Biomedical subjects

Norman Salem

Publications and source records attributed to Norman Salem.

At least 19 recordsLinked to original sources

PubMed2007

Loss of functional ELOVL4 depletes very long-chain fatty acids (> or =C28) and the unique omega-O-acylceramides in skin leading to neonatal death.

Mutations in elongation of very long-chain fatty acid-4 (ELOVL4) are associated with autosomal dominant Stargardt-like macular degeneration (STGD3), with a five base-pair (5 bp) deletion mutation resulting in the loss of 51 carboxy-terminal amino acids and truncation of the protein. In addition to the retina, Elovl4 is expressed in a limited number of mammalian tissues, including skin, with unknown function(s). We generated a knock-in mouse model with the 5-bp deletion in the Elovl4 gene. As anticipated, mice carrying this mutation in the heterozygous state (Elovl4(+/del)) exhibit progressive photoreceptor degeneration. Unexpectedly, homozygous mice (Elovl4(del/del)) display scaly, wrinkled skin, have severely compromised epidermal permeability barrier function, and die within a few hours after birth. Histopathological evaluation of the Elovl4(del/del) pups revealed no apparent abnormality(ies) in vital internal organs. However, skin histology showed an abnormally-compacted outer epidermis [stratum corneum (SC)], while electron microscopy revealed deficient epidermal lamellar body contents, and lack of normal SC lamellar membranes that are essential for permeability barrier function. Lipid analyses of epidermis from Elovl4(del/del) mice revealed a global decrease in very long-chain fatty acids (VLFAs) (i.e., carbon chain > or =C28) in both the ceramide/glucosylceramide and the free fatty-acid fractions. Strikingly, Elovl4(del/del) skin was devoid of the epidermal-unique omega-O-acylceramides, that are key hydrophobic components of the extracellular lamellar membranes in mammalian SC. These findings demonstrate that ELOVL4 is required for generating VLFA critical for epidermal barrier function, and that the lack of epidermal omega-O-acylceramides is incompatible with survival in a desiccating environment.

Animals↗

PubMed2006

Omega-3 fatty acids and rodent behavior.

This paper reviews the role of the n-3 fatty acids in the regulation of cognitive functions, locomotor and exploratory activity and emotional status in rodents. There are disparate data on the performance of n-3 fatty acid deficient animals in the open field test and elevated plus maze. Results obtained in our laboratory indicated slower habituation to the open field in deficient mice, which affects total locomotor and exploratory parameters. We also observed no change in plus maze performance of deficient mice under low-stress but elevated anxiety under high-stress conditions. There is some evidence of elevated aggression and increased immobility time in the forced swimming test caused by n-3 fatty acid deficiency in rodents. Effects of n-3 fatty acid deficiency and supplementation on learning in several tests such as the Morris water maze, two odor olfactory discriminations, radial arm maze performance and avoidance tasks are reviewed in detail. There is some evidence of an enhanced vulnerability to stress of n-3 fatty acid deficient animals and this factor can influence performance in a variety of tests. Thus, behavioral tasks that involve a higher level of stress may better differentiate behavioral effects related to brain docosahexaenoic acid (DHA) status. It is suggested that a fruitful area for future investigations of functional alterations related to brain DHA status will be the delineation of the factors underlying changes in performance in behavioral tasks. The possible role of non-cognitive factors like emotionality and attention in the impaired performance of n-3 fatty acid deficient animals also requires further investigation.

Aggression↗

PubMed2006

Compartmental analyses of plasma 13C- and 2H-labeled n-6 fatty acids arising from oral administrations of 13C-U-18:2n-6 and 2H5-20:3n-6 in newborn infants.

