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© 2006 American Society for Nutrition J. Nutr. 136:2827-2833, November 2006

Nutrient Requirements and Optimal Nutrition

Two Low Protein Diets Differentially Affect Food Consumption and Reproductive Performance in Pregnant and Lactating Rats and Long-Term Growth in Their Offspring1

Ganesh Cherala2, Bernard H. Shapiro3 and Anil P. D'mello2,*

2 Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, Philadelphia, PA 19104 and 3 Laboratories of Biochemistry, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

* To whom correspondence should be addressed. E-mail: a.dmello{at}usip.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
We fed 2 low protein diets (LPD) to rats during pregnancy and lactation, and compared food intake and reproductive performance in the dams, and long-term growth in their offspring. The L93 and LM76 LPDs were derived from the American Society of Nutrition's recommended AIN93G and a modified version of the AIN76A purified control diets, respectively. The LPDs contained 8% crude protein in the form of casein and differed in their fat and carbohydrate sources. The purified control diets contained 19% crude protein. A regular cereal-based diet was also included, therefore, a total of 5 groups were tested. Blood urea nitrogen concentrations in dams of both LPD groups were lower than their respective controls, confirming decreased protein intake. The LM76 diet lowered food consumption of dams and produced energy malnourishment during pregnancy that persisted throughout lactation. In contrast, the L93 diet produced energy malnourishment only during lactation. Offspring of both LPD groups exhibited lower birth weights than their respective controls. Despite initiating nutritional rehabilitation at weaning (d 28), perinatal administration of both low protein diets produced long-term reductions in the body weight of male offspring. Interestingly, in the female offspring, the LM76 diet reduced birth weight for the entire duration of the study (180 d), whereas the L93 diet produced a relatively short-term (up to 58 d) reduction in body weight. This suggests that the imprinting effect of the perinatal nutritional environment on body weight is diet and gender dependent. The performance of the purified control diet groups were similar to the nonpurified diet group in most measured biochemical indices, with the notable exception of a decrease in the body-weight normalized kidney weight of the dams.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Recent epidemiological findings have correlated low birth weight with an increased risk of ischemic heart disease, elevated systolic blood pressure, impaired glucose tolerance, and syndrome X during adulthood (1). Animal models of fetal growth restriction are being developed in an attempt to understand its relation to adult disease and to probe the underlying molecular mechanisms. The administration of a low protein diet during pregnancy and lactation is an extensively used model for producing fetal and early postnatal growth restriction, and there are a striking number of parallels between this model and the aforementioned epidemiological studies. Most studies examining the effect of maternal low protein diet on susceptibility to disease in the offspring normally use diets containing 8% crude protein, whereas the isocaloric purified control diet contains ~19% crude protein. Casein is normally used as the sole source of protein.

Low protein diets are made isocaloric to control diets by increasing the carbohydrate content, and there are differences between diets with regard to the source of these compensatory carbohydrates. Many studies, including those conducted in our laboratory, have used compositions of low protein diet that are variations of the purified diet published by the American Society of Nutrition (ASN), formerly the American Institute of Nutrition (AIN), in 1976 (2,3). Based on the experience acquired with the AIN 76A purified diet and some problems associated with its use, the ASN reformulated its purified diet. The composition of the revised diet, known as the AIN 93 diet, was published in 1993 (4). The major changes in the AIN 93 diet include partial substitution of sucrose with cornstarch and substitution of corn oil with soybean oil. Also, DL-methionine was replaced with L-cystine as the sulfur-containing amino acid and changes were incorporated in the mineral and vitamin mixes. A review of the literature indicates that the effects of two low protein diets based on the two ASN recommended purified diets have not been compared in pregnant and lactating rats. Additionally, whereas a recent study has compared the effects of the AIN 76A and AIN 93 purified control diets in adult rats (5), the comparative effects of these purified control diets in pregnant and lactating rats have not been evaluated.

