(Hypertension. 1996;27:96-101.)
© 1996 American Heart Association, Inc.
Articles |
Effects of Neonatal Growth on Adult Blood Pressures of Borderline Hypertensive Rats
From the Department of Psychiatry, College of Physicians and Surgeons of Columbia University and Division of Developmental Psychobiology, New York State Psychiatric Institute, and the Department of Psychology, Barnard College, Columbia University (S.R.H.-M.), New York.
Correspondence to Michael M. Myers, PhD, Unit 40, New York State Psychiatric Institute, 722 W 168th St, New York, NY 10032. E-mail mmm3@columbia.edu.
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Abstract |
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Abstract We conducted this study to test the hypothesis that there are long-term effects of litter-size manipulations during the preweaning period on growth and adult blood pressure of rats. Litter size of genetically homogeneous borderline hypertensive rats, which were produced by cross-mating male Wistar-Kyoto rats with female spontaneously hypertensive rats, was manipulated from 10 to 16 days of age. In addition, a subset of males and females was castrated within the first 30 hours of life. Body weights were measured at several preweaning and postweaning ages, and tail-cuff blood pressures were recorded at 90 days of age. Intact and castrated pups of both sexes that were reared in small (n=4) litters from 10 to 16 days of age gained nearly twice the weight of animals reared in large (n=9 to 12) litters during this period. Intact males from small litters had significantly higher adult blood pressures than those from large litters. These long-term effects remained even in groups matched for adult weight and length. Neonatal castration of males completely blocked the consequences of litter-size manipulation on adult blood pressure, suggesting either an organizational or activational role for androgens. Neither intact nor neonatally castrated females exhibited differences in adult blood pressure as a function of litter-size manipulation.
Key Words: blood pressure • body weight • rats, inbred strains • castration
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Because high BP is a major risk factor for stroke and other cardiovascular disease, researchers have invested tremendous effort in identifying environmental factors, genetic predispositions, and physiological mechanisms that influence BP. One of the factors most consistently related to BP is body weight. The strength of this relationship has led to the recommendation that weight loss be a primary intervention for controlling hypertension.1 It is well known that positive correlations among body weight, weight gain, obesity, and BP exist in both adults and children.2 3 4 These relationships are particularly evident during phases of rapid growth that are accompanied by periods of rapid increase in BP.5 That these associations can be found early in life has prompted hypotheses that propose fundamental linkages between growth processes and BP.6 7 This contention is supported by results of epidemiological studies, which suggest that the incidence of cardiovascular disease, elevated BP, and diabetes is influenced by nutrient availability and growth during the fetal period.8 These studies indicate that a developmental approach is required to understand how early growth processes influence adult cardiovascular function.
Data from animal studies also suggest that early feeding patterns and infant weight gain can influence adult BP. We found that in rats, the frequencies of nursing and other mother/infant behavioral interactions, are positively correlated with adult BP of the offspring.9 10 A similar correlation was found between adult BP and naturally occurring weight gain of pups from 10 to 16 days of age.11 Finally, increased rates of infant weight gain achieved by means of reducing litter size from 10 to 16 days was also associated with increases in adult BP, but this effect was specific to males.11 Comparable effects of litter-size manipulations have been reported by Plagemann and coworkers,12 who also found that male rats raised in small litters throughout the preweaning period had increases in adult BP.
Although these previous litter-size manipulation studies provide evidence for a link between infant weight gain and BP much later in life, the effects of cross-fostering and genetic background of the experimental animals were not well controlled. In the present study we have manipulated litter size during a specific period of development using a protocol that controlled for both of these factors. Genetically homogeneous BHR13 were used, and all rats were cross-fostered. Finally, in a small subset of animals, we examined the effect of neonatal castration on the long-term consequences of litter-size manipulations. The results show that experimentally induced rapid growth in infancy is associated with increases in adult BP, but this effect is found only in intact males.