Efficacy of (13)C-U-18:2n-6 and (2)H(5)-20:3n-6 toward synthesis of labeled-20:4n-6 was studied in newborn infants utilizing compartmental models of plasma labeled n-6 fatty acids (FA). Ten infants received oral doses of (13)C-U-18:2n-6 and (2)H(5)-20:3n-6 ethyl esters (100 and 2 mg/kg, respectively). Rate constant coefficients and half-lives (t((1/2))) of n-6 FA were determined from the time-course concentrations of labeled-FA. Plasma n-6 FA values approximated steady state concentrations. Synthetic and utilization rates were calculated. Eight percent (range, 2-21%) of plasma (13)C-U-18:2n-6 was used for synthesis of (13)C-18:3n-6, -20:2n-6, and -20:3n-6. Seventy percent of (13)C-20:3n-6 (mean, CV: 0.26) was available for synthesis of (13)C-20:4n-6. The percentage of (2)H(5)-20:3n-6 converted to (2)H(5)-20:4n-6 was lower (mean: 26%, p < 0.02) than the (13)C-labeled analogue. Turnover of 18:2n-6 in subjects and of 20:4n-6 in plasma was 4.2 g/kg/d (CV: 0.58) and 4.3 mg/kg/d (CV: 0.81), respectively. Intake of 18:2n-6 and 20:4n-6 were estimated to be 3.0 g/kg/d (+/-1.7) and 2.8 mg/kg/d (+/- 2.2), respectively. Infants required additional 18:2n-6 and 20:4n-6 (mean: 1.2 g and 1.5 mg/kg/d) above predicted intake amounts to maintain plasma concentrations of 18:2n-6 and 20:4n-6, in order to spare FA from fat stores.

8,11,14-Eicosatrienoic Acid↗

PubMed2006

Effect of docosahexaenoic acid on tissue targeting and metabolism of plasma lipoproteins.

We examined the effect of the docosahexaenoic acid (DHA) content of lipoproteins on their metabolism in vivo by a radioisotope labeling and tracking method. Purified HDL and LDL were labeled with (3)H-cholesteryl oleate tracer. To mimic dietary-related changes in fatty acid composition of lipoproteins, we incorporated lipids acylated with either DHA, arachidonic (AA) or oleic (OA) acid to phosphatidylcholine (didocosahexaenoylphosphatidylcholine (di22:6-PC), diarachidonoylphosphatidylcholine (di20:4-PC) and dioleoylphosphatidylcholine (di18:0-PC), respectively) into the purified particles. The lipids, at the amount added, did not cause detectable alterations in the morphology of the lipoproteins. Levels of radiotracers in blood and in several target tissues such as brain, heart, liver, muscle and adipose were determined at 1.5, 3 and 24h after intravenous injection into C57Bl/6J mice. No statistically significant differences were detected in the tissue distribution of tracers introduced into HDL enriched in DHA, compared to particles enriched with OA. In contrast, we found a significantly higher proportion of radiolabel associated with LDL enriched in DHA in heart, brown adipose and brain tissues. The uptake of labels associated with DHA containing LDL nearly doubled for heart and brown adipose tissues at 1.5 and 3h, and it was 30% higher for brain tissues at 24h. The tissue distribution of labels from the same particles enriched in AA or OA did not show a statistically significant difference from unaltered control lipoproteins. These findings point to the possible role of DHA in the regulation of LDL metabolism and involvement of the lipoproteins in transport of n-3 PUFA to target organs.

Adipose Tissue, Brown↗

PubMed2006

Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease.

PURPOSE: Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS: A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4(+/-) mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS: Although the level of Elovl4 mRNA was reduced in Elovl4(+/-) retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4(+/-) retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4(+/-) mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4(+/-) retinas, particularly the monounsaturated fatty acids. CONCLUSIONS: The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

Animals↗

PubMed2006

Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration.

PURPOSE: To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS: E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS: E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at approximately 10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS: E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.

Animals↗

PubMed2005

Suckling rats actively recycle carbon from alpha-linolenate into newly synthesized lipids even during extreme dietary deficiency of n-3 polyunsaturates.

Docosahexaenoate is usually considered to be the principal endpoint of alpha-linolenate metabolism in mammals. Nevertheless, several studies over the past 30 y have shown that more carbon from alpha-linolenate is recycled into newly synthesized lipids than is used to make docosahexaenoate. Our objective in this study was to assess carbon recycling from alpha-linolenate in suckling rats made deficient in n-3 polyunsaturated fatty acids (PUFA). Female Long-Evans rats were given a diet deficient in n-3 PUFA at weaning and then bred 8 wk later. Pups from the second generation were nursed by their respective dams and gavaged with 1 mg [U-13C]-alpha-linolenate at 10 d old. Brain and liver were obtained 24 h later, and the fatty acid profiles and 13C enrichment analyzed. Docosahexaenoate was markedly depleted in brain (-82%) and liver (-97%) of the n-3 PUFA-deficient rats. In the controls, 13C enrichment in products of carbon recycling (cholesterol and fatty acids other than n-3 PUFA) exceeded that in docosahexaenoate by 2.4-fold (liver) and 7.5-fold (brain). n-3 PUFA deficiency reduced the ratio of 13C enrichment in products of carbon recycling compared with 13C incorporated into docosahexaenoate by 63% in the brain but not in the liver. Despite severe n-3 PUFA deficiency, carbon recycling still consumed 50% more 13C from alpha-linolenate than went into docosahexaenoate in the liver and 2.8-fold more in the brain. We conclude that carbon recycling is an integral part of neonatal metabolism of alpha-linolenate and is not simply an overflow pathway arising from excess availability of preformed docosahexaenoate.