We studied the comparative performance of two low protein diets derived from the AIN 93G purified diet and from a modified version of the AIN 76A purified diet in pregnant and lactating rats. Purified diets containing 19% crude protein (AIN 93G and a modified version of the AIN 76A) were used as controls in these studies. The literature demonstrates that adult rats fed purified control diets exhibit different susceptibility to stress (6), toxins (7), and carcinogens (8) than rats fed regular cereal-based diets. Therefore, we included a group of dams fed a regular nonpurified diet as an additional control. The 5 diets were evaluated with respect to food consumption, reproductive performance in pregnant and lactating dams, and long-term growth and development in their offspring.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Materials

Bovine and rat albumin (both of electrophoretic grade) were obtained from Sigma and aprotinin from Serologicals Corporation.

Diets

A regular nonpurified diet (NP),4 the AIN 93G purified diet (C93), a modified version of the AIN 76A purified diet (M76), and their corresponding low protein formulations LPD AIN 93G (L93) and LPD AIN M76A (LM76) were purchased in pellet form from Purina Test Diets. The purified diets contained 19% crude protein in the form of casein, whereas the isocaloric low protein diets contained 8% crude protein in the form of casein. Compositions of the diets are presented in Supplemental Table 1.

Experimental methods

    Experimental design. The study was approved by the Institutional Animal Care and Use Committee of the University of the Sciences in Philadelphia. Virgin female Sprague-Dawley rats were mated by housing 1 male rat with 2 female rats. Day 1 of pregnancy was assigned upon observation of sperm in the daily morning vaginal smears, at which time rats were randomly assigned to the 5 diet groups. Each group consisted of 7–8 pregnant rats, and these rats received their assigned diet throughout pregnancy and lactation.

Food consumption of pregnant and lactating rats was measured during d 1–4, 5–8, 9–12, 13–16, 17–20, and 21–22 of pregnancy and during d 1–3, 4–8, 9–12, and 13–16 of lactation. The body weights of dams in all groups were measured on d 1, 5, 9, 13, 17, and 21 of pregnancy and on d 1, 4, 9, 17, and 28 of lactation.

Upon birth, pups were sexed and litter size was noted. All litters were randomly culled to 12 pups (6 male and 6 female) on the day of birth, and on d 4 postbirth they were further randomly culled to 8 pups (4 males and 4 females). The remaining pups were killed and their livers and kidneys were collected and weighed. Offspring from all diet groups were weaned on d 28 postbirth and housed in isosexual groups according to perinatal diet treatment. Pups from litters in all 5 groups were weaned onto a nonpurified diet. The different dietary treatments were therefore only administered during gestation and lactation. Body weights of all offspring were measured on d 1, 4, 9, 17, 28, 42, 58, 72, 86, 100, 114, 128, 150, and 180 postbirth. The day the offspring opened their eyes was recorded, and the Lee index, a measure of nutritional outcome (9), was measured on d 58 postbirth.

One hundred and fifty µL tail-tip blood samples were collected from dams in all 5 groups on gestation d 9 and 17 and on lactation d 9, 17, and 28, and also from 28, 65, and 150 d-old offspring in all 5 groups. Blood was collected into cold aprotinin-lined polypropylene tubes, centrifuged at 15,600 g for 10 min at 4°C, and the serum was harvested and stored at –70°C pending analyses for blood urea nitrogen (BUN), total protein, and albumin. All dams were killed on d 28 of lactation. One male and female offspring from each litter in all 5 groups (7–8 male and female offspring in each group) were killed on d 28, 65, and 150 postbirth. Livers and kidneys were collected from all killed rats and weighed.

    Biochemical methods. Serum BUN was measured using a kit purchased from Pointe Scientific. Total serum protein was measured with the Bradford method (10) using bovine serum albumin as the standard and Coomassie brilliant blue dye concentrate (Bio-Rad Laboratories). Serum albumin was measured with the bromcresol green method (11) using rat serum albumin as the standard and bromcresol green solution purchased from Wako Chemicals.

Data analyses

All data were expressed as means ± SD and were analyzed using the SigmaStat software (version 3.1). Data generated from the complete randomized experimental design were analyzed using a 1-way or 2-way ANOVA. Data that did not meet normality or homogeneity of variance requirements were analyzed with a nonparametric 1-way ANOVA (Kruskal-Wallis). Wherever appropriate, multiple comparisons were conducted using the Student Newman-Keuls post-hoc test. All statistical tests were conducted at a 0.05 level of significance.