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Methods |
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Animals and Breeding
All procedures were reviewed and approved by the Institutional Animal Care and Use Committee at the New York State Psychiatric Institute. Adult female SHR and male WKY were purchased from Taconic Farms (Germantown, NY). BHR were produced by breeding male WKY with female SHR in our vivarium. Pregnant females were housed in individual cages. Cages were checked twice daily for births, and the day a litter was found was considered day 1 of life. A total of 10 birth date–matched pairs of litters were formed from dams delivering within 24 hours of each other. Within 30 hours of delivery mothers were removed from their home cages, and all pups from these date-matched litter pairs were pooled. From this pool of pups, two groups of four males and four females were randomly selected. Each group was placed on shavings from the home cage of the dam to which it was to be returned. For 5 of the 10 litter pairs, pups were returned to the dams after 45 minutes and were then left undisturbed until litter-size manipulation at day 10. These pups were individually marked with ear notches on day 10. For the other 5 matched pairs of litters, neonatal castrations and marking were performed as described below.
Neonatal Surgeries
Neonatal castrations were performed within
30 hours of delivery
with hypothermia anesthesia.14 For
ovariectomies, a vertical 1- to 2-mm incision was made on each side of
the animal on the dorsal surface just posterior to the rib cage and
lateral to the spine. The ovary was removed, a stitch was placed in the
muscle wall and in the skin, and a drop of glue was applied to the
external suture. A similar procedure was used to remove the testes of
the male pups, except that the bilateral incisions were made on the
ventral surface, just anterior to the urogenital region on either side
of the naval. After completion of the surgery, each pup was injected
with India ink beneath the skin of the foot pads for unique
identification. The other pups in these litters underwent cold
anesthesia and paw marking only. After surgery the pups
were allowed to recover for 60 minutes in warm (34°C to 35°C) cages
containing the bedding of the mother to which they were to be returned.
Eight pups, consisting of 1 castrated male, 1 castrated female, 3
intact males, and 3 intact females, were returned to each mother.
Litter-Size Manipulation From Days 10 to 16
To form small and
large litters between 10 and 16 days of age,
we cross-fostered pups between dams of birth date–matched
pairs. This procedure was performed such that all pups later studied as
adults were reared by foster mothers through this period. For each of
the five matched pairs of nonsurgical litters, one dam was randomly
designated dam A and the other dam B. Two males and two females from
dam A were placed with dam B on day 10 of age. At the same time, all of
the eight animals of dam B were fostered to dam A. Thus, at day 10 dam
B had 4 pups (all from litter A) and dam A had 12 pups (8 from litter
B, 4 of her own). At day 16 all pups were returned to their original
mothers, thereby reestablishing litter sizes of 8 until weaning at day
23. For each of the five pairs of litters in which neonatal castrations
were performed, the procedure was similar except that the castrated
male and castrated female from each litter were always included in the
pups selected for cross-fostering.
Although the original design was for large litters to contain 12 pups, disturbances in the litters for sexing and/or surgery within the first 30 hours of life led to some reductions in the number of animals that lived until day 10. Accordingly, there was a range of litter sizes in the large litters (large litter of 9, n=1; large litter of 10, n=1; large litters of 11, n=2; and large litters of 12, n=6). No animals died after day 10.
Body Weights and Postweaning Housing
Body weights were
measured during the preweaning period on days
10, 16, and 23. At day 23 rats were placed four per cage in
like-sex, mixed-surgery, and mixed–litter size groups. For
the nonsurgical litters all four pups reared in small litters from days
10 through 16 were selected for later study. Four of the eight
cross-fostered animals that were reared in large litters (two
males, two females) were selected for later study on the basis of
having intermediate body weights at weaning. The selection of pups from
the surgical litters to be followed in adulthood was similar except
that the castrated male and castrated female from each litter were
always included. Postweaning body weights were taken at 56, 70, 84, and
90 days of age.
Tail-Cuff BP
At 90 (±1) days of age, systolic BPs were
taken with a
tail-cuff procedure described previously.9 During
these measurements rats were comfortably restrained in appropriately
sized plastic cylinders that prevented locomotion and turning. Animals
were kept in the dark on a heating pad that maintained the temperature
of the restrainer between 29°C and 31°C. After about 10 minutes,
five readings of systolic BP and heart rate were taken on each
animal at about 1-minute intervals. The median of these five
recordings was used in the data analyses. After BP
testing, each animal was lightly anesthetized with
ketamine (1 mg/kg IM), and the relaxed body length from the tip
of the nose to the base of the tail was recorded.