Animals↗

PubMed2005

A solid-phase extraction/high-performance liquid chromatography-based (32)P-postlabeling method for detection of cyclic 1,N(2)-propanodeoxyguanosine adducts derived from enals.

The cyclic 1,N(2)-propanodeoxyguanosine (PdG) adducts are Michael addition products from reactions of deoxyguanosine (dG) with enals, including acrolein (Acr), crotonaldehyde (Cro), pentenal (Pen), heptenal (Hep), and 4-hydroxy-2-nonenal (HNE). Although this is a general reaction, only the PdG adducts derived from Acr, Cro, and HNE have been detected in vivo as endogenous DNA lesions. Our previous in vitro study demonstrated that PdG adducts of Acr, Cro, and Pen are predominantly derived from oxidation of omega-3 polyunsaturated fatty acids (PUFAs), whereas the long-chain Hep and HNE adducts are from omega-6 PUFAs. PdG adducts are important because they represent a new class of endogenous promutagenic DNA lesions with potential roles in carcinogenesis. Earlier, we developed a (32)P-postlabeling method for detecting PdG adducts from Acr and Cro and a modified method for the long-chain HNE adducts. Both methods require multiple high-performance liquid chromatography steps and, in some cases, time-consuming thin-layer chromatography for purification. There is a lack of a single, versatile, and efficient method for simultaneous detection of all five enal-derived PdG adducts. In this paper, we report an improved (32)P-postlabeling method which permits detection of Acr, Cro, Pen, Hep, and HNE adducts in a single DNA sample. This method relies on solid-phase extraction for adduct enrichment before and after (32)P-labeling; all five PdG adducts were converted to the ring-opened derivatives for confirmation of identities and quantification. The method was validated using the synthetic adducts and enal-modified DNA and was finally applied to rat liver DNA and rat liver DNA samples spiked with different amount of standards. The detection limit was determined to be as low as 0.5 fmol in 80 microg DNA, corresponding to 9 adducts/10(9) dG.

Aldehydes↗

PubMed2005

An extraordinary degree of structural specificity is required in neural phospholipids for optimal brain function: n-6 docosapentaenoic acid substitution for docosahexaenoic acid leads to a loss in spatial task performance.

This study was conducted to determine whether provision of preformed dietary docosapentaenoic acid (DPAn-6) can replace docosahexaenoic acid (DHA) for brain function as assessed by spatial task performance. A newly modified artificial rearing method was employed to generate n-3 fatty acid-deficient rats. Newborn pups were separated from their mothers at 2 days of age and given artificial rat milk containing linoleic acid (LA), or LA supplemented with 1% DHA (DHA), 1% DPAn-6 (DPA) or 1% DHA plus 0.4% DPAn-6 (DHA/DPA). The animals were then weaned onto similar pelleted diets. At adulthood, behavioural tasks were administered and then the brains were collected for fatty acid analysis. The LA and DPA groups showed a lower (63-65%) brain DHA than the dam-reared, DHA and DHA/DPA groups and this loss was largely compensated for by an increase in brain DPAn-6. The brain fatty acid composition in the DPA group was the same as that in the LA group at adulthood. In the Morris water maze, the LA and DPA groups exhibited a longer escape latency than the dam-reared and DHA groups and had a defect in spatial retention. In conclusion, DPAn-6 could not replace DHA for brain function, indicating a highly specific structural requirement for DHA.

Animal Feed↗

PubMed2005

A simplified and efficient method for the analysis of fatty acid methyl esters suitable for large clinical studies.