To assess mean birth weight and subsequent body weight of the offspring, all pups in a litter from a group were weighed and the mean computed. This was repeated for all litters in the group. The mean of these values is reported as the mean birth or body weight of the group. Such a conservative method of data reporting and analysis is recommended for analyses of offspring data in multiparous species. It minimizes inflation of the 0.05 alpha level and the spurious statistical significance that results as a consequence (12,13).

The two low protein groups were compared with their respective purified controls to evaluate the effects of low protein diets. Also, the two purified controls were compared with the nonpurified control to determine effects of purified diets. The low protein diets groups were not compared with the nonpurified control because it was deemed to be an inappropriate control for these groups.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
Diet specific alterations in food consumption were observed during varying intervals in pregnancy and lactation (Table 1). During the first 16 d of pregnancy, food consumption in all 5 groups (except L93 during pregnancy d 1–4) was similar. During the 17- to 20-d interval of pregnancy, food consumption in the LM76 group was significantly lower than its control, M76, and this trend continued throughout lactation. The L93 group also consumed less food than its control, C93 but this effect was only observed beginning on d 9 of lactation. In all intervals during lactation, food consumption of dams fed the purified control diets was lower than dams fed the nonpurified diet. Body weight gain (or loss) in the different measurement intervals during pregnancy and lactation complemented the food/energy intake data (Supplemental Table 2).


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  		TABLE 1 Effect of low protein diets during pregnancy and lactation on food consumption in rats1

 
BUN concentrations, a marker of protein intake, in both low protein diet groups were ~60–70% lower than their respective controls during pregnancy and lactation (Table 2). Surprisingly, BUN concentrations in the M76 group were lower than the NP group starting on d 17 of pregnancy and continuing throughout lactation. On the other hand, BUN concentrations in the C93 group were similar to the nonpurified diet group (with the exception of pregnancy d 17). Similar to the BUN profile, serum albumin concentrations in both low protein diet groups were lower than in their respective controls throughout lactation. Serum albumin concentrations of the purified control groups were similar to the NP group, except on d 28 of lactation when the M76 group exhibited slightly higher serum albumin concentrations than the NP group. Total serum protein concentrations were similar in all 5 groups during pregnancy. During lactation, total serum protein concentrations in the LM76 group were lower than its control on lactation d 9 and 28, whereas concentrations in the L93 group were lower than its control on lactation d 17 and 28. Total serum protein concentrations in both purified control groups were similar to the NP group.


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  		TABLE 2 Effect of low protein diets during pregnancy and lactation on blood urea nitrogen, serum albumin and serum total protein concentrations in rats1

 
The diets differentially affected reproductive performance of dams (Table 3). Gestational length, measured as the duration from d 1 of pregnancy until parturition, was similar among all 5 groups. However, despite this similarity, maternal weight gain and the percentage of maternal weight gain during gestation was smaller in the LM76 group compared with its control. Litter size was similar in all 5 groups. However, birth weights of offspring of both LPD groups were ~16% lower than their respective controls. Also, accompanying the lower birth weight, pup mortality tended to be higher (P = 0.052; nonparametric 1-way ANOVA) in the LM76 group than in the M76 group. The absolute and percentage of maternal body weight loss during lactation in the L93 group was greater than in the C93 group, whereas the LM76 group and its control did not differ. Also, during lactation, a greater maternal weight loss was observed in both the purified control groups than in the nonpurified diet group.


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  		TABLE 3 Effect of low protein diets during pregnancy and lactation on reproductive performance of rats and development of their offspring1

 
Absolute and relative (normalized to body weight) liver weights of the dams on d 28 of lactation in the L93 group were significantly larger than in the C93 group, whereas those in the LM76 group were similar to its control (Table 4). Absolute and relative liver weights in the purified control groups were similar to those in the nonpurified diet group. Absolute and relative kidney weights in both low protein diet groups were significantly smaller than in their respective controls (Table 4). The absolute kidney weights of the purified control diet groups were similar to those in the nonpurified diet group, although the relative kidney weights in both these groups were smaller than those in the nonpurified diet group.


