Mild Choline Deficiency and MTHFD1 Synthetase Deficiency Interact to Increase Incidence of Developmental Delays and Defects in Mice

Folate and choline are interconnected metabolically. The MTHFD1 R653Q SNP is a risk factor for birth defects and there are concerns that choline deficiency may interact with this SNP and exacerbate health risks. 80–90% of women do not meet the Adequate Intake (AI) for choline. The objective of this study was to assess the effects of choline deficiency on maternal one-carbon metabolism and reproductive outcomes in the MTHFD1-synthetase deficient mouse (Mthfd1S), a model for MTHFD1 R653Q. Mthfd1S+/+ and Mthfd1S+/− females were fed control (CD) or choline-deficient diets (ChDD; 1/3 the amount of choline) before mating and during pregnancy. Embryos were evaluated for delays and defects at 10.5 days gestation. Choline metabolites were measured in the maternal liver, and total folate measured in maternal plasma and liver. ChDD significantly decreased choline, betaine, phosphocholine, and dimethylglycine in maternal liver (p < 0.05, ANOVA), and altered phosphatidylcholine metabolism. Maternal and embryonic genotype, and diet-genotype interactions had significant effects on defect incidence. Mild choline deficiency and Mthfd1S+/− genotype alter maternal one-carbon metabolism and increase incidence of developmental defects. Further study is required to determine if low choline intakes contribute to developmental defects in humans, particularly in 653QQ women.

Activation of proneuronal transcription factor Ascl1 in maternal liver ensures a healthy pregnancy

Background & AimsMaternal liver exhibits robust adaptations to pregnancy to accommodate the metabolic needs of developing and growing placenta and fetus by largely unknown mechanisms. We found that achaete-scute homolog-like 1 (Ascl1), a basic helix-loop-helix transcription factor essential for neuronal development, is highly activated in maternal hepatocytes during the second half of gestation in mice.MethodsTo investigate whether and how Ascl1 plays a pregnancy-dependent role, we deleted the Ascl1 gene specifically in maternal hepatocytes from mid-gestation until term.ResultsAs a result, we identified multiple Ascl1-dependent phenotypes. Maternal livers lacking Ascl1 exhibited aberrant hepatocyte structure, increased hepatocyte proliferation, enlarged hepatocyte size, reduced albumin production, and elevated release of liver enzymes, indicating maternal liver dysfunction. Simultaneously, maternal pancreas and spleen and the placenta displayed marked overgrowth; and the maternal ceca microbiome showed alterations in relative abundance of several bacterial subpopulations. Moreover, litters born from maternal hepatic Ascl1-deficient dams experienced abnormal postnatal growth after weaning, implying an adverse pregnancy outcome. Mechanistically, we found that maternal hepatocytes deficient for Ascl1 exhibited robust activation of insulin-like growth factor 2 expression, which may contribute to the Ascl1-dependent phenotypes widespread in maternal and uteroplacental compartments.ConclusionIn summary, we demonstrate that maternal liver, via activating Ascl1 expression, modulates the adaptations of maternal organs and the growth of the placenta to maintain a healthy pregnancy. Our studies reveal Ascl1 as a novel and critical regulator of the physiology of pregnancy.SynopsisHow the maternal liver adapts to pregnancy remains elusive. We found that maternal liver activates the expression of Ascl1, a gene encoding a proneuronal transcription factor, to coordinate the adaptations of maternal organs and the growth of the placenta, enabling a healthy pregnancy and normal postnatal growth of the offspring.Graphical Abstract

Effect of pesticides “Butylcaptax (Russia)” and “Droppa (Russia)” on respiration and oxidative phosphorylation of liver mitochondria of pregnant rats and their embryos

The article provides information on the effect of pesticides - butylcaptax and droppa on respiration and oxidative phosphorylation of liver mitochondria in rat rats and their embryos. It has been shown that butylcaptax and droppa reduce the oxidation of succinate and α-ketoglutarate in the V4*, V3 and Vdnf states and drug conjugation in the liver mitochondria of pregnant animals and their embryos. The most significant inhibition of ADF formation in the respiratory chain of fatal and maternal liver mitochondria occurs via the NAD-dependent pathway, especially when poisoning with butylcaptax on the 19th day of pregnancy. Apparently, inhibition of ADF-stimulated respiration is associated with inhibition of electron transfer along the respiratory chain or is a consequence of inhibition of the transport of phosphate or ADF into mitochondria, which plays a key role in the mechanism of oxidative phosphorylation. A decrease in the conjugation of oxidation and phosphorylation does not create conditions for the accumulation of energy in an utilizable form - in the form of ADF.