Conventional sample preparation for fatty acid analysis is a complicated, multiple-step process, and gas chromatography (GC) analysis alone can require >1 h per sample to resolve fatty acid methyl esters (FAMEs). Fast GC analysis was adapted to human plasma FAME analysis using a modified polyethylene glycol column with smaller internal diameters, thinner stationary phase films, increased carrier gas linear velocity, and faster temperature ramping. Our results indicated that fast GC analyses were comparable to conventional GC in peak resolution. A conventional transesterification method based on Lepage and Roy was simplified to a one-step method with the elimination of the neutralization and centrifugation steps. A robotics-amenable method was also developed, with lower methylation temperatures and in an open-tube format using multiple reagent additions. The simplified methods produced results that were quantitatively similar and with similar coefficients of variation as compared with the original Lepage and Roy method. The present streamlined methodology is suitable for the direct fatty acid analysis of human plasma, is appropriate for research studies, and will facilitate large clinical trials and make possible population studies.

Chemistry, Clinical↗

PubMed2005

Incomplete replacement of docosahexaenoic acid by n-6 docosapentaenoic acid in the rat retina after an n-3 fatty acid deficient diet.

When sources of n-3 fatty acids are not present in the diet, nervous system docosahexaenoic acid (22:6n3) is replaced by docosapentaenoic acid (22:5n6). Dams were fed either an n-3 deficient diet or one containing alpha-linolenic acid (18:3n3) and 22:6n3 throughout pregnancy and lactation. Their male offspring at weaning also received either the n-3 deficient or n-3 adequate diets and were sacrificed at 5, 10, 20, 50 and 91 days of age. Retinal lipids were extracted and analysed by gas chromatography for fatty acyl content. The percentage of retinal 22:6n3 increased continuously over the 13 week course of the experiment but reached its maximal concentration around day 20. Non-reciprocal replacement of 22:6n3 by 22:5n6 was observed at postnatal day 20 and 50 but not at other time points. Complete replacement of 22:6n3 was apparent if elevations in both 22:5n6 and docosatetraenoic acid (22:4n6) were considered. These data indicate that during the rapid period of accretion of retinal 22:6n3 around postnatal day 20, the supply of 22:5n6 to the retina was inadequate to completely replace 22:6n3 in n-3 deficient rats.

Aging↗

PubMed2005

In vivo conversion of 18- and 20-C essential fatty acids in rats using the multiple simultaneous stable isotope method.

An important question for mammalian nutrition is the relative efficiency of C18 versus C20 essential fatty acids (EFAs) for supporting the tissue composition of n-3 and n-6 pathway end products. One specific question is whether C22 EFAs are made available to tissues more effectively by dietary alpha-linolenic acid (18:3n-3) and linoleic acid (18:2n-6) or by dietary eicosapentaenoic acid (20:5n-3) and dihomo-gamma-linolenic acid (20:3n-6). To address this question in a direct manner, four stable isotope compounds were given simultaneously in a novel paradigm. A single oral dose of a mixture of 2H5-18:3n-3, 13C-U-20:5n-3, 13C-U-18:2n-6, and 2H5-20:3n-6 was administered to rats given a defined diet. There was a preferential in vivo conversion of arachidonic acid (20:4n-6) to docosatetraenoic acid (22:4n-6) and of 22:4n-6 to n-6 docosapentaenoic acid (22:5n-6) when the substrates originated from the C18 precursors. However, when the end products docosahexaenoic acid (22:6n-3) or 22:5n-6 were expressed as the total amount in the plasma compartment divided by the dosage, this parameter was 11-fold greater for 20:5n-3 than for 18:3n-3 and 14-fold greater for 20:3n-6 than for 18:2n-6. Thus, on a per dosage basis, the total amounts of n-3 and n-6 end products accreted in plasma were considerably greater for C20 EFA precursors relative to C18.

Animals↗

PubMed2005

Simultaneous quantitative determination of deuterium- and carbon-13-labeled essential fatty acids in rat plasma.

