Brain DNA Content Research Articles

Does Insulin Resistance Contribute to Neuroinflammation, Cognitive Decline and Brain Senescence in Obesity?

The burgeoning prevalence of obesity and overweight conditions from the age of adolescence and throughout the lifespan has reached epidemic proportions in industrialized nations throughout the globe. The development of insulin resistance is one of the most common observations in obesity and is associated with a systemic hypoxia in adipose tissue and a chronic inflammatory state. The insulin resistance affects multiple elements of substrate oxidation and oxidative free radical generation in both somatic and neural tissues and with cytokine-linked chronic inflammation likely originating in adipose tissue depots. In studies with aging congenic lean and obese rats chronic hyperinsulinemia and brain shrinkage has now been reported, albeit it in the absence of Type 2 diabetes (NIDDM), hypertension (HTN) or other comorbidities, thereby suggesting that aspects of disordered substrate metabolism including insulin resistance as commonly observed in obesity may be a key contributory factor in the development of a neuroinflammatory linked brain shrinkage with accompanying decreases in brain mass, protein and DNA content, and which were further compromised when fed an isocaloric high vs. a low glycemic insulinogenic diet containing sucrose vs. cornstarch respectively. These results suggest that chronic insulin resistance of obesity secondary at least in part to dietary factors represents a likely independent risk factor in the progression of neuroinflammation, DNA damage, brain shrinkage and neural senescence in this strain of obese rats.

Effect of Carbohydrate Type on Brain Composition and Senescence in Aging, Hyperinsulinemia-prone OBESE LA/Ntul//-cp Rats

To determine if phenotype and the carbohydrate type resulted in alterations in brain composition in the obese phenotype of the congenic LA/Ntul//-cp rat, groups (n= 8 rats/group) of male littermate lean and obese rats were fed standardized isocaloric diets containing 54% (w/w) cornstarch (ST diet) or 54% (w/w) sucrose (SUC diet) from 1 until 10.5 ± 0.5 months of age. The obese phenotype of his strain develops early onset chronic hyperinsulinemia without NIDDM associated with hypertrophic-hyperplastic obesity during early postweaning growth. Brain tissues were dissected, and representative aliquots subjected to total fat, protein, and DNA analysis. Body weights of obese >> lean and were greater when fed the SUC than the ST diet in both phenotypes. Brain mass of lean > obese, and diet was associated with modestly lower brain weights in rats fed the SUC than the ST diet. Brain total Protein and DNA content of lean rats were > obese rats and were modestly Lower in SUC than ST fed rats in both phenotypes, but the percent of lipid content was proportional to brain mass. Total body fat mass of obese was significantly greater than occurred in lean littermates and was only modestly greater in SUC than ST fed rats in both phenotypes. These results indicate that brain growth and cellular development is impaired in the aging, hyperinsulinemia-prone obese phenotype of this strain, were further impaired when fed SUC than ST diets, and the decreased brain parameters were likely associated with development of a chronic neuronal inflammatory syndrome common to excessive fat accretion and obesity, resulting in premature brain senescence.

Does the epigenetic expression of obesity, insulin resistance and their metabolic sequelae contribute to brain senescence?

Cognitive senescence and brain shrinkage have been reported in Alzheimer’s disease and is often associated with obesity but the pathophysiologic factors which bring about the neural declines remain unclear. A retrospective examination of factors of Insulin resistance and obesity in lean and obese rats indicated that final body weights of obese phenotype were more than double those of their lean littermates throughout adulthood, and carcass fat content at 10.5 months of age 15-fold greater than similarly fed lean littermates. In addition, the life span of the obese phenotype was decreased by approximately 30% in both male and female rats compared to their lean littermates. In addition, glycemic parameters indicated that the obese rats developed significant insulin resistance, while brain lipid, protein and DNA content were significantly reduced by one third or more in the obese phenotype by ~10 months of age, when they had approached their peak body weights. These observations suggest that the onset and progression obesity and its metabolic sequelae contributes to brain shrinkage, decreased DNA and protein content, key factors in the development of cognitive senescence in aging in this strain of rat.

