Inflammation caused by inactivated SARS-CoV-2 virus directly impacts spermatogenesis and reproductive performance and causes fetal impairment in K-18-hECA2 transgenic mice

COVID-19 has been linked to reproductive dysfunction, but the underlying mechanisms remain unclear. In this study, we assessed the effects of inactivated SARS-CoV-2 virus (iSARS-CoV-2) exposure in K18-hACE2 females and males. Pregnant females exposed early in gestation showed reduced fetal number and increased resorptions, accompanied by pulmonary inflammation with elevated TNF, IL-6 and IFN-gamma and histopathological damage. Males displayed impaired sperm quality, reduced reproductive performance and compromised pregnancy outcomes in healthy females. Both sexes exhibited pulmonary inflammation in the absence of viral replication, suggesting immune activation by viral structural components. These findings indicate that exacerbated inflammatory responses independent from viral replication and likely mediated by TLR4—play a central role in SARS-CoV-2–induced reproductive impairment, affecting male fertility and fetal viability.