Exposure to ZnO nanoparticles induced blood-milk barrier dysfunction by disrupting tight junctions and cell injury

Zinc oxide nanoparticles (ZnO-NPs) are one of the most widely used nanomaterials with excellent chemical and biological properties. However, their widespread application has led to increased risk to the natural environment and public health. A growing number of studies have shown that ZnO-NPs deposited in target organs interact with internal barriers to trigger injurious responses. The underlying mechanism of ZnO-NPs on the blood-milk barrier dysfunction remains to be understood. Our results revealed that excessive accumulation of ZnO-NPs induced histopathological injuries in the mammary gland, leading to the distribution of ZnO-NPs in the milk of lactating mice. A prominent diffusion of blood-milk barrier permeability marker, albumin-fluorescein isothiocyanate conjugate (FITC-albumin) was observed at cell-cell junction after ZnO-NPs exposure. Meanwhile, ZnO-NPs weakened the blood-milk barrier function by altering the expression of tight junction proteins. The excessive accumulation of ZnO-NPs also induced inflammatory response by activating the NF-κB and MAPK signaling pathways, leading to the dysfunctional blood-milk barrier. Furthermore, we found that ZnO-NPs led to increased iron accumulation and lipid oxidation, thus increasing oxidative injury and ferroptosis in mammary glands. These results indicated that ZnO-NPs weaken the integrity of the blood-milk barrier by directly affecting tight junctions and cellular injury in different ways.