Statistical Analyses
In all, there were five pairs of
nonsurgical litters in which
all animals were intact and five pairs of litters in which one male and
one female had been castrated at birth. In the five nonsurgical pairs,
two males and two females from each litter were studied. Since
littermates cannot be considered as independent samples, the data from
the two intact males from each nonsurgical litter were averaged to form
a single value. The data from the females within each nonsurgical
litter were also averaged. In the neonatal surgery litters the eight
study animals belonged to one of eight groups (male or
femalexcastrated or intactxsmall litter or large litter). The data
from the intact animals from these surgical litters were combined with
the averaged values from the nonsurgical litters. Thus, in total, data
from 10 litters contributed to the four intact groups (male large
litters, male small litters, female large litters, and female small
litters).
In the five pairs of surgical litters there were two male castration groups (castrated-male large litters, castrated-male small litters). There were also two female castration groups (castrated-female large litters, castrated-female small litters), but since one castrated female from a small litter and one from a large litter died after surgery, there were only four females in each group.
Although all litters contributed data from intact animals, castrated animals were not represented in all litters. Thus, data from intact and castrated groups were analyzed separately. Two-way (sexxlitter size) ANOVAs were performed for weight gain during the period from 10 to 16 days, adult BP, and adult heart rate. Postweaning body weights were analyzed similarly except the analyses were repeated measures ANOVAs. Additional post hoc ANOVAs were performed when significant interactions were found.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Small-litter pups gained much more weight from 10 to 16 days of age than did pups reared in a large litter (see Fig 1
). In
intact males and intact females, weight gain per
day over this period was nearly doubled when animals were reared in
small litters [litter size: F(1,36)=197.42,
P<.001].
There were no significant differences between males and females with
regard to rates of weight gain through this period, nor was there a
significant interaction between sex and litter size. In neonatally
castrated males and females there was also significantly greater weight
gain in the small-litter animals [litter size: F(1,14)=170.43,
P<.001]. As was the case for intact animals, there was no
significant effect of sex, nor was there a significant interaction
between sex and litter size.
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Body weight data obtained at four postweaning ages demonstrated
the expected differences between males and females and between
castrated and intact animals (see Table 1). Intact males
weighed more than intact females [F(1,36)=560.90,
P<.001]. There was a main effect of litter size, with
animals reared in small litters from 10 to 16 days of age weighing more
than those reared in large litters [F(1,36)=5.94,
P=.02]
and a marginally significant interaction between sex and litter size
[F(1,36)=2.95, P=.10]. Post hoc tests within
sexes showed
that effects of litter-size manipulations on postweaning body
weights were significant only in males [males, F(1,18)=5.38,
P=.03; females, F(1,18)=0.66,
P=NS]. There were,
of course, significant increases in weight with age
[F(3,108)=1357.12,
P<.001], and from age to age males gained more weight than
females [F(3,108)=170.46, P<.001]. In neonatally
castrated animals there were no significant differences between males
and females in postweaning body weights. In contrast to intact animals,
there also was no significant effect of litter-size manipulation.
There was a significant sexxlitter size interaction
[F(1,14)=4.68,
P<.05]; however, neither the greater weights of
small-litter males relative to large-litter males nor the
reduced weights of small-litter females relative to
large-litter females achieved statistical significance.
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The results of 90-day adult BP measurements demonstrated that in adult
males BP was increased in animals reared in small litters from 10 to 16
days of age. These effects were not seen in neonatally castrated males
nor in females (see Fig 2). ANOVAs of these data showed
higher BPs in intact males than in intact females [F(1,36)=34.98,
P<.001]; a significant main effect of litter size, with
small-litter animals having higher BPs [F(1,36)=6.36,
P<.05]; and a significant sexxlitter size interaction
[F(1,36)=4.20, P<.05]. Post hoc analyses showed
that the effects of litter size on adult BP were significant for males
[F(1,18)=13.27, P<.01] but not for females
[F(1,18)=0.09, P=NS]. In neonatally castrated
animals
there were no significant BP effects of litter size and sex, nor was
there a significant sexxlitter size interaction.