Does Carbohydrate and Insulin Resistance of Obesity Contribute to the Senescence of Brain Atrophy in Aging? Here is What the Lab Rats May Be Telling Us about Carbohydrates

Since the dietary guidelines were adjusted several decades ago in an effort to improve cardiovascular health by promoting diets containing fewer calories from fats, the consumption of carbohydrate calories including those from refined carbohydrate sources have increased proportionately in much of industrialized society. Refined carbohydrates including sucrose are rapidly digested by brush border glucosidases and have a higher glycemic index and stimulate greater insulinogenic responses than calories obtained from complex carbohydrate sources and tend to contribute to greater body fat accretion over time. High carbohydrate diets promote greater elevations in insulin secretion and can lead to insulin resistance and its multiple pathophysiologic sequelae including increases in body fat accretion, obesity, non-insulin dependent diabetes (NIDDM) chronic inflammation, and other comorbidities that can compromise health and longevity including neurologic demise. In the obese phenotype of the aging congenic, chronically insulin resistant non- diabetic LA/Ntul//-cp rat, measures of brain composition and cellularity as determined by brain mass and DNA content were significantly decreased and were further compromised when fed a high glycemic index, insulinogenic diet where the starch was replaced with isocaloric quantities of sucrose. These observations are consistent with the chronic insulin and amylin resistance linked to high carbohydrate diets in the obese phenotype as a contributing factor in the progression of senescence and brain atrophy and suggest that the factors of obesity and insulin resistance, compounded by the glycemic index of the diet were key factors in the neurologic demise and premature death in the obese phenotype of this strain.

The Epigenetic Expression of Obesity and Its Metabolic Sequelae Contribute to Brain Senescence and Decreased Longevity in Aging Obese LA/Ntul//-cp Rats

Cognitive senescence and brain shrinkage have been reported in Alzheimer’s disease and is often associated with obesity but the pathophysiologic factors which bring about the neural declines remain unclear. A retrospective examination of factors of Insulin resistance and obesity in lean and obese rats indicated that final body weights of obese phenotype were more than double those of their lean littermates throughout adulthood, and carcass fat content at 10.5 months of age 15-fold greater than similarly fed lean littermates. In addition, the life span of the obese phenotype was decreased by approximately 30% in both male and female rats compared to their lean littermates. In addition, glycemic parameters indicated that the obese rats developed significant insulin resistance, while brain lipid, protein and DNA content were significantly reduced by one third or more in the obese phenotype by ~10 months of age, when they had approached their peak body weights. These observations suggest that the onset and progression obesity and its metabolic sequelae contributes to brain shrinkage, decreased DNA and protein content, key factors in the development of cognitive senescence in aging in this strain of rat.

Brain Boron Level, DNA Content, and Myeloperoxidase Activity of Metformin-Treated Rats in Diabetes and Prostate Cancer Model

In this study, the effect of metformin on boron levels and oxidative brain damage in rats due to diabetes and prostate cancer was investigated for the first time. Myeloperoxidase (MPO) activity and the amount of DNA were investigated as tissue oxidative and toxic damage parameters. In Copenhagen rats, Dunning prostate cancer was induced using high metastatic MAT-Lylu cells and diabetes was induced by single dose of streptozotocin (STZ) injection. Metformin was administered for 14 days after diabetes and prostate cancer induced. The rats were divided into six groups as follows: control group, diabetic group (D), cancer group (C), diabetic + cancer (DC) group, cancer + metformin (CM) group, diabetic + cancer + metformin (DCM) group. At the end of the experiment, brains were removed. Significant decrease of brain boron levels and significant elevation of MPO activity and DNA levels were observed in D, C, and DC groups as compared to control group. The effect of diabetes induction on the brain boron levels was much more than prostate cancer induction. The administration of metformin with CM and DCM obviously declined MPO activity and increased brain boron levels almost near to control group level. In conclusion, this study shows that the protective effect of metformin against brain damage in STZ-induced diabetic rats with Dunning prostate cancer may also be related to increased boron levels. The boron levels may be a novel indicator of reduced toxic and oxidative stress. Furthermore, the distribution and mechanism of action of boron should be clarified.

