Yoeju Min

The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants

The risk of central nervous, visual, and auditory damage increases from 2/1000 live births in the normal birthweight to >200/1000 as birthweight falls below 1500 g. Such babies are most likely to be born preterm. Advances in infant care have led to increasing numbers of very-low-birthweight, preterm infants surviving to school age with moderate to severe brain damage. Steroids are one of the current treatments, but they cause significant, long-term problems. The evidence reported here suggests an additional approach to protecting the very preterm infant by supporting neurovascular membrane integrity. The complications of preterm, very-low-birthweight babies include bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular hemorrhage, periventricular leukomalacia, and necrotizing enterocolitis, all of which have a vascular component. Arachidonic acid (AA) and DHA are essential, structural, and functional constituents of cell membranes. They are especially required for the growth and function of the brain and vascular systems, which are the primary biofocus of human fetal growth. Molecular dynamics and experimental evidence suggest that DHA could be the ligand for the retinoid X receptor (RXR) in neural tissue. RXR activation is an obligatory step in signaling to the nucleus and in the regulation of gene expression. Very preterm babies are born with minimal fat stores and suboptimal circulating levels of these nutrients. Postanatally, they lose the biomagnification of the proportions of AA and DHA by the placenta for the fetus. No current nutritional management repairs these deficits. The placental biomagnification profile highlights AA rather than DHA. The resultant fetal FA profile closely resembles that of the vascular endothelium and not the brain. Without this nourishment, cell membrane abnormalities would be predicted. We present a scientific rationale for a common pathogenic process in the complications of prematurity.

Blood fatty acid composition of pregnant and nonpregnant Korean women: Red cells may act as a reservoir of arachidonic acid and docosahexaenoic acid for utilization by the developing fetus

Relative fatty acid composition of plasma and red blood cell (RBC) choline phosphoglycerides (CPG), and RBC ethanolamine phosphoglycerides (EPG) of pregnant (n=40) and nonpregnant, nonlactating (n=40), healthy Korean women was compared. The two groups were of the same ethnic origin and comparable in age and parity. Levels of arachidonic (AA) and docosahexaenoic (DHA) acids were lower (P<0.05) and palmitic and oleic acids higher (P<0.0001) in plasma CPG of the pregnant women. Similarly, the RBC CPG and EPG of the pregnant women had lower AA and DHA (P<0.05) and higher palmitic and oleic acids (P<0.01). The reduction in DHA and total n−3 fatty acids in plasma CPG of the pregnant women was paralleled by an increase in docosatetraenoic (DTA) and docosapentaenoic (DPA) acids of the n−6 series and in DPA/DTA ratio. In the RBC phospholipids (CPG and EPG) of the pregnant women, DTA and DPA acids of the n−6 series and DPA/DTA ratio did not increase with the decrease of the n−3 metabolites (eicosapentaenoic acid, DPA, and DHA) and total n−3. Since pregnancy was the main identifiable variable between the two groups, the lower levels of AA and DHA in RBC CPG and EPG of the pregnant women suggest that the mothers were mobilizing membrane AA and DHA to meet the high fetal requirement for these nutrients. It may also suggest that RBC play a role as a potential store of AA and DHA and as a vehicle for the transport of these fatty acids from maternal circulation to the placenta to be utilized by the developing fetus.

Adverse effect of obesity on red cell membrane arachidonic and docosahexaenoic acids in gestational diabetes

Aims/hypothesisGestational diabetes is a metabolic disorder affecting 2–5% of women and is a predictor of obesity, Type 2 diabetes mellitus and cardiovascular disease. Insulin resistance, a characteristic of gestational diabetes and obesity, is correlated with the fatty acids profile of the red cell and skeletal muscle membranes. We investigated the plasma and red cell fatty acid status of gestational diabetes. The effect of obesity on membrane fatty acids was also examined.MethodsFasting blood obtained at diagnosis was analysed for the fatty acids in plasma choline phosphoglycerides and red cell choline and ethanolamine phosphoglycerides.ResultsThere were reductions in arachidonic acid (controls 10.74±2.35 vs gestational diabetes 8.35±3.49, p<0.01) and docosahexaenoic acid (controls 6.31±2.67 vs gestational diabetes 3.25±2.00, p<0.0001) in the red cell choline phosphoglycerides in gestational diabetes. A similar pattern was found in the ethanolamine phosphoglycerides. Moreover, the arachidonic and docosahexaenoic acids depletion in the red cell choline phosphoglycerides was much greater in overweight/obese gestational diabetes (arachidonic acid=7.49±3.37, docosahexaenoic acid=2.98±2.18, p<0.01) compared with lean gestational diabetes (arachidonic acid=10.03±2.74, docosahexaenoic acid=4.18±1.42).Conclusion/interpretationApparently normal plasma choline phosphoglycerides fatty acids profile in the gestational diabetic women suggested that membrane lipid abnormality is associated specifically with perturbation in the membrane. The fact that the lipid abnormality is more pronounced in the outer leaflet of the membrane where most of receptor binding and enzyme activities take place might provide an explanation for the increased insulin resistance in gestational diabetes and obesity.

