Let’s talk about placental sex, baby: Understanding mechanisms that drive female-and male-specific fetal growth and developmental outcomes

It is well understood that sex differences exist between females and males even before they are born. These sex-dependent differences may contribute to altered growth and developmental outcomes for the fetus. Based on our initial observations in the human placenta, we hypothesised that the male prioritises growth pathways in order to maximise growth through to adulthood, thereby ensuring the greatest chance of reproductive success. However, this male-specific “evolutionary advantage” likely contributes to males being less adaptable to shifts in the in-utero environment, which then places them at a greater risk for intrauterine morbidities or mortality. Comparatively, females are more adaptable to changes in the in-utero environment at the cost of growth, which may reduce their risk of poor perinatal outcomes. The mechanisms that drive these sex-specific adaptations to a change in the in-utero environment remain unclear, but an increasing body of evidence within the field of developmental biology would suggest that alterations to placental function, as well as the feto-placental hormonal milieu, is an important contributing factor. Herein, we have addressed the current knowledge regarding sex-specific intrauterine growth differences and have examined how certain pregnancy complications may alter these female- and male-specific adaptations.Ashley S. Meakin, James S. M. Cuffe, Jack R. T. Darby, Janna L. Morrison and Vicki L. Clifto

COVID-19: Can we treat the mother without harming her baby?

First published online: 25 January 2021Medical care is predicated on ‘do no harm’, yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women; a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.Michael D. Wiese, Mary J. Berry, Pravin Hissaria, Jack R.T. Darby, and Janna L. Morriso

Considerations in selecting postoperative analgesia for pregnant sheep following fetal instrumentation surgery

Abstract not availableTamara J. Varcoe, Jack R.T. Darby, Kathryn L. Gatford, Stacey L. Holman, Pearl Cheung, Mary J. Berry, Michael D. Wiese and Janna L. Morriso

Identification of novel miRNAs involved in cardiac repair following infarction in fetal and adolescent sheep hearts

Aims:Animal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to injury. Manipulating these miRNAs in small animal models provides beneficial effects post-MI; however it is not known if these miRNAs are regulated similarly in large mammals. Studying a large animal where the timing of heart development in relation to birth is similar to humans may provide insights to better understand the capacity to repair a developing mammalian heart and its application to the adult heart. Methods:We used a sheep model of MI that included permanent ligation of the left anterior descending (LAD) coronary artery. Surgery was performed on fetuses (at 105 days gestation when all cardiomyocytes are mononucleated and proliferative) and adolescent sheep (at 6 months of age when all cardiomyocytes contribute to heart growth by hypertrophy). A microarray was utilized to determine the expression of known miRNAs within the damaged and undamaged tissue regions in fetal and adolescent hearts after MI. Results:73 miRNAs were up-regulated and 58 miRNAs were down-regulated significantly within the fetal infarct compared to remote cardiac samples. From adolescent hearts 69 non-redundant miRNAs were up-regulated and 63 miRNAs were down-regulated significantly in the infarct area compared to remote samples. Opposite differential expression profiles of 10 miRNAs within tissue regions (Infarct area, Border zone and Remote area of the left ventricle) occurred between the fetuses and adolescent sheep. These included miR-558 and miR-1538, which when suppressed using LNA anti-miRNAs in cell culture, increased cardiomyoblast proliferation. Conclusion:There were significant differences in miRNA responses in fetal and adolescent sheep hearts following a MI, suggesting that the modulation of novel miRNA expression may have therapeutic potential, by promoting proliferation or repair in a damaged heart.Mitchell C. Lock, Ross L. Tellam, Jack R. T. Darby, Jia Yin Soo, Doug A. Brooks, Mike Seed ... et al

