumors and offspring were euthanized at 16 weeks post-NMU injection. The alcohol group developed more tumors overall as well as more hyperplasias and adenocarcinomas as compared to control groups. Alcohol-exposed animals developed more progesterone receptor positive tumors and exhibited increased Snail, IGF-II, and IGFBP-5, as well as decreased ERα tumor mRNA expression. To determine if fetal alcohol induces alterations in DNA methylation in the mammary gland, we assessed an IGFBP-5 promoter CpG island, the first CpG island in IGFBP-5 exon I, and an estrogen receptor (ER) α promoter/exon I CpG island in tumors and contralateral mammary glands as well as PND 40 mammary glands. While the IGFBP-5 promoter CpG island did not exhibit methylation, low levels of methylation were observed in the IGFBP-5 exon I CpG island in all tissues examined. Tumors from alcohol-exposed animals exhibited partial ERα methylation. These data indicate that alcohol exposure in utero may promote mammary tumorigenesis by inducing changes in the IGF and E2 systems during early development. Furthermore, alterations in PR, Snail, IGF-II, and IGFBP-5 may be involved in the underlying mechanisms of enhanced carcinogen-induced tumorigenesis observed in alcohol-exposed offspring.
NotePh.D.
NoteIncludes bibliographical references
Noteby Catina Crismale-Gann
Genretheses, ETD doctoral
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.