A single neonatal administration of Bisphenol A induces higher tumour weight associated to changes in tumour microenvironment in the adulthood

Abstract

BPA is an oestrogenic endocrine disrupting chemical compound. Exposure to BPA in as early as pregnancy leads to lifelong effects. Since endocrine and immune systems interact in a bidirectional manner, endocrine disruption may cause permanent alterations of the immune system, affecting a future anti-tumoral response. Neonate (PND 3) female syngeneic BALB/c mice were exposed to a single dose of 250 µg/kg BPA. Once sexual maturity was reached, a mammary tumour was induced injecting 4T1 cells in situ, these cells are derived from a spontaneous adenocarcinoma in a BALB/c mouse and therefore allows for an immunocompetent recipient. After 25 days of injection, showing no major endocrine alterations, BPA-exposed mice developed larger tumours. Tumour leukocytic infiltrate analysis revealed a higher proportion of regulatory T lymphocytes in the BPA-exposed group. RT-PCR analysis of tumour samples showed a decreased expression of TNF-α and IFN-γ, as well as the M2 macrophage marker Fizz-1 in the BPA-exposed group. Flow cytometry analysis revealed differences in ERα expression by T lymphocytes, macrophages and NK cells, both associated to BPA exposure and tumour development. These findings show a new aspect whereby early life BPA exposure can contribute to breast cancer development and progression by modulating the anti-tumoral immune response.

The use of patient‐derived breast tissue explants to study macrophage polarization and the effects of environmental chemical exposure

“…Interestingly, BPA exposure has been shown to impede the phagocytic activity of peritoneal macrophages and alter TAM phenotypes. [39][40][41][42] Taken together, these data suggest that BPA-exposed macrophages may be involved the transformation of ductal carcinoma in situ into invasive breast cancer. To this effect, Kim et al 24 recently demonstrated that BPA increases M2 marker expression in murine macrophage cells and in a coculture system, ductal carcinoma in situ cells exposed to BPA-treated macrophages became significantly more migratory.…”

“…BPA is a monomer used in the manufacturing of polycarbonate plastics as well as epoxy resins and is a well‐known environmental endocrine‐disrupting chemical. Interestingly, BPA exposure has been shown to impede the phagocytic activity of peritoneal macrophages and alter TAM phenotypes 39–42 . Taken together, these data suggest that BPA‐exposed macrophages may be involved the transformation of ductal carcinoma in situ into invasive breast cancer.…”

Immune Tumor Microenvironment in Breast Cancer and the Participation of Estrogen and Its Receptors in Cancer Physiopathology

“…In addition to the data described above, our workgroup reported that endocrine-disrupting compounds such as bisphenol A (BPA) have a significant effect on the modulation of ERα expression in T lymphocytes, macrophages, and NK cells of breast cancer tumors as well as in tumor growth. Impressively, a single administration of BPA in neonatal mice resulted in important changes in the presence of Tregs infiltrated into breast tumors in the adult stage (172). These facts provide new approaches to studying the effect of various compounds with estrogenic activity on the modulation of immune cells as well as in the selective inhibition of ER.…”

Potential Novel Risk Factor for Breast Cancer: Toxocara canis Infection Increases Tumor Size Due to Modulation of the Tumor Immune Microenvironment

“…In regard to splenomegaly, T. canis infection induced spleen enlargement (48), but also, the 4T1 tumor induction increased the spleen size (49) and induced splenic Treg depletion (3). Both abnormalities are associated with a leukemoid response and extramedullary (splenic) hematopoiesis in 4T1 tumor-bearing mice, in which an increased proportion of granulocytes diminishes the proportion of lymphocytes (50).…”

“…Nevertheless, other environmental factors also play a prominent role in breast tumor development. Environmental contaminants, including physical, chemical, and biological agents, have been associated with tumor development (3). In fact, 15% of different cancer types are linked to viral, bacterial, or parasite infections (4).…”