The Queen's Medical Research Institute

Maternal prenatal depression and anxiety (PDA) have been associated with increased risks of adverse birth and neurodevelopmental outcomes in children. While fetal exposure to too high or low levels of steroid hormones has been proposed as a potential biological mechanism underlying these effects, few studies have directly investigated this hypothesis using fetal tissue samples, and the existing studies have been limited to examining cortisol, cortisone or testosterone. We studied associations between PDA and steroid hormones in amniotic fluid by measuring a panel of 17 steroid hormones - including progestogens, mineralocorticoids, glucocorticoids, androgens and estrogens - and their substrate-to-product ratios in 173 women with singleton pregnancies undergoing amniocentesis during second trimester. The fetuses had no chromosomal abnormalities. We defined any PDA as meeting at least one of the following criteria: reported symptoms above clinical cut off (CES-D ≥20 or STAI state or trait anxiety ≥40) during pregnancy, lifetime diagnosis (ICD-10 codes F31-33, F41-43), and/or lifetime medication purchases (ATC-codes N06A, N05B). Elastic net regression identified two glucocorticoid metabolites, 20α-dihydrocortisol and 5β-tetrahydrocortisol, with lower amniotic fluid levels in fetuses of mothers with PDA compared to those without PDA (unadjusted mean difference -0.37 SD units, 95 % CI: [-0.68, -0.07]; and -0.40 SD units, 95 % CI: [-0.70, -0.10], respectively). The model with both steroids remained significant after adjusting for maternal age, body mass index, education, smoking during pregnancy, parity, gestational age at amniocentesis and fetal sex, and in sensitivity analyses excluding mothers with diabetes and hypertensive disorders (p-values<.05) and was not moderated by fetal sex (p-value>.40). PDA was not significantly associated with any substrate-to-product ratios of the steroids, used as proxies of steroid hormone metabolizing enzymes, after correction for multiple testing. This study provides support for the prenatal programming hypothesis of PDA influencing fetal environment through suboptimal levels of steroid hormones and highlights the need to expand to a comprehensive panel of steroid metabolism.

Abstract Males during mating never transfer just sperm; to the best of our knowledge, they always deliver a rich seminal fluid as well. The proteins in the seminal fluid have an important sperm supporting role, but they also cause changes in the female physiology and can impose a mating cost. The associated costs and delay in the time of remating, lead to the view that those proteins evolved primarily due to sexual conflict and delay female remating beyond the optimal rate. To examine the role of seminal fluid proteins in sexual conflict we use a mathematical model of reproductive physiology, informed by the accumulated knowledge on Drosophila melanogaster . In accordance with the theory, we find that males always benefit from inducing longer remating intervals in females. But, we also find that this conflict is reduced when female reproduction is regulated by the male proteins. Without seminal fluid proteins females have a single, well-defined, optimal remating rate. However, when seminal proteins are used to regulate females reproduction, females can reach the same offspring production for a range of mating intervals. This wider range of possible remating times could provide females with a buffer against uncertain mating opportunity. It could also allow females to be more selective on male quality, by reducing the cost associated with delaying remating. Our results suggest that, while there is a conflict over the remating rate, seminal fluid proteins reduce its intensity, highlighting their role in aligning the interests of both sexes.

The ovarian hormones, oestrogen and progesterone, have vaso- and neuroprotective effects, potentially due to cerebrovascular interactions. This study investigates their neuroendocrine influence on cerebral and retinal baseline vascular metrics across a healthy menstrual cycle. Twenty-six menstruating females completed imaging sessions and assessment of circulating hormone levels during their early follicular, late follicular and mid-luteal phase. Perfusion, arterial arrival time (AAT), global oxygen extraction fraction (OEF), cerebrovascular metabolic rate of oxygen (CMRO2), carotid artery radius and carotid pulsatility index (PI) were measured using 3 T MRI. Retinal vessel density and blood flow resistance were assessed with optical coherence tomography angiography (OCT-A). Assessed with linear models, increased oestradiol was related to increased global perfusion (χ2 (1) = 91.623; p = 1.049 × 10-21) and decreased AAT (χ2 (1) = 106.950; p = 4.575 × 10-25). An independent progesterone increase was also associated with increased global perfusion (χ2 (1) = 19.512; p = 9.998 × 10-6) and decreased AAT (χ2 (1) = 40.062; p = 2.46 × 10-10). A relationship was also found between increased oestradiol and decreased retinal blood flow resistance (χ2 (1) = 5.28; p = 0.0215), primarily driven by centrally localised vessels. This study finds that circulating oestrogen increases blood flow in the eye and brain, while progesterone is associated with brain perfusion increases alone. Both are associated with decreased cortical blood arrival speed. These effects suggest a potential pathway for neuroprotective mechanisms.

