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,1
Department of Small Animal Clinical Sciences,
* Comparative Nutrition Laboratory, College of Veterinary Medicine and Biomedical Sciences, and
Faculty of Nutrition, Texas A&M University, College Station, TX 77843, and
** Nestle-Purina Pet Care, St. Louis, MO
1To whom correspondence should be addressed. E-mail: jbauer{at}cvm.tamu.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-linolenic acid relative to marine-based (n-3) long-chain fatty acids were studied and fed to dogs from the time of estrus, and throughout pregnancy and lactation. In addition, puppies born to these dams suckled and were weaned using the same diets their mothers had been fed. Plasma cholesterol (total, free, and esterified fractions) and triglycerides were determined at selected time points and lipoprotein fractions were characterized in both mothers and offspring. During gestation, plasma total cholesterol concentrations were depressed early on, then increased in the later stages independently of diet. Both ß- and 2-migrating lipoproteins also increased during these times. Lactation was also characterized by lower lipid and lipoprotein amounts compared with the nonpregnant state. In puppies, total plasma and ß-lipoprotein cholesterol were elevated at 4 and 10 d of age. Diet effects included cholesterol, triglyceride, and lipoprotein lowering with increased amounts of marine (n-3) fatty acids in all life stages investigated. The increase in ß-lipoprotein cholesterol in puppies during wk 1 of life is consistent with an earlier report of increased canine apoprotein B,E receptor activities in immature dogs compared with undetectable activities in mature animals in which the HDL fractions become even more predominant in this species.
KEY WORDS: • lipids • lipoproteins • dogs • fatty acids • reproduction
Hyperlipidemia during normal human pregnancy is characterized by elevations of plasma triglyceride (TG),2 cholesterol, and phospholipid (PL) concentrations, and alterations in lipoprotein (LP) (1,2). Consequently, the maternal dietary lipid intake can affect fetal growth and development (3). Plasma cholesterol elevations are typically more moderate than those of TG (4), and those associated with HDL are thought to be due to hormonal changes during gestation (5). During lactation, plasma lipid concentrations decline toward normal, nonpregnancy values with more rapid lipid lowering in mothers that breast-feed their offspring (4,6). All LP concentrations generally return to normal values by 1 y after pregnancy (2).
The young of certain nonhuman species also have increased lipid and LP concentrations. Breast-fed baboon infants had higher serum cholesterol due to increases in the HDL1- and HDL2-cholesterol fractions (7). Suckling kittens had significantly higher plasma cholesterol and TG concentrations compared with the same kittens after weaning and cats in other age groups (8). Sprague-Dawley rat pups had elevations in plasma cholesterol during suckling, which decreased after weaning (9). As these animals mature, their TG and cholesterol concentrations decline, and there are no differences in lipid and LP-cholesterol (LP-C) concentrations among adolescents, adults, and seniors. These decrements in plasma cholesterol are likely due to high tissue demands during periods of rapid growth and development (8).
Normal mammalian fetal development requires both essential fatty acids (EFAs) and long-chain PUFAs (LCPUFAs) (10). Dietary (n-3) and (n-6) PUFA are needed to ensure development of nervous tissue, kidney, liver, and skin functions.
The LCPUFAs are of particular interest because they are found in high concentrations in PLs of the central nervous system (CNS) tissues (11). Infants consuming low amounts of LCPUFA have lower amounts of these fatty acids in PLs of the cerebral cortex (12). Dietary fatty acid effects on LP metabolism thus have an important role in the development of various species, including humans and canines. In humans, dietary SFA increase LDL cholesterol; this also occurs in dogs (13). Replacing saturated fat with unsaturated fat decreases LDL more than HDL in humans, and PUFA are the most potent fatty acids for reducing LDL cholesterol (14,15). Also, fish and (n-3)–containing fish oil supplements were shown to lower TG (16). One dog study did not find TG lowering with fish oil because plasma TG concentrations are normally too low in dogs to detect any significant lowering effects (17).