The 2100 MHz radiofrequency radiation of a 3G-mobile phone and the DNA oxidative damage in brain

We aimed to evaluate the effect of 2100MHz radiofrequency radiation emitted by a generator, simulating a 3G-mobile phone on the brain of rats during 10 and 40 days of exposure. The female rats were randomly divided into four groups. Group I; exposed to 3G modulated 2100MHz RFR signal for 6h/day, 5 consecutive days/wk for 2 weeks, group II; control 10 days, were kept in an inactive exposure set-up for 6h/day, 5 consecutive days/wk for 2 weeks, group III; exposed to 3G modulated 2100MHz RFR signal for 6h/day, 5 consecutive days/wk for 8 weeks and group IV; control 40 days, were kept in an inactive exposure set-up for 6h/day, 5 consecutive days/wk for 8 weeks. After the genomic DNA content of brain was extracted, oxidative DNA damage (8-hydroxy-2′deoxyguanosine, pg/mL) and malondialdehyde (MDA, nmoL/g tissue) levels were determined. Our main finding was the increased oxidative DNA damage to brain after 10 days of exposure with the decreased oxidative DNA damage following 40 days of exposure compared to their control groups. Besides decreased lipid peroxidation end product, MDA, was observed after 40 days of exposure. The measured decreased quantities of damage during the 40 days of exposure could be the means of adapted and increased DNA repair mechanisms.

Age and Sex-Related Changes in Rat Brain Mitochondrial Function

Aging is responsible for the decline in the function of mitochondria and their increase in size and number - adaptive mechanism to restore mitochondrial function. Estrogens increase mitochondrial function, especially in female rats. The aim of this study was to determine the age-related changes in rat brain mitochondrial function focusing on sex differences. Cellular and mitochondrial protein and DNA content, mitochondrial oxidative and phosphorylative function in male and female rat brain from four different age groups (6, 12, 18 and 24 months old) were analyzed. Mitochondria protein/DNA content decreased with aging shifting toward lesser mitochondrial functional capacity and the mitochondria number increased. A sex dimorphism was determined, with female rat brain showing mitochondria with greater functional capacity than males. These sex differences gradually increased during aging.

Early weaning impairs body composition in male mice

This study aimed to evaluate the effect of early weaning on body composition and on parameters related to nutritional status in mice. The experimental group consisted of male Swiss Webster mice that were weaned early (at postnatal day fourteen) and fed an appropriate diet for growing rodents until postnatal day twenty-one (EW group). The control group consisted of male mice breastfed until postnatal day twenty-one (CON group). All animals were sacrificed on the twenty-first day of life. The EW group showed a decrease in liver and muscle protein content and concentration, brain protein concentration, brain DNA content and concentration, as well as liver and muscle protein/RNA ratio (p<0.05). Concerning body composition, the EW mice showed increased moisture content, increased moisture and lipid percentage, and a smaller percentage and content of protein and ash in the carcass (p<0.05). These results indicate that early weaning impairs body composition and parameters related to nutritional status, which may be explained by retarded chemical maturation processes. This data may contribute to the overall understanding of the influence of breastfeeding versus feeding with artificial milk on body composition and on nutritional status.