Fetal cardiovascular response to acute hypoxia during maternal anesthesia

Preclinical imaging studies of fetal hemodynamics require anesthesia to immobilize the animal. This may induce cardiovascular depression and confound measures under investigation. We compared the impact of four anesthetic regimes upon maternal and fetal blood gas and hemodynamics during baseline periods of normoxia, and in response to an acute hypoxic challenge in pregnant sheep. Merino ewes were surgically prepared with maternal and fetal vascular catheters and a fetal femoral artery flow probe at 105–109 days gestation. At 110–120 days gestation, ewes were anesthetized with either isoflurane (1.6%), isoflurane (0.8%) plus ketamine (3.6 mg·kg−1·h−1), ketamine (12.6 mg·kg−1·h−1) plus midazolam (0.78 mg·kg−1·h−1), propofol (30 mg·kg−1·h−1), or remained conscious. Following 60 min of baseline recording, nitrogen was administered directly into the maternal trachea to displace oxygen and induce maternal and thus fetal hypoxemia. During normoxia, maternal PaO2 was ~30 mmHg lower in anesthetized ewes compared to conscious controls, regardless of the type of anesthesia (p .05), but heart rate was 32 ± 8 bpm lower in fetuses from ewes administered isoflurane (p = .044). During maternal hypoxia, fetal MAP increased, and peripheral blood flow decreased in all fetuses except those administered propofol (p < .05). Unexpectedly, hypoxemia also induced fetal tachycardia regardless of the anesthetic regime (p < .05). These results indicate that despite maternal anesthesia, the fetus can mount a cardiovascular response to acute hypoxia by increasing blood pressure and reducing peripheral blood flow, although the heart rate response may differ from when no anesthesia is present.Tamara J. Varcoe, Jack R. T. Darby, Stacey L. Holman, Emma L. Bradshaw, Tim Kuchel, Lewis Vaughan ... et al

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

Cardiorespiratory consequences of intrauterine growth restriction: influence of timing, severity and duration of hypoxaemia

At birth, weight of the neonate is used as a marker of the 9-month journey as a fetus. Those neonates born less than the 10th centile for their gestational age are at risk of being intrauterine growth restricted. However, this depends on their genetic potential for growth and the intrauterine environment in which they grew. Alterations in the supply of oxygen and nutrients to the fetus will decrease fetal growth, but these alterations occur due to a range of causes that are maternal, placental or fetal in nature. Consequently, IUGR neonates are a heterogeneous population. For this reason, it is likely that these neonates will respond differently to interventions compared not only to normally grown fetuses, but also to other neonates that are IUGR but have travelled a different path to get there. Thus, a range of models of IUGR should be studied to determine the effects of IUGR on the development and function of the heart and lung and subsequently the impact of interventions to improve development of these organs. Here we focus on a range of models of IUGR caused by manipulation of the maternal, placental or fetal environment on cardiorespiratory outcomes.Jack R.T.Darby, Tamara J.Varcoe, Sandra Orgeig, Janna L.Morriso

The reliance on α‐adrenergic receptor stimuli for blood pressure regulation in the chronically hypoxaemic fetus is not dependent on post‐ganglionic activation

Key points: Chronic hypoxaemia is associated with intrauterine growth restriction (IUGR) and a predisposition to the development of hypertension in adult life. IUGR fetuses exhibit a greater reliance on α-adrenergic activation for blood pressure regulation. The fetal blood pressure response to post-ganglionic blockade is not different between control and IUGR fetuses. The decrease in mean arterial pressure is greater in the IUGR sheep fetus after α-adrenergic receptor blockade at the level of the vasculature and this is inversely related to fetal urn:x-wiley:00223751:media:tjp14494:tjp14494-math-0001. The increased reliance that the IUGR fetus has on α-adrenergic activation for maintenance of mean arterial pressure is not a result of increased post-ganglionic sympathetic activation. Abstract: Intrauterine growth restriction (IUGR) is associated with an increased risk of cardiovascular disease in adult life. Placental restriction (PR) in sheep results in chronic hypoxaemia and early onset IUGR with increased circulating plasma noradrenaline concentrations. These IUGR fetuses exhibit a greater decrease in mean arterial pressure (MAP) during α-adrenergic blockade. We aimed to determine the role of post-ganglionic sympathetic activation with respect to regulating MAP in IUGR fetal sheep. PR was induced by carunclectomy surgery prior to conception. Fetal vascular catheterization was performed at 110–126 days gestational age (GA) (term, 150 days) in nine control and seven PR-IUGR fetuses. The fetal blood pressure response to both a post-ganglionic and an α-adrenergic receptor blocker was assessed at 116–120 days GA and/or 129–131 days GA. The effect of both post ganglionic and α-adrenergic blockade on fetal blood pressure was then compared between control and IUGR fetuses at both GAs. There was no difference in the effect of post-ganglionic blockade on MAP in control and IUGR fetal sheep at either 116–120 days GA or 129–131 days GA. α-adrenergic receptor blockade decreased MAP to the same extent in both control and IUGR fetuses at 116–120 days GA. At 129–131 days GA, the drop in MAP in response to α-adrenergic receptor blockade was greater in IUGR fetuses than controls. There was a significant inverse relationship between the drop in MAP in response to α-adrenergic receptor blockade at both GAs with fetal urn:x-wiley:00223751:media:tjp14494:tjp14494-math-0002. Thus, the increased dependence on α-adrenergic activation for blood pressure regulation in the chronically hypoxaemic IUGR fetus is not a result of increased post-ganglionic sympathetic activation.Jack R. T. Darby, Tamara J. Varcoe, Stacey L. Holman, I. Caroline McMillen, Janna L. Morriso

