Placenta · 2026
Gestational cadmium exposure is associated with dysregulated HIF-1α/Parkin-mediated mitophagy: implications for fetal growth restriction.
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Lu Zheyu, Chen Na, Luo Run, Xu Keqi, Xu Cengqi, Wang Fan
Аннотация
INTRODUCTION: Cadmium (Cd) is an environmental toxicant associated with fetal growth restriction (FGR). However, the molecular mechanism underlying Cd-associated placental dysfunction remains incompletely understood. This study investigated whether altered mitochondrial quality control involving HIF-1α and Parkin contributes to Cd-induced trophoblast injury and impaired fetal growth.
METHODS: We integrated a gestational Cd-exposed rat model, human JEG-3 trophoblast cells, and human placenta samples. Interventions included the mitophagy-modulating compound Mdivi-1 (M - 1), the HIF-1α inhibitor PX-478, and Parkin-siRNA, in combination with Western blotting, TUNEL staining, and transmission electron microscopy.
RESULTS: Cd exposure reduced the level of mitochondrial proteins HSP60 and COX IV while upregulating PGC-1α in rat placenta and JEG-3 cells, consistent with enhanced mitochondrial clearance. Pretreatment with M - 1 attenuated these mitochondrial alterations and reduced Cd-induced apoptosis. Mechanistically, Cd exposure increased mitochondrial Parkin accumulation and HIF-1α expression, accompanied by mitophagy-related mitochondrial alterations. Parkin-siRNA suppressed Parkin expression and attenuated Cd-induced mitochondrial loss, whereas the HIF-1α inhibitor PX-478 reversed Cd-associated reductions in HSP60 and COX IV and blunted the upregulation of PGC-1α and Parkin. Functionally, Cd altered the balance of apoptosis-related proteins (upregulating Bax and Cleaved Caspase-3 while downregulating Bcl-2 and total caspase-3), and these changes were partially rescued by M-1. Human FGR placentas exhibited alterations broadly consistent with the mitochondrial changes observed in the experimental models; however, the absence of placental Cd quantification limits these findings to correlative evidence.
DISCUSSION: These findings support the involvement of HIF-1α/Parkin-associated mitochondrial quality-control dysregulation in Cd-induced trophoblast injury and suggest that altered mitochondrial clearance and apoptosis may contribute to Cd-associated FGR.
METHODS: We integrated a gestational Cd-exposed rat model, human JEG-3 trophoblast cells, and human placenta samples. Interventions included the mitophagy-modulating compound Mdivi-1 (M - 1), the HIF-1α inhibitor PX-478, and Parkin-siRNA, in combination with Western blotting, TUNEL staining, and transmission electron microscopy.
RESULTS: Cd exposure reduced the level of mitochondrial proteins HSP60 and COX IV while upregulating PGC-1α in rat placenta and JEG-3 cells, consistent with enhanced mitochondrial clearance. Pretreatment with M - 1 attenuated these mitochondrial alterations and reduced Cd-induced apoptosis. Mechanistically, Cd exposure increased mitochondrial Parkin accumulation and HIF-1α expression, accompanied by mitophagy-related mitochondrial alterations. Parkin-siRNA suppressed Parkin expression and attenuated Cd-induced mitochondrial loss, whereas the HIF-1α inhibitor PX-478 reversed Cd-associated reductions in HSP60 and COX IV and blunted the upregulation of PGC-1α and Parkin. Functionally, Cd altered the balance of apoptosis-related proteins (upregulating Bax and Cleaved Caspase-3 while downregulating Bcl-2 and total caspase-3), and these changes were partially rescued by M-1. Human FGR placentas exhibited alterations broadly consistent with the mitochondrial changes observed in the experimental models; however, the absence of placental Cd quantification limits these findings to correlative evidence.
DISCUSSION: These findings support the involvement of HIF-1α/Parkin-associated mitochondrial quality-control dysregulation in Cd-induced trophoblast injury and suggest that altered mitochondrial clearance and apoptosis may contribute to Cd-associated FGR.