Maternal diet-induced obesity during pregnancy alters lipid supply to mouse E18.5 fetuses and changes the cardiac tissue lipidome in a sex-dependent manner

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in late gestation E18.5 fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female fetal heart lipidomes are more sensitive to maternal obesity than males; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.

Maternal Supplementation of Saccharomyces cerevisiae boulardii during Late-Gestation through Lactation Differentially Modulated Immune Status and Stress Responsiveness of the Progeny to Farrowing and Weaning Stressors

The study aimed to investigate and characterize the maternal effects of feeding Saccharomyces cerevisiae var. boularddii (Scb) to sows from late-gestation through lactation on progeny cortisol, immune status, and stress responsiveness from birth to 14 days post-weaning. Eighty-four piglets were born to sows fed control (CON) or probiotic (PRO) boluses twice daily for 59 days. Blood samples were obtained at birth and 24 h later to assess prenatal effects; 7, 14, and 21 day-of-age to assess potential developmental effects; and at 24 h, 7, and 14 days post-weaning to assess the effects of weaning stress on immune and cortisol responses. Pigs born to PRO sows had less robust cortisol response and enhanced immune parameters at birth and 24 h later, indicating less stress. In response to weaning, pigs born to and nursed by PRO sows displayed unique cortisol and immune profiles than CON pigs. These results indicate that feeding sows Scb probiotics during late gestation reduces stress responsiveness to farrowing stress while increasing immune cell populations. Pigs nursed by PRO sows had a more robust initial cortisol response and enhanced neutrophil function and B-cell lymphocyte proliferation in response to weaning stress. These data imply it may be possible to maternally alter immune and stress responses in utero and during suckling in the short-term and up to 14 days post-weaning. However, more research is needed to optimize this strategy.

Characterizing the effect of incrementally increasing dry bulb temperature on linear and nonlinear measures of heart rate variability in non-pregnant, mid-gestation, and late-gestation sows

Characterizing the sow physiological response to an increased heat load is essential for effective heat stress mitigation. The study objective was to characterize the effects of a 400-min heating episode on sow heart rate variability (HRV) at different reproductive stages. Heart rate variability is a commonly used non-invasive proxy measure of autonomic function. Twenty-seven sows were enrolled in the study according to their gestation stage at time of selection: 1) non-pregnant (NP; n = 7), 2) mid-gestation (MID; 57.3 ± 11.8 d gestation; n = 11), and 3) late-gestation (LATE; 98.8 ± 4.9 d gestation; n = 8). The HRV data utilized in the study were collected from each pig as the dry bulb temperature in the room increased incrementally from 19.84 ± 2.15 °C to 35.54 ± 0.43 °C (range: 17.1 – 37.5 °C) over a 400-min period. After data collection, one 5-min set of continuous heart rate data were identified per pig for each of nine temperature intervals (19 to 20.99, 21 to 22.99, 23 to 24.99, 25 to 26.99, 27 to 28.99, 29 to 30.99, 31 to 32.99, 33 to 34.99, 35 to 36.99 °C). Mean inter-beat interval length (RR), standard deviation of r-r intervals (SDNN), root mean square of successive differences (RMSSD), high frequency spectral power (HF), sample entropy (SampEn), short-term detrended fluctuation analysis (DFAα1), and three measures (%REC, DET, LMEAN) derived from recurrence quantification analysis were calculated for each data set. All data were analyzed using the PROC GLIMMIX procedure in SAS 9.4. Overall, LATE sows exhibited lower RR than NP sows (P < 0.01). The standard deviation of r-r intervals and RMSSD differed between each group (P < 0.01), with LATE sows exhibiting the lowest SDNN and RMSSD and NP sows exhibiting the greatest SDNN and RMSSD. Late-gestation sows exhibited lower HF than both MID and NP sows (P < 0.0001), greater DFA values than NP sows (P = 0.05), and greater DET compared to MID sows (P = 0.001). Late-gestation also sows exhibited greater %REC and LMEAN compared to MID (P < 0.01) and NP sows (all P < 0.01). In conclusion, LATE sows exhibited indicators of greater autonomic stress throughout the heating period compared to MID and NP sows. However, temperature by treatment interactions were not detected as dry bulb increased. Future studies are needed to fully elucidate the effect of gestational stage and increasing dry bulb temperature on sow HRV.

Mendelian gene identification through mouse embryo viability screening

The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes, and found that the members of the early gestation lethal category show distinctive characteristics and a strong enrichment for genes linked with recessive forms of inherited metabolic disease. Based on these findings, we explored a gene similarity approach for novel gene discovery focused on this subset of lethal genes. Finally, we investigated unsolved cases from the 100,000 Genomes Project recruited under this disease category to look for signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes and highlight two novel candidates with phenotypic overlap between the patients and the mouse knockout.