Type 1 diabetes compromises plasma arachidonic and docosahexaenoic acids in newborn babies

The activity of Δ6- and Δ5-desaturase, enzymes required for the synthesis of AA and DHA, are impaired in human and experimental diabetes. We have investigated whether neonates of type 1 diabetic women have compromised plasma AA and DHA at birth. Cord blood was obtained from healthy babies born to mothers with (n=31) and without (n=59) type 1 diabetes. FA composition of plasma choline phosphoglycerides (CPG), TG, and cholesterol esters (CE) was assayed. The neonates of the diabetics had lower levels of AA (20∶4n−6, P<0.0001), adrenic acid (22∶4n−6, P<0.01), Σn−6 metabolites (P<0.0001), docosapentaenoic acid (22∶5n−3, P<0.0001), DHA (22∶6n−3, P<0.0001), Σn−3 (P<0.0001), and Σn−3 metabolites (P<0.0001) in CPG compared with the corresponding babies of the nondiabetic mothers. Similarly, they had lower levels of AA (P<0.05), Σn−6 metabolites (P<0.05), DHA (P<0.0001), and Σn−3 metabolites (P<0.01) in plasma CE. There was also a nonsignificant reduction of AA and DHA in TG in the babies of the diabetic group. The current investigation indicates that healthy neonates born to mothers with type 1 diabetes have highly compromised levels of AA and DHA. These nutrients are of critical importance for neurovisual and vascular system development. In poorly controlled maternal diabetes, it is conceivable that the relative “insufficiency” of AA and DHA may exacerbate speech and reading impairments, behavioral disorders, suboptimal performance on developmental tests, and lower IQ, which have been reported in some children born to mothers with type 1 diabetes mellitus. Further studies are needed to understand the underlying mechanism for this biochemical abnormality and its implications for fetal and infant development.

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

Objective: The polyunsaturated fatty acids, arachidonic (AA) and docosahexaenoic (DHA), are vital structural and functional components of the neural, vascular and visual systems. There is increased demand for these fatty acids during pregnancy. Diabetes impairs the synthesis of both AA and DHA. We have investigated the possibility that pregnancy-induced diabetes compromises the levels of plasma AA and DHA in newly diagnosed expectant mothers.Design: Cross-sectional study.Setting: London, UK.Subjects and methods: Venous blood was obtained from 44 women with gestational diabetes mellitus (GDM) and from the same number of nondiabetics, during the third trimester. Fatty acid composition of plasma choline phosphoglycerides (CPG), triglycerides (TG) and cholesterol esters (CE) was analysed.Results: The GDM women had higher levels of AA (20:4n-6; P<0.0001) and AA/linoleic acid ratio (20:4n-6/18:2n-6; P<0.01) in the CPG, and linoleic acid (LA; P<0.0001), total n-6 (P<0.01), DHA (P<0.05) and n-3 metabolites (P<0.05) in TG compared to their nondiabetic counterparts. Similarly, AA (P<0.0001), osbond acid (22:5n-6; P<0.05), total n-6 metabolites (P<0.0001), AA/LA (P<0.0001) and n-6 metabolites/LA (P<0.01) were higher in the CE of the GDM women. There was no difference in the levels of DHA in CPG and CE between the two groups (P>0.05).Conclusions: The results of this study do not provide evidence that the activity of delta-6 or delta-5 desaturases, which are vital for the synthesis of AA and DHA, is compromised by pregnancy-induced diabetes. However, since the samples were taken at diagnosis, it is conceivable that the duration of the diabetes was too short to have a discernable adverse effect on the levels of AA and DHA in plasma lipids.Sponsorship: Diabetes UK, March of Dimes Birth Defect Foundation, and the Mother and Child Foundation.

Effect of storage temperature and length on fatty acid composition of fingertip blood collected on filter paper

We have compared the fatty acids of the capillary and venous whole blood samples collected on the commercially developed blood collection paper and standard grade filter paper extracted by either the direct methylation or conventional method (including various blood lipids fractions). Also, reproducibility of fatty acids extracted from dried blood on the filter paper after storing at room temperature up to 2 months and at 4°C up to 6 months was assessed. In conclusion, the direct methylation of fingertip blood collected on both brand of papers produced fatty acids that reflected venous blood fatty acids extracted by the conventional method. Of the eight fatty acids evaluated, capillary DHA showed the strongest correlation with DHA of the venous whole lipids as well as various lipid fractions of the plasma and red cells. However, a prolonged storage of blood samples at 4°C had deleterious effect on the qualitative value of fatty acids, especially DHA.

Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women.

Aims  Intrauterine exposure to diabetes is a significant determinant of the development of obesity and early onset of Type 2 diabetes mellitus in the offspring. Both conditions are characterized by insulin resistance and the latter is associated with reduced membrane arachidonic and docosahexaenoic acids. Hence, we investigated if the membrane arachidonic and docosahexaenoic acids are depressed in the cord blood of babies born to women with gestational diabetes.