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  		TABLE 4 Effect of low protein diets during pregnancy and lactation on absolute and relative liver and kidney weights of the rats on d 28 of lactation1

 
As stated earlier, despite similar litter sizes, the birth weight of pups in both low protein diet groups were significantly lower than in their respective control groups (Table 5). Dams in the 5 groups continued to receive their assigned pregnancy diets during lactation. Over the course of the 28-d lactation period, the differences in body weights between offspring of the low protein diet groups and their respective controls were markedly exacerbated (Table 5). Starting on d 9 of lactation and for the remainder of the lactation period, male and female offspring in both purified control groups exhibited higher body weight than those in the nonpurified diet group. Offspring from both low protein diet groups took longer to open their eyes than offspring in the respective control groups (Table 3). The age at eye opening between offspring of purified control diets and nonpurified diet did not differ. The Lee index among offspring in the 5 groups did not differ (Table 3).


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  		TABLE 5 Effects of maternal low protein diets during pregnancy and lactation on the body weight profile of the rat offspring during the preweaning (birth to d 28) period1

 
On d 28, BUN, serum albumin, and total protein concentrations in male and female offspring of both low protein diet groups were lower than in their respective controls (Table 6), but these differences disappeared by d 65 (Supplemental Tables 3 and 4). Surprisingly, d 28 BUN concentrations in the male and female offspring in the M76 group were lower than in the NP and C93 groups. There were sporadic differences in absolute liver and kidney weights (especially on d 1, 4, and 28) between offspring of the low protein diets groups and their respective controls; however, most of these differences were abolished upon normalizing organ weights to body weight (Supplemental Tables 5–8).


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  		TABLE 6 Effect of maternal low protein diets during pregnancy and lactation on blood urea nitrogen, serum albumin, and serum total protein concentrations in 28–d–old male and female rat offspring1

 
On d 28 of life, pups in all 5 groups were weaned onto the nonpurified diet and maintained on this diet for the remainder of the study. Body weights of male and female offspring in the LM76 group were lower than their respective control during the entire postweaning period of the study (Fig. 1). Postweaning body weights of male offspring in the L93 group were also consistently lower than their controls in C93 (Fig. 1A), except for the last day in the study (d 180). However, postweaning body weights of female offspring in the L93 group were lower than the C93 group up to d 58. After d 58, body weights in female offspring in the L93 group were similar to the C93 group, indicating a catch-up growth phenomenon (Fig. 1B). Body weights of male and female offspring of the purified control group, M76, were greater than in the NP group until d 58. Body weights of male and female offspring of the C93 group were similar to the NP group during the entire postweaning period.


Figure 1
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  		Figure 1  Effect of feeding low protein diets to rats during gestation and lactation on body weights of the male (A) and female (B) offspring. Each point is the mean and 1-sided SD, n = 7–8 values. Differences between low protein diet groups and the nonpurified diet group were not evaluated. Numbers indicate significant differences, P ≤ 0.05: 1M76 and LM76; 2C93 and L93; 3M76 and NP; 4C93 and NP; 5M76 and C93.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
The current study is one of the few studies that has evaluated the performance of the more recently recommended AIN 93 low protein diet on food consumption in rats during pregnancy and lactation, on the reproductive performance of the dams, and on growth and development of their offspring. Additionally, the study compared the performance of the two purified control diets to the regular nonpurified diet in pregnant and lactating rats and their offspring.