Role of heme oxygenase in the regulation of the renal hemodynamics in a model of sex dependent programmed hypertension by maternal diabetes

Intrauterine programming of cardiovascular and renal function occurs in diabetes because of the adverse maternal environment. Heme oxygenase 1 (HO-1) and -2 (HO-2) exert vasodilatory, and antioxidant actions, particularly in conditions of elevated HO-1 expression, or deficient nitric oxide levels. We evaluated whether the activity of the heme-HO system is differentially regulated by oxidative stress in the female offspring of diabetic mothers, contributing to the improved cardiovascular function compared to male. Diabetes was induced in pregnant rats by a single dose of Streptozotocin (STZ, 50mg/kg i.p) in late gestation. Three months old male offspring from diabetic mothers (MOD) exhibited higher blood pressure values (BP), higher renal vascular resistance (RVR), worse endothelium -dependent response to Acetylcholine and an increased constrictor response to Phenylephrine, compared to those in aged matched female (FOD), which were abolished by chronic Tempol (1mM) treatment. In anesthetized animals, Stannous mesoporphyrin (SnMP; 40 µmol/kg i.v.) administration, to inhibit HO activity, increased RVR in FOD and reduced glomerular filtration rate in MOD, without altering these parameters in control animals. Compared to MOD, FOD showed lower nitrotirosyne levels, and higher HO-1 protein expression in renal homogenates. Indeed, chronic treatment with Tempol to MOD, prevented elevations in nitrotyrosine levels, and the acute renal hemodynamics response to SnMP. Then, maternal diabetes results in sex specific hypertension, and renal alterations associated to oxidative stress, mainly in adult male offspring, which are reduced in the female offspring, by elevation in HO-1 expression and lower oxidative stress levels.

Reproductive diseases in captive Agoutis (Dasyprocta leporina)

Reproductive diseases have been well documented in domestic livestock such as sheep, goat, cattle and pigs. However, there is very little information on these diseases in the agouti (Dasyprocta leporina). The agouti is used for its meat in South America and the Caribbean. More recently, intensive farming of this animal is being practiced in the Neotropics. There is dearth of information on dystocia and vaginal prolapses in the agouti. This document reports on three cases of reproductive diseases in captive reared agoutis in Trinidad and Tobago. The first case was a female agouti weighing approximately 3 kg that was in the last stage of pregnancy, which was found dead in its cage. The vulva of the mother had the protruding hind-limbs of the fetus. Necroscopic evaluation of carcass revealed little fat tissue and the mother had two fetuses in the right horn of the uterus. Each fetus weighed approximately 200 g. The fetuses were well formed with fur, teeth and eyes. The placenta was attached to each fetus. The pathological findings suggested that dystocia resulted from secondary uterine inertia which was the cause of death of the adult female agouti. The second case was that of an adult female agouti weighing 2.5 kg. This female had given birth to an offspring three weeks prior and was observed to have had a vaginal prolapse. Surgery was performed and the prolapsed vagina was placed back into the pelvic cavity. Further to this intervention, the vagina prolapsed twice. Subsequent to the re-insertion of the vaginal tissue the agouti was euthanized. The third case was also that of a dystocia. However, the fetuses weighed 235 g and 165 g respectively and were in normal presentation, posture and positioning. The fetus however was unable to pass via the vagina and was trapped in the pelvic cavity. This caused secondary uterine inertia which was the cause of death. The causes of reproductive diseases in these cases are unknown but the feeding management and space allowance given to the agouti in late gestation may be contributing factors.

Thermal skin burn in a late gestation period in experimental animals: state of the system “mother-fetus”

Objective. To study the effect of thermal skin burns in experimental animals (rats) on the state of the system “mother-fetus” in a late gestation period.Materials and methods. An experimental study was carried out on 18 female outbred white rats weighing 300–350 g (per 9 rats in the control and experimental groups), which were exposed to third-degree thermal burns with an area of 12 cм2 in a late gestation period. The oxygen transport function and the main blood biochemical markers were studied. The effect of thermal injury on the course of pregnancy was studied.Results. The thermal skin burn in the rats in the late gestation period leads to the development of hypoxia, a decrease in the affinity of hemoglobin for oxygen and metabolic acidosis in the mother’s body. Changes in the blood biochemical markers indicate the presence of endogenous intoxication. In the experimental animal group, a decrease in fetal weight was observed, an increase in the post-implantation fetal death rate was noted.Conclusion. Impaired oxygen homeostasis and endogenous intoxication in skin burns in rats in late gestation periods lead to fetal malnutrition and a qualitative increase in the post-implantation fetal death rate.

Evaluation of maternal-infant dyad inflammatory cytokines in pregnancies affected by maternal SARS-CoV-2 infection in early and late gestation.

Objective: SARS-CoV-2 infection induces significant inflammatory cytokine production in adults, but infant cytokine signatures in pregnancies affected by maternal SARS-CoV-2 are less well characterized. We aimed to evaluate cytokine profiles of mothers and their infants following COVID-19 in pregnancy. Study Design: Serum samples at delivery from 31 mother-infant dyads with maternal SARS-CoV-2 infection in pregnancy (COVID) were examined in comparison to 29 control dyads (Control). Samples were evaluated using a 13-plex cytokine assay. Results: In comparison with controls, interleukin (IL)-6 and interferon gamma-induced protein 10 (IP-10) were higher in COVID maternal and infant samples (p<0.05) and IL-8 uniquely elevated in COVID infant samples (p<0.05). Significant elevations in IL-6, IP-10 and IL-8 were found among both early (1st/2nd Trimester) and late (3rd Trimester) maternal SARS-CoV-2 infections. Conclusions: Maternal SARS-CoV-2 infections throughout gestation are associated with increased maternal and infant inflammatory cytokines at birth with potential to impact long-term infant health.