Arachidonic and docosahexaenoic acids are strongly associated in maternal and neonatal blood.

Background: The red cell membrane fatty acid composition has frequently been used as an index of essential fatty acid (EFA) nutrition. After birth there is a decline in plasma arachidonic acid (AA) and docosahexaenoic (DHA) acids in babies fed on conventional formula which contains only the parent linoleic and α-linolenic acids. In human studies, the red cell phosphoglyceride composition appears to be more constant than that of plasma. In infants fed fish oil without AA, the AA proportions fall in the plasma but much less so in the red cells. This result might be considered to mean that there is no need for preformed AA. On the other hand, in a study where the levels of AA fell there was reduction of infant growth. Indeed, where cell membrane composition does change there is often an associated alteration in physiological functions of membranes. We therefore felt it worth investigating the balance between AA and DHA in a physiological situation where plasma levels are known to change, namely in pregnancy.Purpose: The aim of the study was to investigate a relationship between blood phosphoglyceride AA and DHA in pregnant women and neonates.Subjects: Health pregnant women from London, England (n=193) and their term babies (n=45); healthy pregnant women from Seoul, South Korea (n=40) and their term babies (n=40); and preterm neonates (n=72) from London.Method: Blood samples were taken from British and Korean pregnant women during the third trimester, and from term and preterm babies at birth. These samples were taken for routine monitoring purposes in Korea and were a part of a study on pregnancy outcome for which ethical permission was granted from the East London and The City Health Authority and Lambeth, Southwark and Lewisham Health Authority. Approval was also obtained from the Ethical Committee of the Asan Medical Centre, Seoul, South Korea.Results: AA and DHA correlated in plasma choline phosphoglycerides (CPG) of the British mothers (r=0.52 P<0.0001). The correlation coefficients and significance were much stronger in the red cell CPG and even more so in the term and preterm infant red cell CPGs ( r=0.75, 0.80 and 0.88, respectively). Similarly, AA and DHA correlated in red cell CPGs of the Korean women and their term babies. There was also a significant relationship between the two fatty acids in red cell ethanolamine phosphoglycerides in the mothers and their babies. Both linoleic (LA) and α-linolenic acids (ALA) were inversely associated with AA and DHA in some of the phosphoglyceride fractions of the mothers and babies.Conclusions: Although AA and DHA have different primary dietary origins, there were significant relationships between AA and DHA in the phosphoglycerides of the red cell membrane. This finding seems surprising if the red cell composition is determined by diet. These results suggest a physiological mechanism which attempts to maintain an appropriate balance between AA and DHA. It is plausible that there is an optimum balance between AA and DHA for membrane stability, deformability, enzyme and receptor function.Sponsorship: The British Diabetic Association, March of Dimes Birth Defects Foundation and The Christopher H.R. Reeves Charitable Trust.European Journal of Clinical Nutrition (2000) 54, 50–56

Pregnancy reduces arachidonic and docosahexaenoic in plasma triacylglycerols of Korean women.

Plasma triacylglycerol (TG) fatty acid composition of healthy non-pregnant and non-lactating women, expectant mothers and their term neonates from Seoul, South Korea was investigated. They were ethnically homogeneous and the women had comparable age and parity. Blood samples were obtained at recruitment, third trimester and birth from the non-pregnant women, expectant mothers and neonates respectively. Percent levels of linoleic and arachidonic acids and n-6 metabolites and total n-6 were significantly lower in the pregnant women than in the non-pregnant (p < 0.0001). Similarly, there were lower levels of alpha-linolenic (p = 0.033), eicosapentaenoic and docosahexaenoic acids and n-3 metabolites and total n-3 (p < 0.0001) in the expectant mothers. Compared with their mothers, the neonates had higher proportions of dihomo-gamma-linolenic, arachidonic, docosatetraenoic and docosapentaenoic acids and n-6 metabolites (p < 0.0001) and lower linoleic acid (p < 0.0001). Of the n-3 series, alpha-linolenic acid was lower (p < 0.0001) and eicosapentaenoic, docosapentaenoic and docosahexaenoic acids and n-3 metabolites and total n-3 higher (p < 0.0001) in the neonates compared with their mothers. The study reveals that pregnancy is associated with a reduction in the relative levels of plasma triacylglycerol arachidonic and docosahexaenoic acids. Moreover, it indicates that the decline is a manifestation of selective transfer of these fatty acids to the developing fetus.

Milk of northern Sudanese mothers whose traditional diet is high in carbohydrate contains low docosahexaenoic acid

Aim:  The suckling neonates and infants are reliant primarily on the mother for optimal supply of docosahexaenoic acid (DHA). The richest source of preformed DHA is cold‐water oily fish. Although there is paucity of data, existing evidence suggest women with restricted access to these foods have low or marginal DHA status. The aim of the study was to investigate milk fatty acids of Sudanese mothers whose traditional diet is high in carbohydrate and low in fat and gain some insight into the provision of DHA to the suckling offspring.