Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula ؉ DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 ؎ 0.22%wt DHA and 0.62 ؎ 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13 C] ␣ -linolenic acid (LNA*) and [U-13 C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was ‫ف‬ 3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group. These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels. Supplementary key words stable isotope tracers • isotope ratio mass spectrometry • n-3 long-chain polyunsaturated fatty acids • n-6 longchain polyunsaturated fatty acids It is well established that the long-chain polyunsaturated fatty acids (LCPs) docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are required for proper neural development. Mammals can synthesize DHA from linolenic acid (LNA) and ARA from linoleic acid (LA) by a series of elongation and desaturation reactions (1). LNA and LA are considered to be dietary essential fatty acids (FAs) because mammals are incapable of synthesizing these FAs. The n-3 and n-6 FAs are not interconvertible, and it has long been assumed that they compete for the same elongation and desaturation enzymes; it was shown only recently that the ⌬ 6-desaturase, the first step in DHA and ARA biosynthesis from LNA and LA, respectively, operates on both LNA and LA (2). Tracer studies show that preterm and term human infants (3-5) as well as term and fetal baboons (6-8) convert LNA to DHA and LA to ARA.The most intense period of human brain growth is from ‫ف‬ 28 weeks gestation to 18 months after birth, during which time brain DHA accretion peaks (9). Premature infants born at 28 weeks now routinely survive but have very little adipose tissue stores compared with infants born at term and must obtain all FAs from their diets rather than via placental transfer. Those consuming unsupplemented formula ...

Clinical studies show that docosahexaenoic acid (DHA) and arachidonic acid (ARA) supplemented formula improve visual function in preterm infants, however improved fatty acid status is known only for plasma and red blood cells (RBC) since target organs cannot be sampled from humans. Baboons were randomized to one of four groups: Term breast-fed (B); Term formulafed (TϪ); Preterm formula-fed (PϪ); and Preterm DHA/ARAsupplemented formula-fed (Pϩ). The Pϩ contained 0.61 Ϯ 0.03% DHA and 1.21 Ϯ 0.09% ARA, and breast milk had 0.68 Ϯ 0.22% and 0.62 Ϯ 0.12% as DHA and ARA, respectively. The B and Pϩ groups had significantly higher DHA concentration in all tissues than TϪ and PϪ. The PϪ group showed dramatically lower DHA content of 35%, 27%, 66%, and 75% in the brain, retina, liver, and plasma, respectively, compared with B. Supplementation prevented declines in DHA levels in the retina, and liver, and attenuated the decline in brain, plasma and RBC of preterm animals. In contrast, ARA was not significantly lower compared with B in any group in any tissue but was significantly elevated in liver and brain. RBC and plasma DHA were correlated with DHA in tissues; RBC/plasma ARA were uncorrelated with tissue ARA. We conclude that 1) DHA drops precipitously in term and preterm primates consuming formula without long chain polyunsaturates, while 22:5n-6 concentration rises; 2) tissue ARA levels are insensitive to dietary LCP supplementation or prematurity, 3) plasma and RBC levels of ARA are uncorrelated with total ARA levels; 4) DHA levels are correlated with group effects and are uncorrelated within groups. -6) B, breast-fed CS, cesarean section DHA, docosahexaenoic acid (22:6n-3) EDTA, ethylenediaminetetraacetic acid FA, fatty acid FAME, fatty acid methyl ester GC, gas chromatography LA, linoleic acid (18:2n-6) LCP, (Ն20 carbons) long-chain polyunsaturated fatty acids LNA, ␣-linolenic acid (18:3n-3) PC, phosphatidylcholine PE, phosphatidylethanolamine PI, phosphatidylinositol PL, phospholipids PUFA, polyunsaturated fatty acid RBC, red blood cells Docosahexaenoic acid (DHA, 22:6n-3) is the major n-3 long chain polyunsaturated fatty acid (LCP) in the CNS of humans and nonhuman primates. DHA deficiency induced by severe dietary restriction of n-3 fatty acids has long been known to produce characteristic functional deficits, including impaired electroretinograms and visual-evoked potential responses, and poorer visual acuity (1). Very premature human infants were the first pediatric group for which DHA was hypothesized to be conditionally essential, largely because the beginning of accelerated brain growth at about 28 wk gestation coincides with the conceptual birth age at which survival exceeds 50% (2). Early studies show that preterm infants consuming formulas containing DHA precursors but no DHA itself have poorer visual acuity than those who were supplemented with DHA (3-5). Received October 8, 2002; accepted February 13, 2003. Correspondence: J. Thomas Brenna, Cornell University, Savage Hall, Ithaca, NY 14853; e-mail: j...

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are commonly added to infant formula worldwide; however, dietary concentrations needed to obtain optimal tissue levels have not been established. Hence, we studied tissue responses in piglets fed various doses of DHA and ARA. Doses were 0, 1, 2, and 5 times those used in U.S. infant formulas and DHA/ARA in Diet 0, Diet 1, Diet 2, and Diet 5 were 0, 4.1/8.1, 8.1/16.2, and 20.3/40.6 mg/100 kJ formula, respectively. Supplementation of dietary DHA and ARA increased DHA in brain, retina, liver, adipose tissue, plasma, and erythrocyte by 1.1- to 25.8-fold of Diet 0 (P-trend < 0.01). Tissue ARA (1.1- to 6.0-fold of Diet 0) responded to dietary ARA in liver, adipose tissue, plasma, and erythrocytes (P-trend < 0.05); brain and retina ARA was, however, unresponsive to dietary DHA and ARA. Plasma and erythrocyte DHA were positively associated with DHA in neural (brain and retina) and visceral (liver and adipose) tissues (r(2) = 0.11-0.56; P < 0.001-P = 0.042). Plasma and erythrocyte ARA did not correlate with neural ARA. Only plasma ARA was associated with liver ARA (r(2) = 0.222; P = 0.02) and adipose ARA (r(2) = 0.867; P < 0.001) and erythrocyte ARA correlated with adipose ARA (r(2) = 0.470; P < 0.001). We conclude that dietary DHA supplementation affords an effective strategy for enhancing tissue DHA, ARA in visceral but not neural tissues is sensitive to dietary ARA, and erythrocyte and plasma DHA can be used as proxies for tissue DHA, although blood-borne ARA is not an indicator of neural ARA.

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The results show that dietary vitamin E effectively prevented lipid peroxidation at the LCP concentrations investigated and suggest that levels presently in infant formulas are sufficient.