Food consumption between the low protein diet groups and the purified controls in the first 2 wk of pregnancy did not differ. Dams fed the LM76 diet but not the L93 diet decreased food consumption, and consequently energy intake, toward the end of pregnancy. Therefore, the L93 diet is a good model for instituting selective protein deficiency during pregnancy without the confounding effect of energy malnutrition. Dams in both the LM76 and L93 groups decreased food consumption during lactation. These results suggest that, in our model, protein deficiency is accompanied by energy malnutrition during lactation. Numerous reports in the literature support these findings (14–16). In our studies, the frequent measurement of food intake allowed observation of subtle differences in the onset of alterations in food intake between the two low protein diets. The reasons for the decrease in food consumption are unclear. Sucrose is used in both low protein diets as a compensatory carbohydrate source. In rats, sucrose in low protein diets interacts during pregnancy and lactation to produce food aversion (17). Interestingly, the LM76 diet contained a higher concentration of sucrose, and dams fed this diet also exhibited an earlier onset of food aversion. Other authors have suggested alternative reasons for the decrease in consumption of low protein diets during lactation. Maternal low protein diets decrease birth weight of pups, alter milk composition (15), and decrease milk volume (16). The smaller pups exhibit deficient suckling behavior, which in turn decreases suckling stimulus. Because suckling stimulus is thought to partially govern dam appetite during lactation (18), the decrease in suckling stimulus could also account for the decreased food consumption of the low protein diets during lactation.

Decrease in dietary protein intake in adult rats lowers BUN, serum albumin, and total serum protein concentrations (19–21). Our studies have now comprehensively extended these observations to pregnant and lactating rats. BUN was an extremely sensitive marker of protein deprivation. Its concentrations dramatically decreased in dams of both low diet groups by d 9 of pregnancy and the decrease persisted throughout pregnancy and lactation. Serum total protein and serum albumin concentrations also decreased in the dams fed low protein diets. However, these decreases were smaller in magnitude and occurred only during lactation. Surprisingly, BUN concentrations in the M76 group were lower than the NP group starting on d 17 of pregnancy and continuing throughout lactation. The decrease is probably not a result of lower protein absorption from the M76 diet because plasma albumin and total protein concentrations in this group were not similarly affected. This suggests that the decreased BUN concentrations in the M76 group were due to diet-mediated alterations in protein catabolism and/or alterations in the urea cycle.

Protein-energy malnutrition did not affect gestation length or litter size. These observations are similar to a majority of reports in the literature (22,23) but are in contrast to the results of Courreges et al. (24) that demonstrated elevated mortality in pregnant rats fed an 8% crude protein diet. The LM76 group, but not the L93 group, exhibited a smaller weight gain during pregnancy. The decreased weight gain is probably due to the lower intake of food and energy toward the end of pregnancy. In the LM76 group, the lower maternal weight gain during pregnancy probably contributed to the higher pup mortality. Low protein diets during pregnancy are normally associated with a higher incidence of fetal and pup mortality (25). Surprisingly, pup mortality in the L93 group was similar to its purified control group. The other macro and micronutrients in the L93 diet probably compensated for the lower protein content, which improved the odds of pup survival and attests to the advantage of this more-recently formulated low protein diet.

In dams in the 5 groups, the profile of body weight changes during lactation is highly variable. The NP group gained weight up to d 16 of lactation. The purified control diet groups also gained weight during this period but the gain was smaller than in the NP group. This suggests that the purified diets are not as efficient as the nonpurified diet in ensuring adequate lactational reserves for the dam. In accordance with the literature [(26) and references therein], dams from both low protein diet groups lost weight during d 1–16 of lactation, with the L93 group exhibiting a greater loss of weight than the LM76 group. The results suggest that low protein diets are unable to maintain dam weight during a period of great nutritional demand. This inadequacy is probably a combination of lower protein content of the diet and exacerbation of that deficiency by the decreased food and energy intake of the dams in the LM76 and L93 groups during this period. When examined over the entire 28-d lactation period, the NP group showed no net change in body weight. Dams in this group returned to their postparturition body weight by the end of lactation. In contrast, dams from the purified control groups and the low protein diet groups showed a net loss of weight (compared with their postparturition body weight) at the end of lactation. This was especially marked for the dams fed the L93 diet, although the reason for the weight loss is unclear.