No data exist on canine plasma cholesterol, TG concentrations, and LP distributions during gestation, lactation, and the perinatal period. Given the similarities and differences in which mature dogs transport cholesterol compared with humans, the effect of reproductive state and dietary fat on lipid metabolism in this species is of comparative interest. Lipid and LP alterations in adult dogs fed diets of defined fatty acid content during gestation and lactation and of puppies from these dams during suckling and early adolescence were thus investigated.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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An existing breeding colony of dogs provided bred hound/Labrador retriever dogs and their puppies for this study as previously described (18). Dogs were individually maintained in kennels according to the American Physiological Society Guidelines for Animal Research and protocols were approved by the Texas A&M University Animal Care and Use Committee. Clinically normal, sexually intact female dogs (n = 12), ages 2 to 4 y, were randomly assigned to 1 of 4 diet groups. The 4 diets were prepared by Ralston Purina (presently Nestle-Purina PetCare), and were described previously (19). All diets contained adequate amounts of linoleic acid (LA) and varying amounts of -linolenic acid (ALA) using linseed oil and (n-3) LCPUFA [i.e.20:22 carbon (n-3) fatty acids] from menhaden fish oil. Fat sources included beef tallow, linseed oil, or higher or lower amounts of menhaden fish oil as the primary fat source. The diets were designated Lo/Lo, Lo/Mod, Lo/Hi, and Hi/Lo which refers to their ALA:(n-3) LCPUFA concentrations. Diet fatty acid compositions are indicated in Table 1. All other diet ingredients including protein, amino acid content (Table 2), nitrogen-free extract, vitamin, and mineral sources were identical, resulting in diets with similar nutrient profiles except for fatty acid type (19).
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Sample collection and analyses.
Blood samples were collected into tubes containing EDTA from each bitch on d 0, 3, 7, 14, 28, 42, and 56 of gestation and d 10 and 28 of lactation. The d 0 sample was considered to represent the nonpregnant life stage (NPLS) for comparison with both the gestation and lactation periods. Feed was withheld from the dogs overnight before the collection of blood samples. Blood was obtained from the puppies on d 4, 10, 16, 28, 70, and 84 of age. The puppies were separated from their mothers for 3 h before sampling on d 4, 10, 16, and 28, and feed was withheld overnight on d 70 and 84. Plasma was harvested from the blood samples by slow speed centrifugation at 1500 x g for 5 min. LP analysis was performed using freshly isolated plasma samples on the day of collection. The remaining plasma was then frozen at –45°C for subsequent analysis [TG, total cholesterol (TC), and FC determinations]; plasma esterified cholesterol (EC) was calculated by difference from TC and FC values. TC, FC, and TG concentrations were determined using enzymatic methods (17). LP distributions were determined by electrophoresis on 1% agarose gel and quantified by scanning densitometry (17). Results are presented as mmol LP-C/L.
Statistical analyses.
Values in the text are means ± SEM. Gestation and lactation samples were compared with the NPLS serums using "dam" as the experimental unit (n = 3/group). The data followed a normal distribution with rejection of the null hypothesis of normality at P < 0.05 using the Shapiro-Wilk test. If variances were nonhomogeneous, log10-transformed data were analyzed. Statistical significance was determined using ANOVA for repeated measures for diet, time, and diet x time interactions for plasma lipid and LP values in samples collected from the mothers. Data from the puppy plasma samples were analyzed similarly with P < 0.05 accepted as the critical value for significance in all cases. Puppy sample size varied with the number of pups born in each litter. Tukey’s multiple comparison of means was performed where appropriate.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Plasma TC concentrations were increased during late gestation (G42) compared with early gestation (G14). Both the ß-LP-C and the 2-LP-C fractions were also significantly increased at G42 (Table 4).
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2-LP-C fractions were not significant (P = 0.06).