This study reports methods for the quantitative determination of stable isotope-labeled essential fatty acids (EFAs) as well as an experiment in which deuterium-labeled linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3) were compared with those labeled with carbon-13 in rat plasma in vivo. Standard curves were constructed to compensate for concentration and plasma matrix effects. It was observed that endogenous pools of fatty acids had a greater suppressing effect on the measurements of 13C-U-labeled EFAs relative to those labeled with 2H5. Using these methods, the in vivo metabolism of orally administered deuterated-linolenate, 13C-U-labeled linolenate, deuterated-linoleate, and 13C-U-labeled linoleate was compared in adult rats (n = 11). There were no significant differences in the concentrations of the 2H versus 13C isotopomers of 18:2n-6, 18:3n-3, arachidonic acid (20:4n-6), and docosahexaenoic acid (22:6n-3) in rat plasma samples at 24 h after dosing. Thus, there appears to be little isotope effect for 2H5- versus 13C-U-labeled EFAs when the data are calculated using the conventional standard curves and corrected for endogenous fatty acid pool size and matrix effects.

Animals↗

PubMed2005

A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model.

Epidemiological studies suggest that increased intake of the omega-3 (n-3) polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease (AD). DHA levels are lower in serum and brains of AD patients, which could result from low dietary intake and/or PUFA oxidation. Because effects of DHA on Alzheimer pathogenesis, particularly on amyloidosis, are unknown, we used the APPsw (Tg2576) transgenic mouse model to evaluate the impact of dietary DHA on amyloid precursor protein (APP) processing and amyloid burden. Aged animals (17-19 months old) were placed in one of three groups until 22.5 months of age: control (0.09% DHA), low-DHA (0%), or high-DHA (0.6%) chow. beta-Amyloid (Abeta) ELISA of the detergent-insoluble extract of cortical homogenates showed that DHA-enriched diets significantly reduced total Abeta by >70% when compared with low-DHA or control chow diets. Dietary DHA also decreased Abeta42 levels below those seen with control chow. Image analysis of brain sections with an antibody against Abeta (amino acids 1-13) revealed that overall plaque burden was significantly reduced by 40.3%, with the largest reductions (40-50%) in the hippocampus and parietal cortex. DHA modulated APP processing by decreasing both alpha- and beta-APP C-terminal fragment products and full-length APP. BACE1 (beta-secretase activity of the beta-site APP-cleaving enzyme), ApoE (apolipoprotein E), and transthyretin gene expression were unchanged with the high-DHA diet. Together, these results suggest that dietary DHA could be protective against beta-amyloid production, accumulation, and potential downstream toxicity.

Administration, Oral↗

PubMed2005

Preferential effect of lead exposure during lactation on non-essential fatty acids in maternal organs.

This study determined the effects of lead exposure during the lactational period on maternal organ FA compositions in rat dams that were fed either an n-3 adequate (n-3 Adq) or deficient (n-3 Def) diet prior to conception. On giving birth, dams were subdivided into four groups in a 2 x 2 design with n-3 FA supply and Pb exposure as the dependent variables. Pb acetate (0.2 wt%) was administered in the drinking water from the time they gave birth to weaning 3 wk later. Following weaning, the dams were decapitated, and the liver, plasma, kidney, brain, and retina analyzed for FA composition. The n-3 deficient diets markedly decreased the percentages of total n-3 FA, including docosahexaenoic acid (DHA), and increased total n-6 FA including both arachidonic (AA) and n-6 docosapentaenoic acids in all tissues (P < 0.05). The principal effects of Pb occurred in the liver and plasma, where 20-32% losses in total FA concentration concurrent with increased relative percentages of AA (P < 0.05) were observed. In kidney, the percentages of AA and DHA also increased after Pb exposure (P < 0.05) with lesser effects in the nervous system. There was a diet x Pb interaction for liver, plasma, and retinal 20-C n-6 PUFA (P < 0.05). Generally, shorter-chain saturated and monounsaturated FA concentrations were decreased after Pb exposure. An analysis of the changes in the tissue concentrations induced by Pb indicated that the increases in the percentages of PUFA likely reflected a preferential loss of non-EFA. The mechanisms by which Pb affects saturated and monounsaturated FA concentration are unknown.

Animals↗

PubMed2005

Status of plasma folate after folic acid fortification of the food supply in pregnant African American women and the influences of diet, smoking, and alcohol consumption.

