Larionov, N. | bioRxiv Science

bioRxiv2026

Prenatal fentanyl and Δ9-tetrahydrocannabinol exposure disrupt placental function and fetal growth in a mouse model of multidrug use

Opioid and cannabis co-use during pregnancy is increasingly common, yet the placental mechanisms linking combined exposure to adverse fetal outcomes remain poorly defined. Using a controlled mouse model of gestational drug exposure, we tested how fentanyl, {Delta}9-tetrahydrocannabinol (THC), or their combination altered placental structure, immune signaling, and gene expression and how these changes related to fetal growth. Drug exposure produced fetal growth restriction and reduced placental efficiency, with the greatest impairment in the combined fentanyl+THC group. Placental alterations were detectable by mid-gestation, when fentanyl exposure increased nucleated red blood cells within the labyrinth, consistent with hypoxic stress. By term, placentas showed compartment-specific remodeling, with THC selectively expanding the labyrinth and combined fentanyl+THC exposure increasing decidual area. Labyrinth composition and proliferative activity were altered, ultrastructural analysis revealed disruption of the maternal-fetal exchange interface, and placental interleukin-10 and interferon-{beta} levels were reduced across exposure groups. Transcriptomic analyses identified suppression of innate immune and antiviral defense pathways together with treatment-specific stress responses, and integration of placental gene expression with fetal weight showed coordinated repression of vascular and developmental regulators and activation of hypoxia- and metabolic stress-associated genes. These findings identify the placenta as a key mediator of adverse fetal outcomes associated with prenatal polysubstance exposure.

molecular biology↗

bioRxiv2026

LOSS OF PARKIN DISRUPTS NUCLEAR AND MITOCHONDRIAL PROGRAMS REQUIRED FOR MUSCLE REGENERATION

Skeletal muscle stem cells (MuSCs) rely on precisely coordinated metabolic and nuclear transitions to exit quiescence, enter the cell cycle, and regenerate tissue. How these processes are coupled remains poorly defined. Here, we identify PARKIN as a critical integrator of mitochondrial quality control and nuclear RNA processing programs that together enable balanced MuSC lineage progression. Using a MuSC-specific, inducible Park2 knockout model, we show that PARKIN supports mitophagy in quiescent MuSCs, and its loss triggers premature mitochondrial polarization and fragmentation -- hallmarks of metabolic activation -- that compromise appropriate self-renewal and fate specification. Unexpectedly, MuSCs harbor a constitutive nuclear pool of PARKIN that rises rapidly upon activation and localizes to interchromatin regions, with focal association with nuclear speckles. Park2-deficient MuSCs exhibit transcriptomic signatures consistent with widespread RNA isoform switching and intron retention, particularly affecting splicing machinery components, accompanied by altered nuclear speckle organization and impaired cell cycle progression. These findings reveal that PARKIN safeguards both mitochondrial homeostasis and the RNA processing architecture essential for activation, thereby coordinating metabolic and nuclear reprogramming during early MuSC state transitions. Our work positions PARKIN as a dual compartment regulator required for robust skeletal muscle regeneration.

cell biology↗