Obstructive sleep apnea (OSA), common in pregnancy, is linked to preeclampsia and long-term maternal hypertension, but the underlying mechanisms remain unclear. We hypothesized that intermittent hypoxia (IH), a core feature of OSA, primes the maternal vasculature for heightened responses to hypertensive stressors postpartum. Pregnant Sprague-Dawley rats were exposed to either room air or gestational IH from gestational days 10-21. Two months after delivery, all dams were subjected to a high-salt challenge (2% NaCl in drinking water). Blood pressure and heart rate were measured during gestation and before and following salt loading. Vascular function and protein expression were analyzed in mesenteric arteries at study completion. A parallel group of nonpregnant rats underwent identical IH and salt exposure to delineate pregnancy-specific effects. IH exposure in pregnancy led to gestational hypertension that resolved postpartum, whereas nonpregnant rats showed no blood pressure changes. However, following high-salt challenge, postpartum IH-exposed dams displayed significantly greater increases in blood pressure and heart rate, abnormalities not seen in nonpregnant counterparts. Ex vivo, arteries from IH-exposed dams showed enhanced vasocontraction to phenylephrine and impaired vasodilation to both acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent). Molecular analysis revealed increased endothelial nitric oxide synthase activation and decreased protein kinase G (PKG) in the IH group, with no change in α1-adrenergic receptor expression, indicating disrupted vascular smooth muscle signaling. Virgin rats showed no such alterations. Gestational IH induces a pregnancy-specific predisposition to postpartum salt-sensitive hypertension and vascular dysfunction, driven by disrupted PKG signaling. Early OSA detection and intervention in pregnancy may reduce cardiovascular risk.

Perfluorooctanesulfonic acid (PFOS), a persistent environmental pollutant, is elevated in the plasma of preeclamptic women and may contribute to gestational hypertension. However, its direct effects on placental vascular function remain unclear. This study investigated PFOS' impact on vascular reactivity in human placental chorionic plate arteries (CPAs) and evaluated the therapeutic potential of the mitochondrial-targeted antioxidant mitoquinone (MitoQ). CPAs from normotensive pregnancies were treated with PFOS (10 μM) or vehicle for 24 h. Wire myography assessed contractile responses to KCl and endothelin-1 (ET-1), as well as cyclic adenosine monophosphate (cAMP)-mediated (isoproterenol, forskolin) and cyclic guanosine monophosphate (cGMP)-mediated (sodium nitroprusside, SNP) vasodilation. Adenosine triphosphate (ATP), cAMP, and cGMP levels were quantified, and MitoQ (100 nM) co-treatment was tested for rescue effects. PFOS-exposed CPAs exhibited enhanced maximal contraction to KCl (9.73 ± 0.96 vs. 5.60 ± 0.41 mN) and ET-1 (9.84 ± 1.05 vs. 5.77 ± 0.49 mN). cAMP-dependent relaxation was impaired (isoproterenol: 31.16 ± 4.55% vs. 65.27 ± 6.08%; forskolin: 65.59 ± 2.72% vs. 87.55 ± 1.89%), while SNP-induced cGMP-mediated relaxation remained unaffected. PFOS reduced ATP by 58% (30.43 ± 2.89 vs. 73.71 ± 9.15 μmol/mg) and cAMP by 57% (46.15 ± 9.54 vs. 109.1 ± 8.88 nmol/mg) but did not affect cGMP levels. MitoQ restored ATP/cAMP levels and normalized vascular function, reversing PFOS-induced hypercontractility and cAMP pathway suppression. These findings demonstrate that PFOS directly impairs placental vascular homeostasis via mitochondrial dysfunction and cAMP signaling disruption, implicating it as a mediator of gestational hypertension. Mitochondrial-targeted interventions like MitoQ may mitigate PFOS-associated vascular dysfunction, highlighting therapeutic avenues for high-exposure pregnancies.