BACKGROUND: African American women and socioeconomically challenged women are at risk of compromised folate status and, thus, of folate-related birth defects. Data are limited on circulating folate concentrations in pregnant African American women after folic acid fortification of the food supply was implemented. OBJECTIVE: The objective was to determine the influence of smoking and alcohol consumption on plasma 5-methyltetrahydrofolic acid (5-MTHFA) concentrations in pregnant African American women. DESIGN: Alcohol consumption, smoking exposure, and other characteristics of pregnant African American women reporting to an inner-city antenatal clinic were assessed. At 24 wk of gestation, blood samples and food-frequency intake data were collected. Plasma 5-MTHFA concentrations were determined by liquid chromatography-mass spectrometry for 116 subjects and examined in a correlational study design. RESULTS: Dietary folate and markers of alcohol consumption were positively associated, whereas exposure to smoke was negatively associated with plasma 5-MTHFA. More than one-half of the participants in this population failed to meet the recommended dietary allowance for dietary folate equivalents of 600 microg/d during pregnancy. CONCLUSIONS: Most inner-city African American women are not meeting the recommended dietary allowance for dietary folate during pregnancy, and smoking may further compromise their folate status. Programs to reduce smoking and raise awareness about the importance of folate and multivitamin supplementation during pregnancy need to target this population.

Adolescent↗

PubMed2005

Lead exposure and (n-3) fatty acid deficiency during rat neonatal development affect subsequent spatial task performance and olfactory discrimination.

Docosahexaenoic acid [22:6(n-3), DHA] is important for optimal infant central nervous system development, and lead (Pb) exposure during development can produce neurological deficits. Long-Evans strain rats were fed either an (n-3) deficient [(n-3) Def] diet to produce brain DHA deficiency, or an adequate [(n-3) Adq] diet through 2 generations. At the birth of the 2nd generation, the dams were subdivided into 4 groups and supplied drinking water containing either 5.27 mmol/L (Pb) or sodium (Na) acetate until weaning. Rats were killed at 3 wk (weaning) and 11 wk (maturity) for brain Pb and fatty acid analysis. Spatial task and olfactory-cued behavioral assessments were initiated at 9 wk. Rats in the (n-3) Def group had a 79% lower concentration of brain DHA compared with the (n-3) Adq group with no effect of Pb exposure. At weaning, Pb concentrations were 7.17 +/- 0.47 nmol Pb/g of brain (wet weight) in the (n-3) Adq-Pb group and 6.49 +/- 0.63 nmol Pb/g of brain (wet weight) in the (n-3) Def-Pb group. At maturity, the brains contained 1.30 +/- 0.22 and 1.07 +/- 0.12 nmol Pb/g (wet weight), respectively. In behavioral testing, significant effects of both Pb and DHA deficiency were observed in the Morris water maze probe trial and in 2-odor olfactory discrimination acquisition and olfactory-based reversal learning tasks. Both lactational Pb exposure and (n-3) fatty acid deficiency led to behavioral deficits with additive effects observed only in the acquisition of 2-odor discriminations.

Aging↗

PubMed2005

Lead exposure and (n-3) fatty acid deficiency during rat neonatal development alter liver, plasma, and brain polyunsaturated fatty acid composition.

Lead (Pb) exposure has been reported to increase arachidonic (AA) and docosahexaenoic (DHA) acids. To determine whether Pb effects on fatty acid composition are influenced by dietary (n-3) fatty acid restriction, weanling female rats were fed either an (n-3)-adequate or -deficient diet to maturity and mated. At parturition, dams in each group were subdivided to receive either 0.2% Pb or Na-acetate in their drinking water during lactation only. Pups were analyzed for fatty acid content in liver, plasma, and brain at either 3 or 11 wk. The (n-3)-deficient diets markedly decreased total (n-3) fatty acids, and increased total (n-6) fatty acids including both AA and docosapentaenoic (n-6) in each compartment (P < 0.05). The main effects of Pb were in the livers of weanling rats where there was a 56% loss in total fatty acid concentration concurrent with increased relative percentages of AA and DHA. Thus, because there was a greater percentage of liver nonessential fatty acid lost relative to the essential fatty acids (EFA), there was no net change in AA concentration. There was a diet x Pb interaction for a decrease in liver DHA concentration evident only in the (n-3)-adequate group. There were also diet x Pb interactions in plasma at 11 wk and in brain at 3 wk. These data are consistent with the hypothesis of a Pb-induced increase in fatty acid catabolism, perhaps as a source of energy.

Animals↗