Biology subjects

Harris, L. K.

Publications and source records attributed to Harris, L. K..

4 recordsLinked to original sources

bioRxiv2026

Melatonin Partially Attenuates Oxycodone-Induced Placental Stress Signaling and Fetal Brain Apoptosis in a Sex-Specific Manner.

BackgroundMaternal oxycodone (oxy) exposure can disrupt placental function and fetal neurodevelopment, but the molecular mechanisms remain unclear. We investigated whether prenatal oxy exposure activates inflammation and stress response pathways in the placenta and fetal brain, and if maternal melatonin supplementation attenuates these effects. MethodsFemale Sprague-Dawley rats received either saline or oxy via oral gavage for 15 days before mating (10-15mg/kg/day dose escalation) and throughout pregnancy (15mg/kg/day). From gestational day (GD) 12.5, half of the dams received melatonin (10mg/kg/day). On GD 19.5, placental and fetal brain tissues were collected. Changes in expression of markers of oxidative stress, antioxidant defense signaling, inflammation, ER stress, and apoptosis were assessed by western blotting. Data were analyzed by two-way ANOVA with Tukeys post hoc test. ResultsNeither oxy exposure nor melatonin treatment increased markers of oxidative stress or antioxidant defenses in the placenta and fetal brain. Oxy exposure increased placental IL-1{beta} expression but did not alter expression of the other inflammatory markers examined. Oxy increased phosphorylation of eIF2 and increased the phospho-eIF2:eIF2 ratio in the placentas of male fetuses, and fetal brains of both sexes. CHOP expression was increased in the placentas and brains of female, but not male fetuses after oxy exposure. Oxy exposure increased levels of cleaved caspase-3 and cleaved caspase-9 in the fetal brain, but not the placenta; melatonin treatment attenuated the oxy-induced increase in cleaved caspase-9, but not cleaved caspase-3. ConclusionPrenatal oxy exposure induced a modest inflammatory response in the placenta and activated the integrated stress response and intrinsic apoptotic signaling in the fetal brain. Maternal melatonin supplementation partially mitigated the oxy-induced upregulation of caspase-9 but did not prevent stress signaling in either tissue. These findings demonstrate the presence of sex-specific placental and fetal brain responses to prenatal oxy exposure but suggest that melatonin may not provide complete protection against oxy-induced neurodevelopmental impairment.

developmental biology↗

bioRxiv2026

Delineating the effects of prenatal oxycodone exposure and melatonin treatment on placental and fetal outcomes in pregnant rats

BackgroundPrenatal oxycodone (oxy) exposure has been associated with adverse pregnancy and fetal developmental outcomes. In this study, we assessed whether chronic prenatal oxy exposure impairs placental and fetal growth in rats and if maternal melatonin supplementation would mitigate these effects. MethodsFemale Sprague-Dawley rats received either saline or oxy via oral gavage for 15 days before mating (10-15mg/kg dose escalation) and throughout pregnancy (15mg/kg). From gestational day (GD) 12.5, half of the dams received melatonin (10mg/kg). On GD19.5, maternal and fetal blood, and maternal, placental and fetal tissues were harvested. Placental histomorphometry was assessed and immunohistochemistry for pan-cytokeratin, PCNA, CD34, -SMA, and TUNEL analysis were performed. Maternal and fetal plasma cytokines, angiogenic factors, and pregnancy hormones were measured by ELISA. Anthropometric data were analyzed using general linear mixed models and other outcomes were analyzed using univariate general linear models. ResultsOxy induced fetal growth restriction as evidenced by reduced placental weight, fetal weight, fetal-to-placental weight ratio, crown-rump length, and fetal liver weight. Melatonin also independently reduced some parameters of fetal growth but when administered with oxy it partially improved fetal outcomes including the head-to-abdominal diameter ratio. Oxy exposure increased placental labyrinth zone area, the percentage of CD34-positive cells, and maternal plasma IL-1{beta} and IL-10 concentrations and reduced the percentage of pan-cytokeratin positive cells, while both oxy and melatonin reduced maternal plasma chorionic gonadotropin levels. ConclusionPrenatal oxy exposure disrupts placental structure, labyrinth anatomy, and induces maternal systemic inflammation, associated with impaired fetal growth. The protective effects of melatonin are partial but indicate a potential brain sparing effect.

developmental biology↗

bioRxiv2024

A human induced pluripotent stem (hiPS) cell model for the holistic study of epithelial to mesenchymal transitions (EMTs)

The epithelial to mesenchymal transition (EMT) is a widely studied but poorly defined state change due to the variety of ways in which it has been characterized in cells. There is a need for reproducible cell model systems that enable the integration and comparison of different types of measured observations of cells across many distinct cellular contexts. We present human induced pluripotent stem (hiPS) cells as such a model system by demonstrating its utility through a comparative analysis of hiPS cell-EMT in 2D and 3D cell culture geometries. We developed live-imaging-based assays to directly compare examples of changes in cell function (via migration timing), molecular components (via expression of marker proteins), organization (via reorganization of cell junctions), and environment (via dynamics of basement membrane) in the same experimental system. The EMT-related changes we measured occurred earlier in 2D colonies than in 3D lumenoids, likely due to differences in the basement membrane environments associated with 2D vs. 3D initial hiPS cell culture geometries. We have made the 449 60-hour-long 3D time-lapse movies and the associated tools used for analysis and visualization open-source and easily accessible as a resource for future work in this field.

cell biology↗

bioRxiv2024

Colony context and size-dependent compensation mechanisms give rise to variations in nuclear growth trajectories

To investigate the fundamental question of how cellular variations arise across spatiotemporal scales in a population of identical healthy cells, we focused on nuclear growth in hiPS cell colonies as a model system. We generated a 3D timelapse dataset of thousands of nuclei over multiple days, and developed open-source tools for image and data analysis and an interactive timelapse viewer for exploring quantitative features of nuclear size and shape. We performed a data-driven analysis of nuclear growth variations across timescales. We found that individual nuclear volume growth trajectories arise from short timescale variations attributable to their spatiotemporal context within the colony. We identified a strikingly time-invariant volume compensation relationship between nuclear growth duration and starting volume across the population. Notably, we discovered that inheritance plays a crucial role in determining these two key nuclear growth features while other growth features are determined by their spatiotemporal context and are not inherited.

cell biology↗