INVESTIGATING DIFFERENT ESTROGEN THERAPIES IN A BPA-DISRUPTED MICROENVIRONMENT OF THE MAMMARY GLAND AND OVARIES

• Grant number: 25/12497-4
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: August 15, 2025
• End date: September 14, 2025
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Sebastião Roberto Taboga
• Grantee: Rafael Henrique Borges Coelho
• Supervisor: Christiani Andrade Amorim
• Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil
• Institution abroad: Universitè Catolique de Louvain (UCL), Belgium
• Associated to the scholarship: 23/15426-5 - Effects of supplementation with sex steroids on females induced to carcinogenesis and exposed to Bisphenol A: analysis in mammary glands, BP.IC

Abstract

The Developmental Origins of Health and Disease (DOHaD) field highlights how early-life exposure to endocrine-disrupting compounds (EDCs), such as Bisphenol A (BPA), can predispose individuals to cancer later in life. Hormone-dependent organs like the mammary gland and ovaries are particularly vulnerable due to their high plasticity and dependence on steroid signaling. While perinatal BPA exposure is linked to carcinogenesis, the subsequent impact of common estrogen therapies, such as those used in contraception or hormone replacement, remains a critical knowledge gap, especially regarding their potential to either mitigate or exacerbate cancer risk in a previously disrupted tissue microenvironment. This research project aims to investigate the neoplastic potential in the mammary gland and ovary of a murine model following perinatal BPA exposure and subsequent treatment with different estrogenic compounds. The primary objectives are: (1) in the mammary gland, to elucidate the molecular factors explaining the varied neoplastic outcomes of therapies using endogenous (17-¿-estradiol) versus synthetic (17-¿-ethinylestradiol) estrogens; and (2) in the ovaries, to assess the histopathological and molecular impact of these same hormone therapies on an ovarian microenvironment already dysregulated by BPA. The study utilized female gerbils (Meriones unguiculatus) perinatally exposed to BPA and later subjected to different hormone therapies within a pro-carcinogenic compound (ENU). Preliminary results from our ongoing FAPESP project indicate that therapy with endogenous 17-¿-estradiol (E2) led to a more favorable tissue response against carcinogenesis, whereas the synthetic estrogen (EE2) was associated with the development of progesterone receptor-positive (PR+) neoplasia, suggesting a potential worsening of the condition. These findings underscore the need for a deeper mechanistic investigation. To address this, this project will perform advanced complementary analyses through an international collaboration at UCLouvain. The objectives include: employ multiplex immunofluorescence (mIHCF), Western Blot (WB), and RT-qPCR to investigate key pathways. Analyses will focus on the co-localization and expression of hormone receptors (ER¿, PR, AR, HER2), cell proliferation/death markers, and related genes in both the mammary gland and ovaries. The expected outcomes will clarify the distinct mechanisms of endogenous versus synthetic estrogens in a BPA-disrupted context, providing crucial insights for assessing the safety and risks of hormone therapies.