Insulin-Like Growth Factor-1 Promotes G1/S Cell Cycle Progression through Bidirectional Regulation of Cyclins and Cyclin-Dependent Kinase Inhibitors via the Phosphatidylinositol 3-Kinase/Akt Pathway in Developing Rat Cerebral Cortex

Although survival-promoting effects of insulin-like growth factor-1 (IGF-1) during neurogenesis are well characterized, mitogenic effects remain less well substantiated. Here, we characterize cell cycle regulators and signaling pathways underlying IGF-1 effects on embryonic cortical precursor proliferation in vitro and in vivo. In vitro, IGF-1 stimulated cell cycle progression and increased cell number without promoting cell survival. IGF-1 induced rapid increases in cyclin D1 and D3 protein levels at 4 h and cyclin E at 8 h. Moreover, p27(KIP1) and p57(KIP2) expression were reduced, suggesting downregulation of negative regulators contributes to mitogenesis. Furthermore, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway specifically underlies IGF-1 activity, because blocking this pathway, but not MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase), prevented mitogenesis. To determine whether mechanisms defined in culture relate to corticogenesis in vivo, we performed transuterine intracerebroventricular injections. Whereas blockade of endogenous factor with anti-IGF-1 antibody decreased DNA synthesis, IGF-1 injection stimulated DNA synthesis and increased the number of S-phase cells in the ventricular zone. IGF-1 treatment increased phospho-Akt fourfold at 30 min, cyclins D1 and E by 6 h, and decreased p27(KIP1) and p57(KIP2) expression. Moreover, blockade of the PI3K/Akt pathway in vivo decreased DNA synthesis and cyclin E, increased p27(KIP1) and p57(KIP2) expression, and prevented IGF-1-induced cyclin E mRNA upregulation. Finally, IGF-1 injection in embryos increased postnatal day 10 brain DNA content by 28%, suggesting a role for IGF-1 in brain growth control. These results demonstrate a mitogenic role for IGF-1 that tightly controls both positive and negative cell cycle regulators, and indicate that the PI3K/Akt pathway mediates IGF-1 mitogenic signaling during corticogenesis.

Effect of Leptin Replacement on Brain Structure in Genetically Leptin-Deficient Adults

The hormone leptin profoundly affects body weight and metabolism. Three human adults (two women, 35 and 40 yr old; one man, age 27) have been identified with a recessive mutation in the ob gene, which is homologous to the mutation in ob/ob mice, and produces leptin deficiency and morbid obesity. Because leptin replacement increases brain weight and changes brain protein and DNA content in ob/ob mice, we hypothesized that analogous treatment of leptin-deficient humans would alter brain tissue composition. Volumetric T1-weighted magnetic resonance images of the brain were acquired before and at 6 and 18 months after initiation of replacement therapy (daily sc injections of recombinant methionyl human leptin), which produced dramatic loss in body weight. We used voxel-based morphometry to test for increased gray matter tissue concentration after initiation of leptin replacement and detected increases at 6 months in the anterior cingulate gyrus, the inferior parietal lobule, and the cerebellum. These increases were maintained for over 18 months, with identical stereotaxic coordinates of the maxima for the effects. Our findings suggest that leptin can have sustained effects on tissue composition in the human brain and broaden the potential spectrum of leptin's influence beyond feeding behavior and endocrine function.

Ethanol Intake During Lactation Impairs Milk Production in Rats and Affects Growth and Metabolism of Suckling Pups

TAVARES DO CARMO, M. G., C. M. OLLER DO NASCIMENTO, A. MARTIN AND E. HERRERA. Ethanol intake during lactation impairs milk production in rats and affects growth and metabolism of suckling pups. ALCOHOL 18(1) 73–78, 1999.—From parturition, lactating Wistar rats were given 20% alcohol in drinking water and fed a solid diet ad lib (group AL). Pair-fed (PF) and control (C) rats were fed solid diet and given water ad lib (C). All animals were sacrificed on the 12th day of lactation. Ethanol treatment decreased food intake and milk production in lactating rats to a greater level than in PF rats, and a greater reduction in body weight of the AL pups was noted. Brain weight, protein concentration, and DNA content were also lower in pups of AL dams than of PF dams, whereas liver glycogen concentration was higher in the former. Pups from AL dams had higher circulating levels of β-OH-butyrate, triglyceride, and free fatty acids than those from either C or PF dams. Plasma glucose concentration was lower in both PF and AL than in C pups, whereas the AL group had lower plasma protein concentration than any of the other groups. We conclude that maternal alcohol intake during lactation greatly impairs milk production, and although the known increase of lipid content in milk in rats studied under similar conditions allows an enhanced lipidic components in the pups, this adaptation does not allow normal growth and brain development.

