Microcystin-LR Impairs Endometrial Receptivity during the Peri-Implantation Window via Disruption of STAT3/HIF-1α Signaling

Microcystin-LR (MC-LR), an emerging contaminant present in aquatic environments, poses health risks owing to its widespread distribution, bioaccumulation potential, and well-documented human exposure. However, its impact on endometrial function during early pregnancy remains poorly understood. This study investigates the effects and mechanisms of MC-LR exposure during the peri-implantation period on endometrial receptivity. Pregnant mice were administered with MC-LR at a biologically relevant dose (1/2 NOAEL, 20 μg/kg/day) from gestational days 3.5 to 5.5. MC-LR exposure impaired uterine morphology, reduced serum progesterone, and suppressed expression of key receptivity markers, resulting in decreased implantation sites. Transcriptomic analysis revealed dysregulation of the extracellular region, immune response, and hormone activity, with STAT3 signaling identified as a key regulator. MC-LR also disrupted uterine immune homeostasis, causing macrophage dysfunction and reduced IL-6 levels. The IL-6-dependent STAT3/HIF-1α signaling pathway was inhibited by MC-LR but reactivated by Garcinone D. Pharmacological activation of STAT3 prevented MC-LR-induced impairments, including cytokine dysregulation, extracellular matrix degradation, angiogenesis inhibition, reduced gland numbers, and decreased implantation capacity, though serum progesterone levels remained unaffected. These findings suggest that MC-LR disrupts endometrial receptivity via STAT3/HIF-1α signaling, independent of progesterone restoration, providing novel insights into microcystin-induced reproductive toxicity and a potential therapeutic target for implantation failure.