Male infertility has been linked with exposure to endocrine-disrupting chemicals, including perfluoroalkyl and polyfluoroalkyl substances (PFASs). However, the underlying mechanisms remain largely unknown. This study investigated the effects of perfluorooctane sulfonate (PFOS), a prevalent PFAS, on the testicular proteome, serum testosterone levels, and testicular histology in pre-pubertal male Sprague-Dawley rats. Rats were exposed to PFOS via drinking water at concentrations of 0 μg/mL (control), 10 μg/mL (P10), and 50 μg/mL (P50) for 21 days. Serum and testicular tissue were then collected. Serum testosterone levels were measured by enzyme-linked immunosorbent assay (ELISA), and testicular proteomic composition was assessed using tandem mass tag labeling and nanoLC-MS/MS. While there were no detectable changes in testicular histology, serum testosterone levels were significantly reduced in the P50 group compared to the control (P < 0.05). Testicular proteomic analysis identified 4619 proteins, with 4559 common to all groups. Among these, 35 were upregulated and 64 downregulated in the P10 group, while 130 were upregulated and 36 were downregulated in the P50 group (P < 0.05). Functional enrichment analysis of differentially expressed proteins (DEPs) revealed significant alterations in biological processes crucial for male reproductive function, including nucleosome assembly, translation, chromatin organization, and spermatogenesis. Notably, PFOS exposure impacted the expression of proteins involved in spermatogenesis, chromatin condensation, and sperm fertility. These findings were further supported by Western blot validation of four key DEPs. This study provides evidence that PFOS exposure alters the testicular proteome and disrupts key proteins essential for male reproductive function, offering insights into the molecular mechanisms underlying PFAS-induced male infertility.

Elevated maternal testosterone (T) during pregnancy disrupts neurodevelopment and behavior in offspring, mimicking features of autism spectrum disorder (ASD). In a rat study, dams received daily T injections (0.5 mg/kg) from gestational days 12–20, doubling maternal plasma T to mimic levels seen in pregnancy complications. Controls received vehicle. Offspring were assessed neonatally (postnatal day 9) for communication (ultrasonic vocalizations), neurogenesis (NeuN+ neurons), myelination (MBP+ area), and brain docosahexaenoic acid (DHA). Adolescent offspring (6–8 weeks) underwent behavioral tests for cognition (Y-maze, novel object recognition) and sociability (three-chamber test). T-exposed pups had lower birth weights and reduced vocalizations during maternal separation. Sex-specific neural changes observed: males showed reduced cortical neuron density, while females had diminished corpus callosum myelination. Both sexes exhibited decreased brain DHA. In adolescence, T offspring displayed cognitive deficits (impaired spatial/recognition memory) and social impairments (reduced sociability and social novelty preference). The study highlights maternal T as a risk factor for neurodevelopmental disorders, with sex-specific effects on brain structure and function. Reduced brain DHA suggests a mechanistic link, implicating lipid metabolism in T-associated neurodevelopmental disruptions. These findings support further exploration of DHA supplementation as a therapeutic strategy to mitigate adverse outcomes in high-risk pregnancies.

The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra's dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that urethral neuroendocrine cells (UNECs), and the serotonin they synthesize, protect the bladder from bacterial colonization. We tested the hypothesis that serotonin initiates urethral contraction to expel ascending bacteria. We identified transient receptor potential cation channel subfamily A member 1, a noncanonical lipopolysaccharide receptor, in human and mouse UNECs and localized the serotonin receptors (HTR) 2B and 3, as well as the calcium-activated chloride channel anoctamin 1 (ANO1) to the pacemaker cells of the human and mouse urethra, the interstitial cells of Cajal (ICCs). HTR2B or ANO1 activation is sufficient for urethral contraction and is required for serotonin-induced mouse urethral contraction. Our results support the hypothesis that the urethra actively surveils its environment and responds to an ascending pathogen by evoking UNECs and ICC to induce urethral contraction and pathogen expulsion.