Inhibition of murine AIDS by a new azidothymidine homodinucleotide.

A new antiretroviral drug (azidothymidine homodinucleotide, AZTp2AZT), designed for the protection of macrophages against retroviral infection, was evaluated in a murine retrovirus-induced immunodeficiency model of AIDS (MAIDS) alone and in combination with oral azidothymidine (AZT). C57BL/6 mice were infected with the retroviral complex LP-BM5 and treated for 3 months by weekly administrations of 15 nmol of AZTp2AZT encapsulated into autologous erythrocytes for macrophage protection. AZTp2AZT treatment was found to reduce lymphoadenopathy (48%), splenomegaly (26%), and BM5d proviral DNA content in lymph nodes, spleen, and brain of 37%, 40%, and 36%, respectively, compared with untreated animals. AZT administration in drinking water (0.25 mg/ml) was more effective than administration of AZTp2AZT encapsulated into erythrocytes in reducing lymphoadenopathy, splenomegaly, gammaglobulinemia, and proviral DNA content in lymph nodes, but it caused a reduction in erythrocyte count and hematocrit levels. Although combined treatments do not provide additive responses in the several parameters investigated, they were found to be much more effective in reducing the proviral DNA content in brain (67%) than were monotherapies. Furthermore, no apparent signs of hematotoxicity were observed. Thus, macrophage delivery of antiviral drugs may contribute to brain protection from retroviral infections by mechanisms other than those exerted by oral AZT administration.

Impaired brain development and reduced astrocyte response to injury in transgenic mice expressing IGF binding protein-1

Numerous reports indicate that insulin-like growth factor-I (IGF-I) has a critical role in brain development, that it contributes to neuronal survival and that its activity is regulated by a family of IGF binding proteins (IGFBPs). In the present study, brain development was investigated in transgenic (Tg) mice that overexpress rat IGFBP-1 under the control of phosphoglycerate kinase promoter. Adult Tg mice had significantly decreased brain weight (299±17 vs. 499±11 mg), brain DNA content (684±8 vs. 810±31 μg) and brain protein (37±1 vs. 48±2 mg) compared with wild-type (Wt) mice and these deficits were already evident at birth. In Tg mice, myelin staining was generally reduced and there was a diminished thickness of the corpus callosum. The total area of hippocampus and dentate gyrus were significantly reduced by 55% and 72%, respectively. Bromodeoxyuridine labeling of proliferating cells in 3-day-old mice was markedly reduced by 41% in the dentate gyrus and by 19% in ventricular zones of Tg mice. Reactive astrogliosis reflected by morphology and glial fibrillary acidic protein expression of astrocytes in response to a mechanical lesion was substantially less in Tg compared with Wt mice. Mixed glial cell cultures from Tg animals were significantly less responsive to stimulation of proliferation by IGF-I than cultures from Wt mice. We conclude that overexpression of IGFBP-1 impairs brain development and reduces glial cell proliferation in response to injury.

Adaptive response of the chicken embryo to low doses of x-irradiation.

Chicken embryos were x-irradiated in ovo with 5-30 cGy (=priming dose) at the 13th-15th day of development. After 3-48 h, brain- and liver-cell suspensions were x-irradiated in vitro with (challenge) doses of 4-32 Gy. Significantly less radiation damage was observed when the radiation response was measured by scheduled DNA synthesis, nucleoid sedimentation and viscosity of alkaline cell lysates 12-36 h after the priming exposure. In vivo, pre-irradiation with 10 cGy enhanced regeneration as evidenced by the DNA content of chicken embryo brain and liver 24 h following a challenge dose of 4 Gy. From nucleoid sedimentation analyses in brain and liver cells immediately after irradiation with 16 Gy and after a 30-min repair period in the presence of aphidicolin, dideoxythymidine and 3-aminobenzamide or in the absence of these DNA repair inhibitors, it is concluded that a reduction of the initial radiation damage is the dominant mechanism of the "radio-adaptive" response of the chicken embryo. Sedimentation of nucleoids from ethidium bromide (EB) (0.75-400 micrograms/ml)-treated cells suggests a higher tendency of "radio-adapted" cells to undergo positive DNA supercoiling in the presence of high EB concentrations.

