Biology subjects

Goedken, M.

Publications and source records attributed to Goedken, M..

3 recordsLinked to original sources

bioRxiv2026

Inhalation of nanoparticles during pregnancy enhances placental glucose transport in rats

Fetal health is heavily dictated by the maternal environment. Inhaling airborne pollutants, like particulate matter, is associated with pregnancy complications and fetal developmental pathologies, including fetal growth restriction (FGR). Because fetal growth is dependent on the placental transfer of nutrients from the maternal circulation, particularly glucose, investigating glucose transport capacity is critical to understanding the development of FGR associated with gestational inhalation of particulate matter. Pregnant Sprague Dawley rats were exposed to titanium dioxide nanoparticles (9.8{+/-}1.0 mg/m3) as a proxy for ultrafine particulate matter, from gestational day (GD) 5 to GD 19 via whole-body inhalation. Glucose transporters (GLUTs) 1, 3 and 4 were evaluated in term placentas on GD 20 and ex vivo placental perfusion was conducted as a functional assessment of glucose transport. Exposure resulted in a reduction in Glut3 mRNA and GLUT1 protein. However, exposed placentas exhibited an adaptation, characterized by increased GLUT4 expression and membrane localization of both GLUT1 and GLUT4. Placental perfusion confirmed these molecular changes, revealing increased glucose flux in exposed placentas compared to control (AUC 95% CI: 77.4 to 127.5 vs 39.1 to 73.6, respectively). Contrary to our hypothesis, exposure to these nanoparticles enhanced glucose transport across the placenta. Here we have demonstrated that inhaling airborne pollutants during pregnancy modulates placental function and nutrient transport mechanisms, which can have direct effects on fetal development. Furthermore, we provide evidence for targeted interventions, aimed at mitigating fetal developmental pathologies. HighlightsO_LIGestational inhalation of nanoparticles decreases GLUT1 expression in the placenta. C_LIO_LIThe placenta adapts to gestational nanoparticle inhalation by enhancing GLUT4 expression and GLUT1 and GLUT4 membrane localization. C_LIO_LIEx vivo placental perfusion demonstrated increased glucose flux across to the placenta to the fetus following gestational inhalation of nanoparticles. C_LI

pharmacology and toxicology↗

bioRxiv2026

Gestational inhalation of nanoparticles disrupts placental zone structure and induces vascular placentation in rats

Airborne contaminants represent a significant environmental health concern for vulnerable populations, including pregnant individuals. In particular, maternal inhalation of particulate matter (PM) during pregnancy has been linked to adverse outcomes such as fetal growth restriction (FGR). Increasing evidence identifies placental dysfunction as a mechanism for this condition. Placental efficiency, defined as the ratio of fetal mass to placental mass, is frequently altered in FGR. Many aspects contribute to placental efficiency including surface area available for nutrient and waste exchange and placental vascularization. In this study, we hypothesized that maternal inhalation of ultrafine PM during pregnancy would reduce the size and/or number of placental structures that are necessary for nutrient transport. Engineered titanium dioxide nanoparticles (nano-TiO2) were used as a proxy for ultrafine PM and pregnant Sprague Dawley rats were exposed via whole-body inhalation to nano-TiO2 aerosols (9.23 {+/-} 0.39 mg/m3) from gestational day (GD) 5 to 19. On GD 20, placentas were collected and processed for histological evaluation. While gestational inhalation of nano-TiO2 did not affect placental weight or efficiency, it reduced decidua and labyrinth zone size. Exposed placentas exhibited compensatory adaptations characterized by increased blood space number and maternal blood space expansion. Together, these findings indicate that inhalation of nanoparticles disrupts placental structure while simultaneously eliciting adaptive vascular responses that may preserve nutrient exchange capacity. By characterizing the effects of PM exposure on placental morphology and structure, this study highlights the placenta as a vulnerable target of inhaled pollutants and provides mechanistic insight into pathways contributing to PM-induced FGR.

pharmacology and toxicology↗

bioRxiv2026

Nephrotoxicity of Immune Checkpoint Inhibitors in Mice with a Human Immune System

IntroductionImmune checkpoint inhibitors (ICIs) enhance antitumor responses by blocking inhibitory receptors, including PD-1 and CTLA-4. Overactivation can trigger systemic toxicity akin to autoimmune diseases, including kidney manifestations. We sought to 1) profile immune signaling and 2) interrogate potential mechanisms of ICI-related kidney injury in a Human Immune System (HIS) tumor-bearing mouse model treated with nivolumab and ipilimumab. MethodsImmunodeficient BRGS (BALB/c-Rag2nullIl2r{gamma}nullSirpNOD) neonates were engrafted with human CD34+ cells to generate HIS-BRGS mice. Human MDA-MB-231 tumor cells were implanted subcutaneously; once tumors reached [~]150 mm3, mice received weekly intraperitoneal vehicle (PBS) or ICI (nivolumab 20 mg/kg + ipilimumab 10 mg/kg) for 4 weeks (Veh BRGS n=4; ICI BRGS n=6; Veh HIS-BRGS n=7; ICI HIS-BRGS n=7). Kidneys were evaluated by histopathology (H&E, TEM), flow cytometry for human immune phenotypes, multiplex ELISA (80 human proteins; 10 injury biomarkers), bulk RNA sequencing, and targeted qPCR. Pearson correlations identified predictors of histopathological injury. ResultsRenal vasculitis and interstitial nephritis were observed only in ICI-treated HIS-BRGS mice. These kidneys showed a shift toward CD4+ T-cell enrichment with an increased TNF- production capacity compared to CD8+ counterparts. Toxicity was accompanied by increased renal concentrations of human cytokines, chemokines, and soluble receptors. ICI treatment significantly elevated serine proteases (Granzyme A/B) and NGF-{beta}, while decreasing IL-4. Interstitial nephritis correlated with renal PD-1 and MIF. Renal vasculitis correlated with kidney PD-1, CCL1, MIF, Granzyme A, IL-15, and BAFF. Traditional injury biomarkers (KIM-1, NGAL) remained unchanged; however, a trending decrease in EGF was observed. ConclusionsOur study suggests that shifts in human T-cell populations and specific immune proteins could serve as promising biomarkers and mechanistic targets for ICI nephrotoxicity. The tumor-bearing HIS-BRGS mouse model reproducibly recapitulates the histopathological and immunological features of human ICI-induced nephrotoxicity and represents a validated preclinical platform for testing novel therapeutic interventions to preserve kidney function during cancer immunotherapy. Translational StatementImmune checkpoint inhibitor (ICI)-associated nephrotoxicity occurs in up to 25% of treated patients, yet the immunological mechanisms driving renal injury remain poorly characterized due to the scarcity of human biopsy material and the absence of robust preclinical models that recapitulate human immune responses. This study demonstrates that tumor-bearing humanized immune system (HIS) mice treated with combined nivolumab and ipilimumab reproducibly develop renal vasculitis and interstitial nephritis mediated by a human CD4+ T cell-dominant infiltrate, mirroring the clinicopathological features reported in patients with ICI-associated acute kidney injury. By integrating histopathology, flow cytometry, multiplex proteomics, and transcriptomics, we identify a coordinated immune network, including IL-15, CCL1, MIF, GZMA, and BAFF, that correlates with the severity of renal pathology and represents tractable mechanistic targets and candidate biomarkers. These findings provide a validated preclinical platform for dissecting irAE mechanisms and testing novel therapeutic strategies to preserve kidney function during cancer immunotherapy.

pharmacology and toxicology↗