Paradoxical zinc toxicity and oxidative stress in the mammary gland during marginal dietary zinc deficiency

•In marginally Zn deficient (ZD) mice, mammary glands accumulate Zn.•Zn accumulation is associated with changes in mammary gland microenvironment.•ZD glands have oxidative stress, macrophage infiltration and collagen deposition.•In ZD mammary glands ZIP6, ZIP10 and ZnT2 expression is increased.•The microenvironment in ZD mammary gland is associated with impaired architecture.

Zinc (Zn) regulates numerous cellular functions. Zn deficiency is common in females; ∼80% of women and 40% of adolescent girls consume inadequate Zn. Zn deficiency enhances oxidative stress, inflammation and DNA damage. Oxidative stress and inflammation is associated with breast disease. We hypothesized that Zn deficiency increases oxidative stress in the mammary gland, altering the microenvironment and architecture. Zn accumulated in the mammary glands of Zn deficient mice and this was associated with macrophage infiltration, enhanced oxidative stress and over-expression of estrogen receptor α. Ductal and stromal hypercellularity was associated with aberrant collagen deposition and disorganized e-cadherin. Importantly, these microenvironmental alterations were associated with substantial impairments in ductal expansion and mammary gland development. This is the first study to show that marginal Zn deficiency creates a toxic microenvironment in the mammary gland impairing breast development. These changes are consistent with hallmarks of potential increased risk for breast disease and cancer.