BACKGROUND:Teratogens and other environmental factors influence human birth defect risk, but our understanding of how they reach the developing conceptus is surprisingly limited. The placenta is often invoked as a key mediator of teratogenicity by acting as a physical barrier that can block or regulate the transfer of harmful substances to the embryo or fetus. METHODS:In this review, we compare the timing of teratogen susceptibility with the development of the placenta. Teratogenicity data from multiple published studies were plotted on a unified multi-species developmental timeline to relate findings from animal models to human developmental timing. RESULTS:The critical periods for most teratogen-induced structural birth defects, including fetal alcohol syndrome-related defects, neural tube defects, orofacial clefts, and limb malformations translate to the 3rd to 6th week of human embryonic development, while the human hemochorial placenta matures later, between 8 and 12 weeks of pregnancy. CONCLUSIONS:This developmental chronology challenges the seemingly pervasive notion that placental transfer capacity plays a major role in mediating teratogenicity and highlights the need to further investigate the barrier capacity of the structures that surround and protect the developing embryo (e.g., trophoblast, yolk sac) prior to formation of the definitive placenta, and when the embryo is most sensitive to teratogenic insult.

We have reported that an endogenous aryl hydrocarbon receptor (AhR) ligand, 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), inhibits functions of human umbilical vein endothelial cells (HUVECs) and induces preeclampsia (PE)-like symptoms in rats. Herein, we tested the hypothesis that ITE impairs endothelial functions via disturbing transcriptome and phosphoproteome in HUVECs. We measured AhR activity in human maternal and umbilical vein sera from PE and normotensive (NT) pregnancies. The serum-induced changes in CYP1A1/B1 mRNA (indexes of AhR activation) in HUVECs were quantified using quantitative reverse transcription polymerase chain reaction (RT-qPCR). ITE's effects on endothelial proliferation and monolayer integrity in female and male HUVECs were determined. We profiled ITE-induced changes in transcriptome and phosphoproteome in HUVECs using RNA-seq and bottom-up phosphoproteomics, respectively. After 12 h of treatment, umbilical vein sera from PE increased CYP1A1 mRNA (1.7-fold of NT) in HUVECs, which was blocked by CH223191, an AhR antagonist. ITE dose-dependently inhibited endothelial proliferation (76%-87% of control) and time-dependently reduced endothelial integrity with a maximum inhibition (∼10%) at 40 h. ITE induced 140 and 80 differentially expressed genes in female and male HUVECs, respectively. ITE altered phosphorylation of 92 and 105 proteins at 4 and 24 h, respectively, in HUVECs. These ITE-dysregulated genes and phosphoproteins were enriched in biological functions and pathways that are relevant to heart, liver, and kidney diseases, vascular functions, and inflammatory responses. Thus, endogenous AhR ligands may impair endothelial functions by disturbing transcriptome and phosphoproteome. These AhR ligand-dysregulated genes and phosphoproteins may be therapeutic and cell sex-specific targets for PE-induced endothelial dysfunction.NEW & NOTEWORTHY Preeclampsia elevates AhR agonistic activities in fetal circulation and alters immune cell gene signatures of human umbilical vein endothelial cells (HUVECs). An endogenous AhR ligand (ITE) decreases cell proliferation and monolayer integrity in HUVECs in vitro. ITE dysregulates transcriptome in HUVECs in a fetal sex-specific manner. ITE also disrupts phosphoproteome in HUVECs. These ITE-dysregulated genes and phosphoproteins are highly relevant to diseases of the heart, vascular function, and inflammatory responses.

