Citation:

Suen, A., W. Jefferson, C. Williams, AND C. Wood. Differentiation patterns of uterine carcinomas and precursor lesions induced by neonatal estrogen exposure in mice. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, 46(5):574-596, (2018). https://doi.org/10.1177/0192623318779326

Impact/Purpose:

Identifying latent health risks resulting from chemical exposures has important implications for public health. Currently, EPA has limited ability to identify vulnerable populations that may be at-risk following a chemical exposure early in life. In this case study, we developed a putative AOP for increased susceptibility to uterine cancer following early-life exposure to estrogenic chemicals. Our findings identify candidate biomarkers of aberrant cellular differentiation that are persistently altered by estrogen early in life and predominate within cancers later in life. The ultimate goal of this work is to enable more rapid identification of AOPs for cancer incorporating life stage susceptibility.

Description:

Developmental exposure to estrogenic chemicals is an established risk factor for cancer of the female reproductive tract. This increase in risk has been associated with disruption of normal cellular differentiation during critical stages of development. The goal of this study was to document uterine epithelial phenotypes over time following neonatal treatment with the synthetic estrogen diethylstilbestrol (DES) or the soy phytoestrogen genistein (GEN) in female CD-1 mice. Both DES and GEN induced three distinct populations of abnormal endometrial epithelial cells: luminal (SIX1+/P63-/CK14-/CK18+), basal (SIX1+/P63+/CK14+/CK18-), and mixed/bipotential (SIX1+/P63-/CK14+/CK18+), which were all established by early adulthood. In older animals, DES and GEN resulted in uterine carcinomas with mixed glandular, basal, and squamous cell elements. All carcinomas were composed largely of the three abnormal cell types. These findings identify novel epithelial differentiation patterns in the uterus and support the idea that disruption of cellular programming in early development can influence cancer risk later in life.

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