Cardiac growth and metabolism of the fetal sheep are not vulnerable to a 10 day increase in fetal glucose and insulin concentrations during late gestation

Aims: To evaluate the effects of fetal glucose infusion in late gestation on the mRNA expression and protein abundance of molecules involved in the regulation of cardiac growth and metabolism. Main methods: Either saline or glucose was infused into fetal sheep from 130 to 140 days (d) gestation (term, 150 d). At 140 d gestation, left ventricle tissue samples were collected. Quantitative real-time RT-PCR and Western blot were used to determine the mRNA expression and protein abundance of key signalling molecules within the left ventricle of the fetal heart. Key findings: Although intra-fetal glucose infusion increased fetal plasma glucose and insulin concentrations, there was no change in the expression of molecules within the signalling pathways that regulate proliferation, hypertrophy, apoptosis or fibrosis in the fetal heart. Cardiac Solute carrier family 2 member 1 (SLC2A1) mRNA expression was decreased by glucose infusion. Glucose infusion increased cardiac mRNA expression of both Peroxisome proliferator activated receptor alpha (PPARA) and peroxisome proliferator activated receptor gamma (PPARG). However, there was no change in the mRNA expression of PPAR cofactors or molecules with PPAR response elements. Furthermore, glucose infusion did not impact the protein abundance of the 5 oxidative phosphorylation complexes of the electron transport chain. Significance: Despite a 10-day doubling of fetal plasma glucose and insulin concentrations, the present study suggests that within the fetal left ventricle, the mRNA and protein expression of the signalling molecules involved in cardiac growth, development and metabolism are relatively unaffected.Jack R.T. Darby, Song Zhang, Stacey L. Holman, Beverly S. Muhlhausler, I. Caroline McMillen, Janna L. Morriso

In utero substrate restriction by placental insufficiency or maternal undernutrition decreases optical redox ratio in foetal perirenal fat

Intrauterine growth restriction (IUGR) can result from reduced delivery of substrates, including oxygen and glucose, during pregnancy and may be caused by either placental insufficiency or maternal undernutrition. As a consequence of IUGR, there is altered programming of adipose tissue and this can be associated with metabolic diseases later in life. We have utilised two sheep models of IUGR, placental restriction and late gestation undernutrition, to determine the metabolic effects of growth restriction on foetal perirenal adipose tissue (PAT). Two-photon microscopy was employed to obtain an optical redox ratio, which gives an indication of cell metabolism. PAT of IUGR foetuses exhibited higher metabolic activity, altered lipid droplet morphology, upregulation of cytochrome c oxidase subunit genes and decreased expression of genes involved in growth and differentiation. Our results indicate that there are adaptations in PAT of IUGR foetuses that might be protective and ensure survival in response to an IUGR insult.Joanna Lazniewska, Jack R.T. Darby, Stacey L. Holman, Alexandra Sorvina, Sally E. Plush, Massimiliano Massi, Doug A. Brooks, Janna L. Morriso