Lead exposure promotes the inflammation via the circRNA-05280/miR-146a/IRAK1 axis in mammary gland.

Lead, the most widely used heavy metal in industry, is detrimental to human health if exposed to living and occupational environment. Although several studies have been conducted on lead exposure, little has been reported on its harm to mammary gland and its mechanisms. In view of this, our study is the first to verify that lead exposure could promote apoptosis and inflammation in mouse mammary tissue (in vivo) and cow mammary epithelial cells (in vitro). After establishing a lead exposed mouse model, the expression profile of mammary gland tissue was constructed by high-throughput sequencing technology. In the profile, 917 differentially expressed genes were screened, of which IRAK1 was up-regulated by 4.33 times. Then, from qRT-PCR, Western blot and Luciferase report, IRAK1 was found to promote the release of inflammatory factors and tissue apoptosis and could be a specific target of miR-146a. On the other hand, double luciferase reporter system and qRT-PCR predicted the existence of a binding site between circRNA-05280 and miR-146a sequence. Experiments such as immunohistochemistry, apoptosis and EdU demonstrated that circRNA-05280 could promote not only cell apoptosis but also the expression level of inflammatory genes. Nevertheless, the function of miR-146a is opposite to that of circRNA-05280. Specifically, circRNA-05280 can regulate the level of apoptosis and inflammation of mammary gland by binding miR-146a and releasing the expression of miR-146a on target gene IRAK1. This study concludes that circRNA-05280/ miR-146a/ IRAK1 signaling pathway could mediate the mammary gland damage resulting from lead exposure. Accordingly, it sheds new light on further exploration of molecular mechanisms of mammary gland tissue damage caused by lead exposure, the risk assessment of lead, and the mechanism of lead mammary gland toxicity.