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Heart rate data, obtained at the same time as BP determinations, are not shown. Analyses indicated that the only significant differences were for heart rates to be higher in intact females than in intact males [females, 417±8 beats per minute; males, 390±8 beats per minute: F(1,36)=5.23, P<.05]. There were no significant effects of sex or litter size on the heart rates of neonatally castrated animals.
We conducted one additional analysis to address the question of
whether the increases in adult BP in small-litter intact males
could be accounted for by increases in body size. By removing the three
heaviest males from the small-litter group and the three lightest
males from the large-litter group, subsets of animals were formed
that were matched in 90-day weights, lengths, and
weight-to-length ratios (see Table 2). These
groups of animals also did not differ in their heart rates. In
contrast, as shown in Table 2, even in these well-matched sets
of
animals, males reared in small litters from 10 to 16 days of age had
higher adult BPs than those reared in large litters through this
period.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study shows that in genetically homogeneous BHR, reductions in litter size from 10 to 16 days of age result in rapid growth through this period and increased adult BP of males but not of females. The effects of litter-size manipulation on adult BP of male BHR are blocked by neonatal castration and cannot be accounted for solely by changes in body size.
These results are consistent with observations made over 30 years ago by Widdowson and colleagues,15 16 who reported that rats reared in small litters had larger hearts and a much greater incidence of kidney lesions at the time of death when compared with animals from large litters. Interestingly, these particular effects were more pronounced in male rats. In addition, Bai and coworkers17 have found that adult heart weight, myocyte size, and body weight were increased in animals reared in small litters in infancy. Again, these effects of altered neonatal growth were seen only in males.
Long-term effects of litter-size manipulations are also consistent with a study performed by Plagemann and coworkers,12 who found that normotensive Wistar male rats reared in small litters throughout the preweaning period had significantly higher adult BPs than animals reared in large litters. Litter-size manipulations also had pronounced effects on adult weight and weight-to-length ratios, and these effects on body size were correlated with the changes in BP. These authors suggest that effects of rapid growth in infancy are a manifestation of changes in insulin regulation that ultimately render rapidly grown animals at risk for adult diabetes.12 18 Moreover, Dörner and Plagemann19 have proposed a model in which they attribute these long-lasting effects to altered development of the hypothalamus that is mediated by the high levels of insulin found in rapidly growing animals.
There is another mechanism by which early feeding experience could influence adult BP. Each time rat mothers deliver milk to their young, BPs of the nursing pups rise dramatically, and these responses are mediated by activation of the autonomic nervous system.20 21 22 It may be that these repetitive activations in infancy lead to adaptive changes in vascular development and morphology, resembling the etiologic hypothesis for hypertension suggested by Folkow.23 It is clear that this possibility and the model proposed by Dörner and Plagemann19 are not mutually exclusive because both insulin and BP are acutely stimulated by feeding.
There is also the question as to whether increases in BP observed in intact males reared in small litters might be secondary to increases in adult weight or adiposity. In the present study, analyses of data from intact males were repeated on a subset of 14 animals, 7 from small litters and 7 from large litters. These animals were matched for adult weight, length, and weight-to-length ratio. Despite tight matching for body size, the small-litter animals had significantly higher adult BPs than the large-litter animals. This implies that changes in adult body weight alone cannot account for the effects of early litter-size manipulations on BP. However, as shown in a pioneering study by Faust et al,24 litter-size manipulations can have a life-long effect on fat cell number and weight gain responses to high-fat diets. Thus, it is likely that there are many changes in the regulation of body composition in small-litter animals. Even though body size per se does not account for increases in adult pressure in these animals, alterations in metabolism might underlie a propensity to become obese and to have higher adult BP.
The data obtained in the present experiment demonstrate that in intact males, changes in weight gain during a critical developmental period are associated with changes in adult BP. However, castrated males and both intact and castrated females do not have higher adult BP as a result of rapid weight gain during this period. This indicates that ovarian hormones do not protect females from the effects of rapid growth in infancy but rather implicates testicular hormones in the mediation of these long-term effects. Because the castrations in this current study were conducted only during the neonatal period, we cannot determine whether the effects of male hormones are organizational in nature during early development or activational later in life. Further studies should include postweaning castration of male BHR and hormonal manipulations of females and castrated males in order to resolve this issue.
