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Prenatal one carbon metabolism-gene interactions, placenta trace element content and their effect on pregnancy outcomes

  • Autores: José María Colomina Muela
  • Directores de la Tesis: Michelle M. Murphy (dir. tes.)
  • Lectura: En la Universitat Rovira i Virgili ( España ) en 2017
  • Idioma: español
  • Materias:
  • Enlaces
  • Resumen
    • One carbon (1C) metabolism is highly important in foetal development, maternal-placental-foetal unit development and function, and optimal pregnancy outcome. The folate and methionine cycles, betaine homocysteine methyltransferase (BHMT) pathway and related reactions of 1C unit transfer are key components of the 1C metabolic network. These pathways interact and their activity may be modulated by status in the nutrients that regulate them. Nutrients involved in 1C metabolism (including amino acids, osmolytes, B vitamins, nitrogenous bases, phospholipids and methyl donors) are essential for cell proliferation, metabolism, regulation and differentiation. The trace elements, zinc, copper, selenium and iron are also essential. Enzymes and other proteins containing these trace elements are involved in processes such as oxygen transport, respiratory chain, metal detoxification and oxidative stress. The effects of frequent 1C metabolism genetic polymorphisms on 1C metabolism components or whether they are modulated by folate are not clearly understood, especially during pregnancy. There is much interest in the effect of folate because mandatory fortification of flour with folic acid has been implemented in numerous countries but not European countries, among others. Placenta functions include nutrient and metabolite transport, defence against toxicity, as well as endocrine functions. The role of the above trace elements in the placenta is unclear and evidence on determining factors of their concentrations in the placenta is inconsistent. No previous study has investigated whether 1C metabolism affects these.

      The aims of the thesis are to investigate: 1) the effects of frequent maternal 1C metabolism polymorphisms (methylenetetrahydrofolate reductase MTHFR c.665C>T, betaine homocysteine methyltransferase BHMT c.716G>A, reduced folate carrier SLC19A1 c.80G>A and methionine synthase reductase MTRR c.66A>G) on related metabolite concentrations in blood during pregnancy and whether these effects are modulated by folate status.

      2) whether lifestyle, obstetrical and demographic parameters and 1C metabolism affect placental concentrations of zinc, copper, selenium and iron.

      3) whether these polymorphisms or placenta trace element concentrations are associated with adverse pregnancy outcomes such as miscarriage and intrauterine growth restriction (IUGR), or preterm delivery and IUGR.

      The study was based on 617 pregnancies from the Reus-Tarragona Birth Cohort (RTBC), a longitudinal observational pregnancy study including a subset of 212 pregnancies from which placentas were collected plus other 6 placentas of participants recruited at labour with focus on adverse pregnancy outcomes. Lifestyle, biological and obstetrical data was collected from the first trimester throughout pregnancy by questionnaires and from prenatal check-ups. Fasting blood samples were collected at ≤12, 15, 24-27 and 34 gestational weeks (GW). Blood samples from the mother and cord were also collected at labour. Red blood cell (RBC) and plasma folate, and plasma cobalamin were determined by microbiological assays. Gas Chromatography - Mass Spectrometry was used for plasma total homocysteine (tHcy) concentrations, and Liquid Chromatography - tandem Mass Spectrometry for plasma betaine, dimethylglycine (DMG), choline and cotinine. The genotypes of the four polymorphisms were determined in maternal and cord leukocyte DNA by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. Placenta concentrations of zinc, copper and selenium were determined by Inductively Coupled Plasma - Mass Spectrometry, and those of iron by Inductively Coupled Plasma - Optic Emission Spectrometry.

      The tHcy enhancing effect in MTHFR c.665 variant homozygotes was modulated by RBC folate at ≤12 GW and by plasma folate from 15 GW on and in the cord: the MTHFR c.665TT genotype was not associated with elevated (tHcy) during pregnancy when folate status was high. We suggest the modulation by RBC or plasma folate at different stages of pregnancy could be due to the pattern of folic acid supplement use. The BHMT c.716 variant genotypes were associated with lower DMG concentration and ratio DMG/betaine in late pregnancy, but in early pregnancy this was found only with high plasma folate status. We speculate that the activity of the variant BHMT might be lower at the extremes of the folate status distribution. Plasma folate was an independent negative predictor of plasma DMG, supporting the idea that the BHMT pathway is upregulated under low folate status conditions. Plasma/RBC folate and tHcy did not vary with SLC19A1 c.80G>A genotype. Higher plasma tHcy was found in MTRR c.66 variant homozygotes only in early pregnancy. After stratification by folate status the effect was lost in the lowest and highest plasma folate tertiles. We suggest the absence of effect in early pregnancy with low folate status and in mid-late pregnancy might be due to upregulation of the BHMT pathway. We also suggest the absence of effect in early pregnancy with high folate status could be due to reduction of this effect by higher S-adenosyl methionine (SAM) and lower S-adenosyl homocysteine (SAH). More IUGR neonates had the MTHFR c.665 normal homozygote genotype compared to other genotypes. A speculative explanation for this might be that embryos with variant genotypes are less likely to survive when combined with factors leading to IUGR.

      Lower zinc concentrations were found in placentas of male than female neonates. Although the reason is not clear a speculative explanation is that it may be the NBDY g.56811695C>T polymorphism in the X chromosome (important for zinc status in RBCs). Users of supplements containing any of the 4 trace elements in the second and third trimesters had lower placenta copper concentration, and given that most of these supplements contain only iron, we suggest non-haem iron intake redistributes copper from the placenta to the intestine to increase ferroxidase activity at that location. Smoking during pregnancy was associated with higher placenta concentrations of copper and selenium. Birth weight was negatively correlated with placenta zinc, copper and selenium, however, after adjustment this was true only for copper. Unlike selenium, copper was associated with higher IUGR risk after adjustment. In addition to the associations with smoking and birth weight, placenta zinc, copper and selenium were positively correlated and not associated with total, food or supplement intake. All this led us to suggest the levels of these 3 trace elements in the placenta depend mostly on overlapping functions, namely oxidative stress and metal toxicity defence. 1C metabolism was only associated with placenta copper. Plasma cobalamin in early pregnancy was negatively associated with placenta copper and late pregnancy tHcy was positively associated with it. Both associations are unclear but we suggest the mediator of the negative association between tHcy and copper is the placental adenosylhomocysteinase enzyme.

      As major conclusions, with the exception of SLC19A1 c.80G>A, the addressed polymorphisms affect 1C metabolism during pregnancy and their effects are modulated by folate status in different ways in each case. Some of the analysed factors were associated with the 4 trace elements in the placenta, but multivariate models explained very little variability in the observed concentrations. Therefore, other unknown factors, or factors not considered in these models must be involved. The normal allele for MTHFR c.665 in the offspring and placenta copper concentration were positively associated with IUGR risk.

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