Brain growth retardation due to the expression of human insulin like growth factor binding protein-1 in transgenic mice: an in vivo model for the analysis of igf function in the brain

Three lines of transgenic (Tg) mice carrying a fusion gene linking the mouse metallothionein-I promoter to a cDNA encoding human insulin-like growth factor binding protein-1 (hIGFBP-1) were found to express the transgene in brain. As judged by comparing Tg brain weights to those of non-transgenic littermates, adult hemizygotic Tg mice of each line exhibited brain growth retardation (16.2%, 14.4% and 8.1% reductions in weight, respectively in each line). In two lines, total brain DNA and protein content were decreased. Further analysis indicated that the brain growth retardation was manifested in the second week of postnatal life. Given that the insulin-like growth factors (IGFs) stimulate cell proliferation and/or survival in neural cultures and that hIGFBP-1, when present in a molar excess, inhibits IGF interactions with their cell surface receptors, the brain growth retardation in hIGFBP-1 Tg mice likely results from hIGFBP-1 inhibition of IGF-stimulated growth-promoting actions. These hIGFBP-1 Tg mice should prove useful in defining IGF actions during postnatal brain maturation.

75 FAILURE OF HEAD GROWTH SPARING IN CYSTIC FIBROSIS

There is little data on head growth in CF, over the first two years, when brain growth is rapid and nutritional deficiency may affect brain cell growth and DNA content. We report the results of a longitudinal study in CF children from birth to 4 years of age. Head circumference (OFC), linear height and weight were measured monthly in 52 CF children by a single auxologist using standard anthropometric techniques. Standard deviation (SD) scores were calculated for height, weight and head circumference measurements. Mean length and OFC SD scores were significantly low at birth (−1.3 and −1.8 respectively, p<0.001). The length SD score showed a significant improvement from birth to 4 years(−1.3 to −0.07 p<0.001). The OFC SD score remained significantly low throughout (−1.1, p=0.001 at 4 years). Weight SD score also improved from a mean of −0.77 at birth to −0.42 at 4 years. Catch up head growth has been found in malnourished children after nutritional rehabilitation and also in children treated for isolated growth hormone deficiency. CFTR expression has been reported in brain although its significance is unclear. It is possible that CSF secretion is influenced by presence of CFTR and this is deficient in CF. Further studies using NMR scans to calculate ventricular volume may throw light on this matter. Intelligence in CF is normally distributed, but regular psychometric testing may be required to reveal deficiencies. In conclusion despite good nutritional management head growth lags behind gain in height and weight in CF children.

The influence of the maternal thyroid hormone environment during pregnancy on the ontogenesis of brain and placental ornithine decarboxylase activity in the rat.