Abstract Plastic pollution is a significant ecological challenge of the 21st century. Conventional recycling and disposal strategies remain inadequate, and there is growing interest in biological approaches to counter plastic waste. Here, we discuss insect-based plastic degradation, highlight the potential of cockroaches and their gut microbiota and examine molecular mechanisms, to contribute to the United Nations Sustainable Development Goals. We argue that insects should be considered not only as opportunistic feeders but also as living bioreactors capable of extending their metabolic repertoire through microbial symbiosis.

To compare the associations of HbA1c and continuous glucose monitoring (CGM)-derived average glucose with microvascular complications in adults with type 1 diabetes, and to assess the clinical utility and stability of metrics capturing glycation discordance. Observational assessment of 9023 paired measurements of CGM data (14 days) and HbA1c in 2721 adults with type 1 diabetes. CGM metrics, HbA1c, and markers of discordance between HbA1c and CGM average glucose were associated with prevalent retinopathy (any and proliferative) and microalbuminuria. HbA1c was higher than expected in older individuals (62 mmol/mol [54-71] age >45 vs. 61 mmol/mol [52-71], p = 0.004) and in women (62 mmol/mol [54-71] vs. 61 mmol/mol [53-71], p < 0.001) despite lower or similar average glucose levels. Fewer than one-third of individuals remain within the same HbA1c-average glucose discordance category over time. HbA1c (p < 0.001), average glucose (p < 0.001), CV glucose (p < 0.001), and socioeconomic deprivation (p = 0.003) were all independently associated with retinopathy risk (with similar results for proliferative retinopathy). Higher glycation was associated with a lower likelihood of prevalent retinopathy (p < 0.001). CGM-derived average glucose appears superior to HbA1c as a marker of prevalent microvascular complications. These data challenge the high-glycator hypothesis and also suggest glucose variability may be an independent risk marker for microvascular disease.

Pancreatic cancer (PC) represents one of the biggest challenges in terms of cancer treatment, mainly due to its continuously rising incidence, advanced stage at time of diagnosis, and dismal 5-year overall survival, which has not improved in recent decades despite the major advances made in oncological therapies. The limited progress in developing more effective therapies is, in part, attributable to the vast desmoplastic stroma present in PC. Additionally, immunosuppressive steroid-signalling has recently been shown to aid the development and metastasis of various tumour types. Therefore, we sought to explore whether local steroidogenesis and steroid signalling within the tumour microenvironment (TME) play a role in pancreatic cancer development. Reanalysis of publicly available datasets, including single cell RNA sequencing, as well as in vivo metastatic pancreatic ductal adenocarcinoma (PDAC) mouse models, allowed us to identify Hsd11b1 as the key enzyme responsible for locally elevated levels of the immunosuppressive glucocorticoid hormone, corticosterone. We identified fibroblasts as the major Hsd11b1-expressing populations in the pancreatic TME. Specifically, in mice, Hsd11b1 expression is primarily observed in iCAFs. Additionally, we found that patients with higher HSD11B1 expression present an increased mortality rate as well as an enriched fibrotic signature and inhibited immune activity. Collectively, these findings suggest that Hsd11b1 upregulation in iCAFs could be aiding PDAC development by promoting the activation of glucocorticoids directly in the TME. The presence of glucocorticoids inhibits inflammation and could also be enhancing local fibrosis by autocrine signalling in the fibroblast population. Given the urgent need for effective treatments in this fatal disease, targeting HSD11B1 represents a promising therapeutic strategy to overcome the immunosuppressive desmoplastic barrier and improve patient outcomes in pancreatic cancer.