Hypoxia-induced metabolic shifting and AHR/BCRP axis impairment drive placental dysfunction in early-onset preeclampsia and FGR.

BACKGROUND

Placental hypoxia and vascular dysfunction are hallmarks of preeclampsia (PE). The Breast Cancer Resistance Protein (BCRP) is critical for maintaining the placental barrier against oxidative stress. We investigated whether the hypoxic microenvironment drives BCRP dysregulation and how this correlates with fetal growth restriction (FGR) in severe preeclampsia.

METHODS

This case-control study enrolled 59 normotensive and 72 preeclamptic pregnancies to compare clinical phenotypes and placental BCRP expression across distinct gestational age subgroups. Mechanistic investigations were conducted using human BeWo trophoblasts under pathological hypoxia (1%O2​). We integrated metabolic profiling (glycolytic shift and JC-1 mitochondrial assays) with rigorous molecular techniques-including Co-immunoprecipitation (Co-IP) and subcellular fractionation-to elucidate the competitive crosstalk between HIF-1α and AHR, further validating barrier impairment via Hoechst 33342 functional efflux assays.

RESULTS

Clinically, patients with early-onset preeclampsia (28-33+6 weeks) exhibited a markedly higher incidence of FGR compared to late-onset or control groups. In these compromised placentas, BCRP expression was significantly suppressed and inversely correlated with the hypoxia marker GLUT1. In vitro assays delineated a "dual-hit" pathological cascade triggered by chronic hypoxia. First, trophoblasts underwent severe metabolic reprogramming characterized by massive glycolytic upregulation and mitochondrial dysfunction. Second, stabilized HIF-1α competitively sequestered the obligate co-receptor ARNT, systematically dismantling the AHR/ARNT transcriptional complex. This specific molecular "competitive binding" impaired AHR-mediated protective signaling, resulting in a critical loss of functional BCRP efflux capacity.

CONCLUSION

Our study defines a distinct "dual-hit" molecular phenotype in early-onset preeclampsia. Chronic hypoxia not only drives an acute metabolic crisis but also actively dismantles the protective AHR/BCRP placental barrier via HIF-1α-mediated ARNT sequestering. This synergistic failure compromises placental xenobiotic detoxification, exacerbates fetal toxicological vulnerability, and fundamentally contributes to the profound severity of FGR.