The influence of maternal hypothyroxinaemia on early brain and placental development was examined in a partially thyroidectomized (parathyroid-spared; TX) rat dam model. Ornithine decarboxylase (ODC) specific activity, along with more general indices of cell growth, were determined in prenatal whole brain (at 15, 19 and 22 days of gestation), postnatal brain regions (at 5, 10 and 14 days) and placenta. Maternal hypothyroxinaemia resulted in reductions in fetal body weight, brain weight, brain DNA content and brain total protein content at 15 days of gestation; the latter effect persisting until 19 days of gestation. Further changes in brain cell growth were observed near term, when an increase in the DNA concentration was accompanied by a decrease in the total protein:DNA ratio. Growth of the postnatal brain regions appeared normal, with the exception of an isolated increase in the protein content of the cerebellum at postnatal day 5. Determination of the specific activity of brain ODC revealed a complex pattern of change in the progeny of TX dams, superimposed upon the normal ontogenetic decline. In the fetal brain, activity was initially deficient at 15 days of gestation but was increased at 22 days of gestation relative to controls. The compromise extended into the postnatal period; ODC specific activity being transiently reduced in the brainstem, the subcortex and the cerebral cortex. Placental development was less consistently affected; wet weight, gross indices of cell growth (DNA content, DNA concentration, total protein:DNA ratio) and ODC specific activity were all normal in the TX dam. However, cytosolic and total protein concentrations were reduced at 15 and 19 days of gestation respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurotoxicity of 2,4-dichlorophenoxyacetic butyl ester in chick embryos.

Fertilized hens' eggs were externally treated, before starting incubation, with a single dose of 2,4-Dichlorophenoxyacetic butyl ester (2,4-D b.e., 3.1 mg/egg). Chicks at different developmental stages were examined, extending from 10 day embryos to one day after hatching. Previously, we demonstrated that 2,4-D b.e. produces hypomyelination in chicks born from treated eggs. In search of the causes of this hypomyelination, "myelin markers" such as sulphatides, cerebrosides and 2'3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) activity, as well as protein and nucleic acid contents were determined in the embryonic brains. We have shown in the present study that the chemical alterations occurred even before the period of active myelination, since myelin appears in chicken brain stem and cerebrum approximately after 17 days of incubation, and most of the chemical parameters studied are diminished before that time. The DNA content in brain of treated group is increased from the 14th embryonic day (with a transient diminution at 12th day) to the first hatching day, when compared to the control, suggesting a proliferation of glial cells, possibly oligodendrocytes.

Protein and RNA biosynthesis in various cellular fractions of the brain of undernourished rats

Body and brain weight; DNA, RNA, and protein content; total free nucleotides; amino acids and their specific activities; as well as the in vitro incorporation of 14C-phenylalanine into protein and of 2H-orotate into RNA of homogenates and various cellular brain fractions were measured in well-fed (WF) and undernourished rats during gestation (EI) and during growth, gestation, and lactation (EII). Body weight was significantly decreased in both EI and EII while brain weight and DNA content per organ were lower in EII than in WF and EI rats. The brain weight:DNA ratio was increased significantly in EII animals compared with the WF group. RNA content did not show any significant alterations in homogenates, nuclear, microsomal and pH-5 enzyme fractions but was elevated in mitochondrial and soluble fractions of the brain of EI rats compared with the WF group. Brain RNA content in EII animals was decreased in homogenates and all cellular fractions with the exception of the nuclear fraction in which it did not change significantly. The RNA:DNA ratio tended to increase (non-significantly) in the EI and EII groups as compared with the WF controls. Protein content was decreased in homogenates and all cellular fractions of EII rats while it was reduced only in the mitochondrial and pH-5 enzyme fractions of the EI group. The RNA:protein ratio fell in the microsomal fraction and rose in the soluble and pH-5 enzyme fractions of EI and EII animals. The protein:DNA ratio increased significantly in homogenates and the nuclear fraction of the EII Group: 14C-phenylalanine/mg protein incorporation was augmented in homogenates, mitochondrial, and soluble fractions, was diminished in the microsomal fraction, and did not change in the nuclear fraction of the brain of EI and EII rats. 3H-Orotate/mg RNA incorporation was decreased in the nuclear and microsomal fractions and was increased in the soluble and pH-5 enzyme fractions of the brain of EI and EII groups. Incorporation was also elevated in brain homogenates of EII rats and was reduced in the EI group. It was increased in the mitochondrial fraction of EI animals but did not show any change in the EII group. From these results, it can be concluded that dietary stress during gestation alone (EI) and during growth, gestation, and lactation (EII) modulates the metabolism of nucleic acids and proteins in the whole brain and in various cellular brain fractions.