Maternal Liver Metabolic Response to Chronic Vitamin D Deficiency Is Determined by Mouse Strain Genetic Background

ABSTRACT Background Liver metabolite concentrations have the potential to be key biomarkers of systemic metabolic dysfunction and overall health. However, for most conditions we do not know the extent to which genetic differences regulate susceptibility to metabolic responses. This limits our ability to detect and diagnose effects in heterogeneous populations. Objectives Here, we investigated the extent to which naturally occurring genetic differences regulate maternal liver metabolic response to vitamin D deficiency (VDD), particularly during perinatal periods when such changes can adversely affect maternal and fetal health. Methods We used a panel of 8 inbred Collaborative Cross (CC) mouse strains, each with a different genetic background (72 dams, 3–6/treatment group, per strain). We identified robust maternal liver metabolic responses to vitamin D depletion before and during gestation and lactation using a vitamin-D-deficient (VDD; 0 IU vitamin D3/kg) or -sufficient diet (1000 IU vitamin D3/kg). We then identified VDD-induced metabolite changes influenced by strain genetic background. Results We detected a significant VDD effect by orthogonal partial least squares discriminant analysis (Q2 = 0.266, pQ2 = 0.002): primarily, altered concentrations of 78 metabolites involved in lipid, amino acid, and nucleotide metabolism (variable importance to projection score ≥1.5). Metabolites in unsaturated fatty acid and glycerophospholipid metabolism pathways were significantly enriched [False Discovery Rate (FDR) &lt;0.05]. VDD also significantly altered concentrations of putative markers of uremic toxemia, acylglycerols, and dipeptides. The extent of the metabolic response to VDD was strongly dependent on genetic strain, ranging from robustly responsive to nonresponsive. Two strains (CC017/Unc and CC032/GeniUnc) were particularly sensitive to VDD; however, each strain altered different pathways. Conclusions These novel findings demonstrate that maternal VDD induces different liver metabolic effects in different genetic backgrounds. Strains with differing susceptibility and metabolic response to VDD represent unique tools to identify causal susceptibility factors and further elucidate the role of VDD-induced metabolic changes in maternal and/or fetal health for ultimately translating findings to human populations.

Effects of QDs exposure on the reproductive and embryonic developmental toxicity in mice at various pregnancy stages

Quantum dots (QDs) have recently attracted considerable attention in the biomedical fields because of their unique and excellent optical properties. However, information on their health effects, particularly in the reproductive system, is limited. The present study focuses on the effects of intravenous injection of CdSe/ZnS QDs on the reproductive system and embryo development at various stages of pregnancy in mice. The CdSe/ZnS QDs intravenously injected in mice during pregnancy accumulated in the maternal liver, uterus and placenta. This accumulation affected the growth and development of the embryo during the early and middle stages of pregnancy. Moreover, genotoxicity to the placenta after exposure to CdSe/ZnS QDs was demonstrated by the increased expression levels of genes related to oxidative stress and apoptosis and the reduced expression levels of genes related to the nutrient and waste transportation. Alterations in the gene expression levels have hindered the transport of metabolites across the placenta, which in turn affected the ability of the fetus to obtain nutrients.