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The 2 sample collection days during lactation (L10 and L28) were compared with the NPLS of each dog. Plasma TC and FC concentrations were significantly lower during lactation compared with the NPLS but did not differ from each other on the 2 sampling days (Table 4). Both -LP-C fractions were approximately half those of the respective NPLS fractions (Table 4). Plasma TG on L28 was lower than during the NPLS (P = 0.095).
The plasma EC fraction was lower in the Lo/Hi group than in the other 3 groups during lactation (Table 5). In addition, significant decreases in both ß- and 2-LP-C occurred in dogs fed the Lo/Hi diet compared with the Hi/Lo group.
Neonate.
Higher plasma TC, FC, and EC concentrations were present on d 4, 10, and 16 compared with samples collected at d 28 and after weaning (d 70 and 84) (Table 6). Plasma TG concentrations were also higher early in the neonatal period (d 4 and 10). On d 16, they decreased and then decreased further with maturation on d 28, 70, and 84 (Table 6). Chylomicron and pre-ß LP-C elevations also occurred early in life (d 4,10, and 16) compared with later samples. Elevations of ß-LP-C and both -LP-C fractions were also present early on and declined thereafter (Table 6).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In all canine breeds, HDLs are the major transporter of plasma cholesterol accounting for >65% of TC in the circulation. By comparison, LDL cholesterol in dogs is low, ranging from 
13% in smaller breeds to 31% in larger breeds (20). Hyperlipidemia during normal gestation is not uncommon and reflects a metabolically demanding life stage (2,6). Such lipid metabolic alterations likely help maintain cholesterol homeostasis for both mother and offspring.
Results of the present investigation were consistent with studies in other gestating species, including humans, in which increases in plasma TC during late gestation (G42) are observed compared with early gestation (G14). Considering the differences in gestation length between dogs and humans, G42 is comparable to the second trimester in humans, in which Potter and Nestel found an 50% increase in plasma cholesterol (21). Silliman et al. (22) also reported elevated cholesterol as well as increased LDL-associated apolipoprotein (apo) B concentrations during late human pregnancy. In the present study, increases in both LDL and HDL cholesterol during late gestation were found. Although increased LDL is similar to that observed during human pregnancy, the HDL increase reflects the fact that this fraction is the primary carrier of cholesterol in dogs.
Lipid changes in adult dogs during lactation are consistent with the conclusions of numerous investigators that this period is the most energetically demanding stage of mammalian reproduction (23–28). Overall, TC concentrations were lower during lactation compared with the NPLS, and both -LP-C values (i.e., HDL) were approximately half those seen in the NPLS. A similar result was reported by Qureshi et al. (22), who found that breast-feeding human mothers had a strikingly rapid fall in plasma cholesterol and TG during lactation. Although there was no significant decrease in TG in this study, a tendency for lower maternal plasma TG was observed in later lactation. This trend was reported in human mothers by various investigators and was not unexpected because milk fat is composed primarily of this lipid fraction (6,21,29–31).
Rapid maturation of the CNS occurs during the final week of gestation (32). Because the CNS contains the second highest amount of lipid compared with other organs (33), it is expected that infants would need EFA and their LCPUFA derivatives to sustain proper growth and development of neurological structures (34). Late gestation and the early postnatal period are 2 very important stages of infant growth and development (32). The metabolic demands of this period were thus apparent with elevations of TC in puppy plasma during the first 10 d of life. Investigations using other species including baboons, kittens, and rat pups reported similar increases in cholesterol concentrations during suckling (7–9). It should also be noted that, during suckling, the ß-LP-C fractions of puppy plasma were increased in the first days after birth compared with d 28 and 70. Because LDL cholesterol (ß-LP-C fraction) transports cholesterol to peripheral tissues for cell growth and maintenance, it is likely that elevations of the ß-LP-C fraction reflect increased tissue demands for cholesterol during early neonatal cell growth.
Plasma TG concentrations of puppies were similarly increased early on (d 4 and 10), then declined somewhat on d 16 and continued to decrease with maturation (d 28, 70, and 84). These data are consistent with other studies showing that plasma TG concentrations rise rapidly after birth and decrease with age (35).
