Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

Pereira-Carvalho, D.; Valim, A. C. C.; Andrade, C. B. V.; Bloise, E.; Dias, A. F.; Nascimento, V. M. O.; da Silveira, F. L. B.; Medeiros, I.; Coelho, S. V. A.; Arruda, L. B.; Todeschini, A. R.; Dias, W. B.; Ortiga-Carvalho, T. M.

doi:10.1101/2023.03.30.534997

bioRxiv · 10.1101/2023.03.30.534997

Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways

Pereira-Carvalho, D.·Valim, A. C. C.·Andrade, C. B. V.·Bloise, E.·Dias, A. F.·Nascimento, V. M. O.·da Silveira, F. L. B.·Medeiros, I.·Coelho, S. V. A.·Arruda, L. B.·Todeschini, A. R.·Dias, W. B.·Ortiga-Carvalho, T. M.

View original source ↗Export metadata ↓

Abstract

Maternal Zika virus (ZIKV) infection during pregnancy can associate with severe intrauterine growth restriction (IUGR), placental damage, and metabolism disturbance, as well as newborn neurological abnormalities. Here, we investigated whether maternal ZIKV infection affects placental nutrient transporters and nutrient-sensitive pathways. Immunocompetent (C57BL/6) mice were injected with Low (103 PFU-ZIKVPE243) and High (5x107 PFU-ZIKVPE243) ZIKV titers at gestational day (GD) 12.5, for tissue collection at GD18.5 (term). Feto-placental growth of male fetuses was dramatically affected by ZIKV, whereas no differences were observed in female fetuses. ZIKV promoted increased expression of glucose transporter type 1 (Slc2a1/Glut1) and decreased levels of glucose-6-phosphate in female placentas, with no differences in amino-acid transport potential. In contrast, glucose transport in male placentas was not affected by ZIKV, whilst a decreased placental protein expression of sodium-coupled neutral amino acid 2 (Snat2) was detected in the male low-dose ZIKV-infected group. There were also sex-dependent differences in the hexosamine biosynthesis pathway (HBP) and O-GlcNAcylation in ZIKV infected pregnancies, showing that ZIKV can cause disturbance in the nutrient handling in the placental tissue. Our findings thus identify relevant molecular alterations in the placenta caused by maternal ZIKV infection related to nutrient transport and availability. Notably, our results suggest that female and male placentas adopt different strategies to cope with the altered metabolic state caused by ZIKV. This may have relevance for understanding the effects of congenital Zika syndrome and could potentially assist future therapeutic strategies. Author SummaryThe Zika virus (ZIKV) has emerged as a major global health concern in the past decade. ZIKV infection during pregnancy can cause infants to be born with microcephaly and fetal growth restriction, among other pregnancy complications. Currently, the number of cases of ZIKV disease declined onwards globally. However, transmission persists at low levels in several countries in the Americas and other endemic regions, with neither a licensed vaccine nor an antiviral drug available for prevention and treatment. Here, we use a mice model of maternal ZIKV infection to analyze placental nutrient transporters and nutrient-sensitive pathways as a potential link to the complications related to congenital ZIKV infection. We found that feto-placental growth of male fetuses was dramatically affected by ZIKV, whereas no differences were observed in female fetuses. We also found that placental nutrient transporters and nutrient-sensitive pathways were altered in response to ZIKV infection, depending on the fetal sex. Our study presents relevant molecular alterations caused by maternal ZIKV infection and suggests that female and male placentas adopt different strategies in response to the altered environment caused by ZIKV. Our observations may have relevance for understanding the effects of ZIKV infection and could potentially assist future therapeutic strategies.

Source connections

Published article ↗

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Pereira-Carvalho, D., Valim, A. C. C., Andrade, C. B. V., Bloise, E., Dias, A. F., Nascimento, V. M. O., da Silveira, F. L. B., Medeiros, I., Coelho, S. V. A., Arruda, L. B., Todeschini, A. R., Dias, W. B., Ortiga-Carvalho, T. M.. 2023-04-03. Sex-specific effect of antenatal Zika virus infection on murine fetal growth, placental nutrient transporters, and nutrient sensor signaling pathways. https://doi.org/10.1101/2023.03.30.534997

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗

bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗

bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