Cariaco, Y. | 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↗

bioRxiv2023

NAD+ depletion and altered mitochondrial function are key to the establishment of placental dysfunction in an inflammatory-driven subclass of preeclampsia

Preeclampsia (PE) is a pregnancy associated hypertensive disease. It is one of the major causes of pregnancy-related maternal/perinatal adverse health outcomes, with a lack of highly effective preventative strategies and/or therapeutic interventions. Our group has previously identified distinct subclasses of pathophysiology underlying a PE diagnosis, one of which exhibits heightened immune activation at the gestational parent-fetal interface, identified as inflammatory-driven PE. In non-pregnant populations, chronic inflammation is associated with reduced cellular availability of NAD+, a vitamin B3-derived metabolite involved in energy metabolism and mitochondrial function. Interestingly, specifically in placentas from women with inflammatory-driven PE, we observed increased activity of NAD+-consuming PARP enzymes and reduced NAD+ content. Moreover, these placentas had decreased expression of several mitochondrial oxidative phosphorylation (OXPHOS) proteins and evidence of oxidative damage. This human data was supported by cell culture findings, which likewise demonstrated increased PARP activity, coupled to decreased mitochondrial respiration rates and decreased invasive function of cultured HTR8 human trophoblast cells, following inflammatory induction by TNF-. Importantly, these adverse inflammatory effects were attenuated by boosting cellular NAD+ levels with nicotinamide riboside (NR). Finally, using an LPS-induced rodent model of inflammatory-driven PE, we demonstrated that NR administration (200mg/kg/day) from gestational day (GD) 1-19 could prevent the development of maternal hypertension and fetal/placental growth restriction, improve placental mitochondrial function, reduce placental inflammation and oxidative stress. Thus, this study demonstrates the critical role of NAD+ metabolism in maintaining healthy placental function and identifies NAD+ boosting as a promising preventative strategy for the inflammatory-driven subclass of PE. One sentence summaryBoosting NAD+ levels prevent inflammatory-driven preeclampsia by improving placental mitochondrial function.

molecular biology↗