The administration of a low protein diet throughout pregnancy and lactation had minimal effect on liver weight of the dams. Dams fed both low protein diets had decreased body-weight normalized kidney weights compared with their respective controls, suggesting that the kidneys are particularly susceptible to the effect of decreased protein intake. Dams fed the purified control diets also exhibited lower relative kidney weights than the nonpurified diet group. It is well established in rodents that kidney size and function are directly related to protein intake (27,28). The progressively smaller relative kidney weights of rats in the NP, purified control, and low protein diet groups is probably a consequence of their exposure to the decreasing amounts of protein in the 3 broad diet groups.

Despite similar litter sizes in all 5 groups, birth weight of pups in both low protein diet groups was smaller than those in their respective control groups. The lower birth weights were observed despite a conservative method of statistical analyses of birth weight data (see Methods), and confirms literature demonstrating that a low protein diet mediates fetal growth retardation (23,29–32). The dams in the LM76 and L93 groups continued to receive low protein diets during lactation and the ~16% decrease in birth weight of the pups in these two groups progressed to a 50–60% decrease in body weight on d 28 (weaning). Studies in the literature show that body weight of rodents are particularly susceptible to protein-energy malnutrition during the lactation period (29,33,34). Our results confirm these literature reports. Offspring from the LM76 and L93 groups also exhibited lower BUN, serum albumin, and total serum protein concentrations at the time of weaning. These decreases confirm exposure of offspring in the 2 LPD groups to a lactation environment of protein malnutrition.

In our studies nutritional differences among the groups were confined only to the gestation and lactation period, and offspring from all 5 groups were weaned to a regular nonpurified diet on d 28. However, despite such nutritional rehabilitation, the decrease in body weight in male and female offspring of dams fed the L93 diet persisted up to d 150 and d 58, respectively. More interestingly, the decrease in body weight in male and female offspring of dams fed the LM76 diet persisted up to d 180, at which time the study was terminated. The long-term, possibly irreversible, decrease in body weight represents the imprinting effect of perinatal protein-energy malnutrition. Other investigators have also demonstrated persistent perinatal low protein diet or undernutrition-mediated decreases in body weight (29,33–35). The mechanism(s) underlying this imprinting effect is not clearly understood. A limited body of literature demonstrated that appetite is programmed by nutritional status during lactation with undernutrition during this period producing a permanent decrease in the set point of appetite (36). The lowering of the set point might involve a perinatal nutrition environment–mediated programming of the secretory profiles of leptin and insulin and accompanying regulatory changes of appetite controlling centers in select hypothalamic nuclei (30,35). Surprisingly, the decrease in offspring body weight produced by the L93 diet was not as long lasting, especially in the female offspring. The reasons for these differences in the duration of the imprinting effect between the two low protein diets are not clear, and it is probable that macronutrient (fat source and the resultant differences in linolenic acid and cholesterol content) and micronutrient (source of sulfur containing amino acids) differences between the diets might account for these findings. These latter results suggest that the unusual imprinting effect of low protein diets on body weight are diet and gender dependent.


   ACKNOWLEDGMENTS
 
The authors acknowledge the assistance of undergraduate researchers Mahmud Ansari, Josephat Waigwa, and Sheetal Patel in the conduct of the animal studies and in the analyses of BUN, serum albumin, and serum total protein concentrations.


   FOOTNOTES
 
1 Supplemental Tables 1–8 are available with the online posting of this paper at jn.nutrition.org. Back

4 Abbreviations used: BUN, blood urea nitrogen; C93, AIN 93G purified control diet; L93, low protein diet based on the AIN 93G purified diet; LM76, low protein diet based on the modified version of the AIN 76A purified diet; LPD, low protein diet; M76, modified version of the AIN 76A purified control diet; NP, nonpurified diet. Back

Manuscript received 14 December 2005. Initial review completed 27 January 2006. Revision accepted 14 August 2006.


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TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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G. Cherala, B. H. Shapiro, and A. P. D'mello
Effect of Perinatal Low Protein Diets on the Ontogeny of Select Hepatic Cytochrome P450 Enzymes and Cytochrome P450 Reductase in the Rat
Drug Metab. Dispos., July 1, 2007; 35(7): 1057 - 1063.
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