The Endocrine Disruptor Compound Bisphenol-A (BPA) Regulates the Intra-Tumoral Immune Microenvironment and Increases Lung Metastasis in an Experimental Model of Breast Cancer.

Breast cancer (BC) metastasis represents the main physiopathology leading to poor prognosis and death. Bisphenol A (BPA) is a pollutant, classified as an endocrine-disrupting chemical compound with estrogenic properties, their exposure in the early stages of neonatal life leads to an increase in the size and weight of breast tumors and induces cellular changes in the tumoral immune microenvironment where cytokines play a key role. Thus, we used female BALB/c mice exposed neonatally to a single dose of BPA. Once mice reached sexual maturity, a mammary tumor was induced, injecting 4T1 cells in situ. After 25 days of injection, we evaluated endocrine alterations, cytokine expression, tissue alterations denoted by macro or micro-metastasis in the lung, and cell infiltration induced by metastasis. We found that BPA neonatal treatment did not show significant endocrine alterations. Noteworthy, BPA led to an augmented rate of metastasis to the lung associated with higher intratumoral expression of IL-1ß, IL-6, IFN-γ, TNF-α, and VEGF. Our data suggest that cytokines are key players in the induction of BC metastasis and that BPA (an environmental pollutant) should be considered as a risk factor in the clinical history of patients as a possible inductor of BC metastasis.

Effect of allopurinol on damage caused by free radicals to cryptorchid testes.

Cryptorchidism causes apoptosis of germ cells. It has been suggested that the redox regulatory system is involved in this process. The free radicals produced are thought to be generated during the production of uric acid, a reaction catalyzed by xanthine oxidase. This enzyme is inhibited by allopurinol; however, the role of allopurinol in neonate rats with inguinal cryptorchidism has not been assessed yet. Sixty male Wistar rats were used and five groups were formed: a control, a sham, a sham group with allopurinol administration and two groups with surgical unilateral cryptorchidism, which either did not receive, or received, allopurinol. The rats were assessed at 40 days post-partum. Reactive oxygen species concentration and epithelial area were measured and the histopathological, apoptotic and cellular proliferation indexes were determined. We found a decrease in reactive oxygen species, histopathological and apoptotic indexes and an increase in proliferation index and epithelial area in rats with cryptorchidism treated with allopurinol in comparison with rats with untreated cryptorchidism. We suggest that the over-production of reactive oxygen species plays an important role in the damage of the cryptorchid testes. Allopurinol administration decreases reactive oxygen species concentrations as well as the damage to the germ epithelium.

The effect of estrogen on testicular gonocyte maturation.

During the first days of postnatal life in rats the male germ cells (gonocytes) proliferate and move towards the seminiferous tubule basal lamina maturing into spermatogonia. This process is necessary for spermatogenesis and can be affected by estrogen (E); therefore, it is important to determine whether the damaging mechanism induced by E administration during the postnatal period impairs gonocyte maturation. One-day-old rat pups were given 1 microg 17-beta-estradiol daily and studied at 3, 5, 8, 10 and 16 days of age, corresponding to the critical gonocyte differentiation period in the rat. Testicles were isolated and the number of gonocytes in contact with the basal lamina of the seminiferous tubule was estimated, as well as the proliferation rate and apoptosis of the gonocytes. We observed that the administration of E changed the migration of gonocytes towards the basal lamina, decreased cell proliferation and increased apoptosis, resulting in a decrease in spermatogonia and spermatocytes. The migration of gonocytes and subsequent proliferation is required for survival of this germ cell type. The lack of maturation and the death of gonocytes could be one of the causes of infertility following exogenous E treatment.