Biology subjects

Steane, S. E.

Publications and source records attributed to Steane, S. E..

3 recordsLinked to original sources

bioRxiv2023

An allele-resolved nanopore-guided tour of the human placental methylome

The placenta is a temporary organ present during pregnancy that is responsible for coordinating all aspects of pregnancy between the mother and fetus. It has a distinct epigenetic, transcriptomic, and mutational landscape with low levels of methylation, high numbers of transcribed loci, and a high mutational burden relative to somatic tissues. We present this landscape through the application of nanopore sequencing technology to provide a more comprehensive picture of female placental genomics and methylomics along with integrated haplotype-resolved transcriptomic analyses across eight trios. Whole genome sequencing of trios allows robust phasing, permitting comprehensive genome-wide investigation of parent-of-origin methylation and transcription. This enhanced view facilitates identifications of many new differentially methylated regions (DMRs), both conserved and differing between individuals, as well as novel imprinted genes including ILDR2 and RASA1 which are potentially important for healthy placental and fetal development.

genomics↗

bioRxiv2020

Sotagliflozin, a dual SGLT1/2 inhibitor, improves cardiac outcomes in a mouse model of early heart failure without diabetes

AimsSelective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in non-diabetic and diabetic mice with cardiac pressure overload. Methods and ResultsFive-week old male C57BL/6J mice were randomized to receive a high fat diet (HFD; 60% of calories from fat) to induce diabetes or remain on normal diet (ND) for 12 weeks. Transverse aortic constriction (TAC) was then employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in features representative of heart failure with preserved ejection fraction. At five weeks into the dietary protocol, mice were treated for seven weeks by oral gavage once daily with sotagliflozin (10mg/kg body weight) or vehicle (0.1% tween 80). In ND non-diabetic mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilisation nor increased cardiac ketolysis. In HFD diabetic mice, sotagliflozin did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound diuresis and glucosuria, which may have compromised drug action and subsequent cardio-protection. ConclusionWe demonstrate the utility of dual SGLT1/2 inhibition in treating heart failure risk factors in the non-diabetic state. Its efficacy in high fat-induced diabetes with proximal tubular damage requires further study.

pharmacology and toxicology↗

bioRxiv2019

Prenatal alcohol exposure programs offspring disease: Impacts on metabolic health and dietary preference in a rat model of acute exposure

Alcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and program chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague-Dawley rats received an oral gavage of ethanol (1g/kg maternal body weight, n=9 dams) or an equivalent volume of saline (control, n=8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05-0.06% 1h post-gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6-month old offspring (P>0.5). However, there was evidence of insulin resistance in PAE male offspring at 6 months of age, with significantly elevated fasting plasma insulin (P = 0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge (P = 0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls (P = 0.04). These data suggest that a relatively low-level, acute PAE programs metabolic dysfunction in offspring in a sex-specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long-term health of offspring.\n\nKey points summaryO_LIPrenatal alcohol exposure has the potential to affect fetal development and program chronic disease in offspring.\nC_LIO_LIPrevious preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour.\nC_LIO_LIIn this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring.\nC_LIO_LIAlthough female offspring were relatively unaffected, there was evidence of insulin resistance in 6-month old male offspring exposed to prenatal alcohol, suggestive of a pre-diabetic state.\nC_LIO_LIThis result suggests that even a relatively low-dose, acute exposure to alcohol during pregnancy can still program metabolic dysfunction in a sex-specific manner.\nC_LI

developmental biology↗