The absence of effects in females and castrated males suggests another interesting possibility. It might be that castrated males and intact and castrated females, which are all much lighter than intact males, do not reach a critical body size threshold required to trigger the effects of rapid infant weight gain. Consequently, while increased adult weight may not itself be responsible for the increases in adult BP of intact males, it may represent a risk factor for the expression of effects set in motion by events early in life.
The findings from these studies are particularly interesting in light of the growing evidence from human studies that there are effects of growth during the prenatal period on the subsequent development of both insulin-mediated processes and the cardiovascular system. Results from these epidemiological studies have shown that in adulthood, men and women born with low birth weights (6.5 lb or less) were 10 times more likely to develop syndrome X (a form of type 2 non–insulin-dependent diabetes mellitus with hypertension and hyperlipidemia) than men and women born weighing 9.5 lb or more.25 As babies, in addition to having low birth weights, these subjects also had low ponderal indexes and small circumferences of the skull. Other research from this group has demonstrated consistent relationships between birth weight and adult BP, with lighter babies having higher adult systolic BP.26 Interestingly, independent of birth weight, body weight at 1 year of age was not related to adult BP. This suggests that there is a sensitive period during which characteristics of the cardiovascular system can be shaped by nutrition and growth rates and that in humans this falls in fetal development rather than in infancy. Although these findings evidence the opposite relationship between early growth and adult pressure from that found in our animal studies, the human investigations have not yet determined whether growth rates at various age ranges after 1 year are correlated with later life BP.
Evidence from animal studies also shows that increases in growth rates during early life can be associated with reductions rather than increases in adult BP. Cierpial and McCarty27 have found that when SHR pups are cross-fostered to WKY dams, they are heavier at weaning than when reared by SHR dams, but they have significantly reduced BPs as adults. Moreover, these effects are found only when the cross-fostering occurs before day 15 of age.28 Methodological factors may contribute to the difference in the direction of the relationship between early weight gain and adult BP in our studies versus those of McCarty and colleagues.27 28 First, the times of cross-fostering used by McCarty and Fields-Okotcha28 were not isolated to the sensitive period from 10 to 16 days we have studied. Second, McCarty's studies used direct measurements of resting mean arterial BP, whereas our studies used systolic BP by the tail-cuff method. Thus, the increased systolic BP observed in the present study may reflect changes in contractility or compliance of the large arteries rather than changes in total peripheral resistance. Furthermore, since our animals were restrained, BP reactivity would contribute more to our measurements. Perhaps there are opposite effects of rapid weight gain in infancy on basal versus reactive pressures. In addition, we have not examined the effects of weight gain, either naturally occurring or those induced by litter-size manipulation, in SHR, which may respond differently to increases in infant weight gain than the F1 (BHR) or F2 generations we studied previously.11
Factors other than methodological may also explain the direction of effects seen in the SHR cross-fostering studies. Recent work by Rose and McCarty29 demonstrates that SHR mothers deliver less milk to offspring than do WKY mothers. The increased growth rates exhibited by SHR pups when they are reared by WKY dams may reflect more a normalization of growth than overfeeding. Thus, in the SHR, as appears to be the case for human fetal development, growth restriction may contribute to adult hypertension.
Together, these studies suggest that there may be multiple periods in neonatal or prenatal life that are important in determining adult BP. It may be that at some stages of development the ultimate consequences of rapid growth on adult cardiovascular function are such that increases in systemic pressure result in, while at other stages impaired growth leads to, a similar long-term outcome. The goal of future research should be to delineate these sensitive periods, to study possible mechanisms in greater detail, and to integrate results from animal investigations with those from human epidemiological studies.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by the New York State Office of Mental Health. We gratefully acknowledge the role of the program for senior thesis research in Biopsychology at Barnard College as a kindling force for this work and, in particular, Dr Rae Silver's help and advice throughout all phases of the study.
Received May 11, 1995; first decision May 31, 1995; accepted October 9, 1995.
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