Per- and polyfluoroalkyl substances (PFAS) are linked to preeclampsia (PE), a condition involving abnormal angiogenesis. Prior research on this association has been inconclusive. We investigated the relationship between maternal PFAS exposure and PE risk in Wisconsin. We also examined if PFAS disrupts angiogenesis and, if so, what mechanisms are involved. We conducted a case-control study with 40 PE cases and 40 controls. Maternal serum was analyzed for 38 different PFAS compounds using LC MS/MS. Functional in vitro experiments assessed PFOS effects on angiogenesis and mechanisms. Maternal serum samples from women with PE exhibited significantly higher PFOS and PFHPS concentrations than controls. After adjusting for confounders, each log-scale IQR increase in PFOS and PFHPS concentrations was associated with a 7.18-fold (95 % CI: 2.24, 23.0) and 5.40-fold (95 % CI: 1.81, 16.1) higher odds of PE, respectively. Furthermore, PFOS and PFHPS were positively associated with sFLT1 levels and the sFLT1/PLGF ratio. In vitro experiments revealed that PFOS exposure impaired HUVEC proliferation, migration, and tube formation, essential processes for angiogenesis. The membrane-based antibody array showed that PFOS decreased expression of multiple angiogenic proteins, including I-TAC, uPAR, VEGFR2, MMP-1, IL-1α, Angiopoietin-2, IL-1β, PECAM-1, TIE-2, and TIMP-2. The qPCR analysis demonstrated that PFOS decreased VEGFR2, the upstream target of VEGF, at the transcriptional level. In conclusion, elevated PFAS, especially PFOS and PFHPS, are linked to increased PE risk. PFOS may suppress angiogenesis via attenuated VEGFR2-mediated signaling, providing a molecular mechanism linking PFAS and PE pathogenesis.

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants frequently detected in drinking water worldwide. Reports linking PFAS exposure to cardiovascular disease have increased significantly in recent years. Furthermore, women appear to be more susceptible to the adverse effects of PFAS. However, the potential role of ovaries in the increased vulnerability of females to PFAS-related health effects remains unknown. In this study, we investigated the impact of perfluorooctane sulfonate (PFOS), a prominent PFAS, on the cardiovascular function in female rats with intact ovaries and ovariectomized (OVX) females. Bilateral OVX or sham surgeries were performed in 8-week-old female SD rats. Following recovery from surgeries, the rats were given drinking water containing 50 μg/mL of PFOS for 3 weeks. Control groups received PFOS-free water. PFOS exposure significantly reduced body weight but increased blood pressure similarly in both intact and OVX rats. Echocardiography analysis revealed that PFOS exposure decreased cardiac output, end-systolic volume, and end-diastolic volume in intact but not OVX rats. Vascular function studies demonstrated that PFOS equally reduced endothelium-dependent and -independent relaxation responses in intact and OVX rats. The endothelium-independent contractile responses were more pronounced in both intact and OVX rats. eNOS protein levels were similarly decreased in both intact and OVX rats. In conclusion, PFOS affects cardiac function through hormone-dependent mechanisms, while vascular function is impaired independent of ovarian status, indicating an intricate interplay between PFOS exposure, ovarian status, and cardiovascular function.

The Earth is adorned with a rich and varied array of flora.It has been estimated that the botanical diversity in India contributes significantly, comprising about 11.4% of the total global species diversity.In a paradigm shift towards safer and more diverse alternatives, plants, known for their absence/least side effects, are emerging as readily available substitutes for commercial drugs.Traditional pharmaceuticals, often laden with toxicity, high costs, and adverse reactions, are being challenged by the exploration of plant-derived alternatives.This study centers on the synthesis and characterization of silver nanoparticles (AgNPs) derived from the methanol leaf extract of Santalum album.Silver nitrate and leaf methanol extracts are employed separately as the precursor and capping reducing agent.The characterization of the synthesized silver nanoparticles is conducted through various techniques, including UV-Visible Spectrophotometry (UV), Dynamic Light Scattering (DLS), Scanning Electron Microscopy (SEM), and Fourier-transform Infrared Spectroscopy (FT-IR).Antimicrobial assessments involve testing against both gram-positive bacteria (Escherichia coli and Klebsiella pneumoniae) and gram-negative bacteria (Staphylococcus aureus and Bacillus subtilis), as well as two fungal species (Aspergillus niger and Candida albicans) using the agar well diffusion method.Furthermore, the AgNPs from Santalum album methanol leaf extract exhibit in vitro antioxidant activity, assessed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method.Their potential in combating cancer is explored through the evaluation of anticancer properties against MCF-7 cell lines (Breast Cancer cell lines) using the MTT assay and the determination of nuclear morphology via AO/PI staining.The findings of this study suggest that silver nanoparticles from Santalum album methanol leaf extract may serve as a promising natural drug for both the treatment and prevention of cancer progression.