Pre-Conception Avocado Powder Diet Decreases Fetal Viability Despite Increasing Placental Energetics in C57BL/6J Mice

Objectives To investigate the effects of commercial avocado powder (Hass variety) during pre-conception and gestation on metabolic and reproductive aspects of C57BL/6J mice dams. Methods Female C57BL/6J mice were kept on either a control (AIN 93; CON) or avocado (dextrose and sucrose replacement with 25% commercial avocado power; AVO) isoenergetic diet for 6 weeks prior to conception and during pregnancy (n = 8 per group). Body weight and dietary intake were daily recorded. At day 17 of pregnancy (E17), an intraperitoneal glucose tolerance test (IPGTT) was done. At E18, dams were euthanized by cervical dislocation. Blood was collected for lipid analysis. Maternal liver, placental and foetal weights and sexing were recorded. 1H Nuclear Magnetic Resonance metabolomics was performed in maternal liver and placenta. Results Pre-conception body weight was higher in AVO damns despite similar dietary intake. At E1, average weight was similar in both groups, ∼21 g. AVO diet promoted a hypolipidemic effect where dams showed a tendency to reduce triacylglycerol, total cholesterol and VLDL in 27% and LDL in 43%. AVO dams presented a significant 6% increase in the AUC in the IPGTT (P &lt; 0.05). Body weight at E18 of AVO was 16% lower than the CON dams (P &lt; 0.05). Fetal, placental weights and placental efficiency were similar between groups. However, AVO dams had 25% less viable fetuses and more number of reabsorption spots (P &lt; 0.05). Liver metabolite profile from AVO dams were similar to CON, except for a significant 2-fold increase in glucose and 1.6-fold increase in the fumarate: succinate ratio. Placentas from male fetuses were more susceptible to changes in metabolites compared to female's, in both groups. Male placentas from AVO compared to CON dams had significant increase in methionine, phenylalanine and 3-hydroxybutyrate and increased glucose, lactate and glutamate contents (P &lt; 0.09). Female placentas from AVO dams showed higher contents of AMP, IMP (P &lt; 0.05) and lactate (P &lt; 0.09). A significant interaction between diet and sex for choline content was found, with an increase in its content in male placenta from AVO. Conclusions The hypolipidemic effect of AVO diet might have contributed to its negative effects on reproduction. Whilst, placenta from both sexes seem to be energetically competent and with high availability of methyl donors. Funding Sources CAPES and FAPERJ.

Pregnancy facilitates maternal liver regeneration after partial hepatectomy

Liver resection induces robust liver regrowth or regeneration to compensate for the lost tissue mass. In a clinical setting, pregnant women may need liver resection without terminating pregnancy in some cases. However, how pregnancy affects maternal liver regeneration remains elusive. We performed 70% partial hepatectomy (PH) in nonpregnant mice and gestation day 14 mice, and histologically and molecularly compared their liver regrowth during the next 4 days. We found that compared with the nonpregnant state, pregnancy altered the molecular programs driving hepatocyte replication, indicated by enhanced activities of epidermal growth factor receptor and STAT5A, reduced activities of cMet and p70S6K, decreased production of IL-6, TNFα, and hepatocyte growth factor, suppressed cyclin D1 expression, increased cyclin A1 expression, and early activated cyclin A2 expression. As a result, pregnancy allowed the remnant hepatocytes to enter the cell cycle at least 12 h earlier, increased hepatic fat accumulation, and enhanced hepatocyte mitosis. Consequently, pregnancy ameliorated maternal liver regeneration following PH. In addition, a report showed that maternal liver regrowth after PH is driven mainly by hepatocyte hypertrophy rather than hyperplasia during the second half of gestation in young adult mice. In contrast, we demonstrate that maternal liver relies mainly on hepatocyte hyperplasia instead of hypertrophy to restore the lost mass after PH. Overall, we demonstrate that pregnancy facilitates maternal liver regeneration likely via triggering an early onset of hepatocyte replication, accumulating excessive liver fat, and promoting hepatocyte mitosis. The results from our current studies enable us to gain more insights into how maternal liver regeneration progresses during gestation. NEW & NOTEWORTHY We demonstrate that pregnancy may generate positive effects on maternal liver regeneration following partial hepatectomy, which are manifested by early entry of the cell cycle of remnant hepatocytes, increased hepatic fat accumulation, enhanced hepatocyte mitosis, and overall accelerated liver regrowth.