This study also demonstrates that dietary fatty acids can modify both maternal and neonatal plasma LP distributions and plasma lipid concentrations. During gestation, dogs fed the Lo/Hi diet had lower plasma cholesterol concentrations in both the FC and EC fractions, lower ß-LP-C, and tended to have lower 2-LP-C. Similarly, during lactation, decreases in both the ß- and 2 -LP-C fractions were observed in dogs fed the Lo/Hi diet. Although this diet contained the highest amounts of marine (n-3) LCPUFA of all diets studied, it was also high in SFA and lower in LA compared with the other diets. Thus the lipid-lowering effect of the Lo/Hi diet was somewhat unexpected. By comparison, cholesterol lowering was not observed when ALA was the (n-3) fatty acid source even though this diet had a low saturated and high LA content. Thus, when (n-3) fatty acids are present, their types (vegetable vs. marine) and amounts may be important determinants of plasma cholesterol metabolism separate from the lipid-lowering effects that occur with low dietary saturated fat and increased LA. Whether this effect is unique to the canine species or possibly related to reproductive status is unknown. However, -LP-C lowering was observed in studies with other species fed marine fatty acids (36–39). Furthermore, such an effect may predominate in canine species in which the majority of plasma cholesterol is in the -LP-C fractions.
Effects of the diets were also observed in the puppies. Plasma TC and all LP-C fractions in puppies whose mothers were fed either the Lo/Mod or Lo/Hi diets were significantly lower than in those fed the Lo/Lo and Hi/Lo diets. This effect again appears to be mediated by the (n-3) LCPUFA content of the diets fed. Finally, plasma TG concentrations were higher in puppies fed the high ALA diet (Hi/Lo diet). However, it cannot be determined whether this effect was specifically attributable to the presence of high ALA, low (n-3) LCPUFA, low saturated fat, or high total PUFA content of this diet and further study is warranted.
It is of particular interest that plasma LDL cholesterol fractions of immature puppies were increased compared with normal adult dogs especially because dogs transport cholesterol predominantly via HDL. The present work is the first report of increased LDL cholesterol in puppies during suckling. An early study of canine LP metabolism showed that immature dogs demonstrated greater hepatic LDL receptor activities than mature animals in which such activities were undetectable at 24 mo of age (40). Canine liver contains 2 distinct LP receptors, an apo-B,E receptor, which binds both LDL and HDL cholesterol, and an apo-E receptor, which binds only HDL cholesterol. The apo-B,E receptor is active in immature, growing dogs, whereas only the apo-E receptor is present in mature animals (40). This observation is consistent with the increased concentration of LDL fractions present during early life in this study and reflects a period of increased metabolic demands for cell growth and maintenance. The reduction in plasma lipid and lipoprotein cholesterol concentrations with maturation suggests that apo-B,E receptors necessary for lipid metabolism are active soon after birth and decline rapidly thereafter.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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-linolenic acid; apo, apolipoprotein; CNS, central nervous system; EC, esterified cholesterol; EFA, essential fatty acid; FC, free cholesterol; G, gestation day; Hi/Lo, diet containing large amount of ALA and small amounts of (n-3) LCPUFA; L, lactation day; LA, linoleic acid; LCPUFA, long-chain PUFA; Lo/Hi, diet containing small amount of ALA and large amounts of (n-3) LCPUFA; Lo/Lo, diet containing small amount of ALA and small amounts of (n-3) LCPUFA Lo/Mod, diet containing small amount of ALA and moderate amounts of (n-3) LCPUFA; LP, lipoprotein; LP-C, LP-cholesterol; NPLS, nonpregnant life stage; PL, phospholipid; TC, total cholesterol, TG, triglyceride. 
Manuscript received 25 February 2005. Initial review completed 14 April 2005. Revision accepted 26 June 2005.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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