Background: Hypertensive disorders of pregnancy (HDP) remain a significant global health burden despite medical advancements. HDP prevalence appears to be rising, leading to increased maternal and fetal complications, mortality, and substantial healthcare costs. The etiology of HDP are complex and multifaceted, influenced by factors like nutrition, obesity, stress, metabolic disorders, and genetics. Emerging evidence suggests environmental pollutants, particularly Per- and polyfluoroalkyl substances (PFAS), may contribute to HDP development. Objective: This review integrates epidemiological and mechanistic data to explore the intricate relationship between PFAS exposure and HDP. Epidemiological evidence: Studies show varying degrees of association between PFAS exposure and HDP, with some demonstrating positive correlations, particularly with preeclampsia. Meta-analyses suggest potential fetal sex-specific differences in these associations. Mechanistic insights: Mechanistically, PFAS exposure appears to disrupt vascular hemodynamics, placental development, and critical processes like angiogenesis and sex steroid regulation. Experimental studies reveal alterations in the renin-angiotensin system, trophoblast invasion, oxidative stress, inflammation, and hormonal dysregulation - all of which contribute to HDP pathogenesis. Elucidating these mechanisms is crucial for developing preventive strategies. Therapeutic potential: Targeted interventions such as AT2R agonists, caspase inhibitors, and modulation of specific microRNAs show promise in mitigating adverse outcomes associated with PFAS exposure during pregnancy. Knowledge gaps and future directions: Further research is needed to comprehensively understand the full spectrum of PFAS-induced placental alterations and their long-term implications for maternal and fetal health. This knowledge will be instrumental in developing effective preventive and therapeutic strategies for HDP in a changing environmental landscape.

Background:Gestational intermittent hypoxia (GIH), a hallmark of maternal obstructive sleep apnea, sex-differentially causes hypertension and endothelial dysfunction in adult male offspring but not in females. This study investigated whether the GIH-exposed female offspring, a "protected" group against the hypertensive effects of maternal GIH exposure, exhibit increased susceptibility to hypertension and cardiovascular dysfunction when fed a high-fat high-sucrose (HFHS) diet and whether this effect could be reversed by pharmacological intervention activating the angiotensin II type 2 receptor (AT2R). Methods:Female offspring of control and GIH-exposed (10.5% O2, 8 h/d, E10-21) dams were assigned either an HFHS diet or a standard diet from 12 weeks of age. Blood pressure was monitored. At 28 weeks, a systemic CGP42112 (AT2R agonist) or saline infusion was administered through the osmotic pump. At 30 weeks, the heart was weighed and collected for H&E staining, mesenteric arteries for vascular reactivity assessment and protein analysis, and plasma for ELISA. Results:The HFHS diet induced similar increases in body weight gain and blood pressure in control and GIH female offspring. HFHS feeding did not affect heart structure, but impaired endothelial-dependent vascular relaxation with associated decreased AT2R and eNOS expression and reduced plasma bradykinin levels in both control and GIH offspring. CGP42112 administration effectively mitigated HFHS-induced hypertension and endothelial dysfunction only in control offspring, accompanied by restored AT2R, eNOS, and bradykinin levels, but not in the GIH counterparts. Conclusion:These findings suggest that GIH induces endothelial dysfunction and AT2R insensitivity in female offspring exposed to an HFHS diet.

Obstructive sleep apnea (OSA), a respiratory sleep disorder associated with cardiovascular diseases, is more prevalent in men. However, OSA occurrence in pregnant women rises to a level comparable to men during late gestation, creating persistent effects on both maternal and offspring health. The exact mechanisms behind OSA-induced cardiovascular diseases remain unclear, but inflammation and oxidative stress play a key role. Animal models using intermittent hypoxia (IH), a hallmark of OSA, reveal several pro-inflammatory signaling pathways at play in males, such as TLR4/MyD88/NF-κB/MAPK, miRNA/NLRP3, and COX signaling, along with shifts in immune cell populations and function. Limited evidence suggests similarities in pregnancies and offspring. In addition, suppressing these inflammatory molecules ameliorates IH-induced inflammation and tissue injury, providing new potential targets to treat OSA-associated cardiovascular diseases. This review will focus on the inflammatory mechanisms linking IH to cardiovascular dysfunction in males, pregnancies, and their offspring. The goal is to inspire further investigations into the understudied populations of pregnant females and their offspring, which ultimately uncover underlying mechanisms and therapeutic interventions for OSA-associated diseases.

ABSTRACT Background Preeclampsia (PE) is one hypertensive disorder and a leading cause of maternal and fetal mortality and morbidity during human pregnancy. Aryl hydrocarbon receptor (AhR) is a transcription factor, which regulates vascular functions. Exogenous and endogenous AhR ligands can induce hypertension in animals. However, if dysregulation of endogenous AhR ligands contributes to the pathophysiology of PE remains elusive. Methods We measured AhR activities in human maternal and umbilical vein sera. We also applied physiological, cellular, and molecular approaches to dissect the role of endogenous AhR ligands in vascular functions during pregnancy using pregnant rats and primary human umbilical vein endothelial cells (HUVECs) as models. Results PE elevated AhR activities in human umbilical vein sera. Exposure of pregnant rats to an endogenous AhR ligand, 2-(1’H-indole-3’-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) increased blood pressure and proteinuria, while decreased uteroplacental blood flow and reduced fetal and placental weights, all of which are hallmarks of PE. ITE dampened vascular growth and fetal sex-specifically altered immune cell infiltration in rat placentas. ITE also decreased cell proliferation and cell monolayer integrity in HUVECs in vitro . RNA sequencing analysis revealed that ITE dysregulated transcriptome in rat placentas and HUVECs in a fetal sex-specific manner. Bottom-up phosphoproteomics showed that ITE disrupted phosphoproteome in HUVECs. These ITE-dysregulated genes and phosphoproteins were enriched in biological functions and pathways which are highly relevant to diseases of heart, liver, and kidney, vascular functions, inflammation responses, cell death, and kinase inhibition. Conclusions Dysregulation of endogenous AhR ligands during pregnancy may lead to the development of PE with underlying impaired vascular functions, fetal sex-specific immune cell infiltration and transcriptome, and phosphoproteome. Thus, this study has provided a novel mechanism for the development of PE and potentially other forms of hypertensive pregnancies. These AhR ligand-activated genes and phosphoproteins might represent promising therapeutic and fetal sex-specific targets for PE-impaired vascular functions.

Background:Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with adverse maternal and fetal outcomes. While placental dysfunction is implicated in PE pathogenesis, the impact of PE on placental lipid metabolism and its potential sexual dimorphism remains poorly understood. Methods:We conducted a comprehensive analysis of term placentas from PE and normotensive pregnancies with male and female fetuses. Lipid profiles were quantified using mass spectrometry, and mRNA expression of genes involved in fatty acid oxidation, esterification, and transport was assessed using qPCR. Results:Placentas from PE pregnancies exhibited elevated lipid levels, with male placentas showing a more pronounced increase in triacylglycerols, cholesteryl esters, and free cholesterol compared to female placentas. Gene expression analysis revealed sexually dimorphic alterations, with male PE placentas exhibiting upregulation of genes involved in fatty acid uptake, oxidation, and esterification, while female PE placentas showed a more complex response with both upregulation and downregulation of certain genes. Notably, peroxisomal fatty acid oxidation was upregulated in male PE placentas but suppressed in female PE placentas. Conclusions:Our findings reveal sexually dimorphic alterations in placental lipid metabolism in PE, suggesting that male placentas may be more vulnerable to lipotoxicity. These insights may have implications for understanding the pathogenesis of PE and developing sex-specific interventions to improve maternal and fetal outcomes.