Pedro Rosso

The effect of severe early malnutrition on cellular growth of human brain.

Extract: In ten ‘normal’ brains, obtained from well-nourished Chilean children who died accidentally, weight, protein, and DNA and RNA content were all normal when compared with those values derived from similar children in the United States. Table I demonstrates the values obtained in these children. In nine infants who died of severe malnutrition during the first year of life, there was a proportional reduction in weight, protein, and RNA and DNA content. The actual values for these determinations are given in table II. The number of cells was reduced but the weight or protein per cell was unchanged Three infants who weighed less than 2,000 grams at birth (Infants 2, 3, and 4, table II) were the most severely affected. These data are similar to previous data in animals and demonstrate that in children, severe early malnutrition can result in curtailment of the normal increase in brain cellularity with increase in age.Speculation: At present there is growing concern that malnutrition early in life may retard normal development. Studies conducted in Africa, in South America, in Mexico, in Guatemala, and in our own country suggest that this is true. Retarded brain growth has also been suspected in malnourished children. The decreased head circumference often noted has been cited as evidence for retardation in brain growth. Although numerous chemical changes secondary to undernutrition have been shown in brain of animals, similar studies have not been available in human brain. This study demonstrates such changes and establishes that cell division is curtailed in human brain by severe early malnutrition. The data provide yet another link in the ever lengthening chain of evidence linking malnutrition to faulty brain growth and development.

Fetal Growth Retardation due to Maternal Tobacco Smoke Exposure in the Rat

Summary: Smoking during pregnancy results in offspring with an average birth weight 200 g less than those of non-smoking mothers. The pathogenesis of this effect is still unknown and there is no general agreement about the causal relationship between maternal smoking and subsequent fetal growth retardation. In the present study, a model of maternal smoking during pregnancy in the rat was established using the P & I Walton Exposure Machine. The study consisted of three groups: control, pair-fed, and smokeexposed. Smoke-exposed animals were exposed continuously to tobacco smoke for cycles of 7 min, 16 times a day from d 5 to d 20 of gestation. On d 21 of gestation, fetuses from all groups were removed by cesarean section, weighed, and dissected. The fetal brain, liver, and lungs as well as the placentas were weighed and analyzed for nucleic acid content. Fetal weight was found to be significantly reduced in both pair-fed and smoke-exposed groups compared with the control group. There was also a significant reduction in fetal body weight of the animals in the smoke-exposed group in comparison to those in the pair-fed group. Exposing the mother to smoke affected neither fetal brain weight nor nucleic acid content whereas fetal liver and lungs showed a significant decrease in both weight and nucleic acid content. These results indicate that the fetal growth retardation associated with maternal exposure to tobacco smoke in the rat corresponds to a disproportionate type. In addition, the present results indicate that the maternal tobacco smoke exposure induced fetal growth retardation without placental growth retardation.

Prenatal Alcohol Exposure: Abnormalities in Placental Growth and Fetal Amino Acid Uptake in the Rat

On day 20 of gestation, after ethanol feeding (27% ethanol calories, 25% protein), placental weights, DNA, RNA and water content were greater than in controls pair-fed an isocaloric diet without ethanol or those ad lib fed a pellet diet of similar composition. Rat litter size and fetal body, liver and brain weights were similar in all groups. In vivo fetal amino acid accumulation was significantly lower after alcohol exposure despite similar placental uptake. These results indicate that both placental hyperplasia and abnormal fetal amino acid uptake occur at a low alcohol dose when fetal body weight is unaffected.

Maternal-fetal exchange during protein malnutrition in the rat. Placental transfer of glucose and a nonmetabolizable glucose analog.

Maternal-fetal transfer of glucose and methyl alpha-D-glucopyranoside (AMG) was studied in rats fed either a 6% or a 27% casein diet. On day 21 of pregnancy 3H-labeled glucose and 14C labeled AMG were injected into the maternal circulation of both groups of dams and concentration of tritium and 14C in maternal plasma, placentas and fetuses were determined 10 and 20 minutes later respectively. In malnourished rats both substances tended to be slightly, although non-significantly, increased in maternal plasma and were significantly decreased in placentas and fetuses. This lower concentration in fetal tissues reflected a marked reduction in the amount of glucose and AMG transported into the fetuses per g of placental tissue per minute. The proportionality of the changes found for both substances suggests that their reduced rate of transfer may be due to similar mechanisms.

Changes in the transfer of nutrients across the placenta during normal gestation in the rat

Transfer of labeled glucose and alpha-amino isobutyric acid from the maternal circulation into the fetus was studied in the rat at various times during gestation and the results were correlated with placental and fetal growth. It was found that the rate of transfer of both substances per gram of placental tissue increase markedly near term in coincidence with a simultaneous fetal growth spurt. The data suggest a bimodal sequence of growth of the conceptus with a first phase of rapid placental growth and reduced placental transfer and a second phase of slow placental growth, increased transfer, and rapid fetal growth.

Placental Blood Flow and Transfer of Nutrient Analogs in Large, Average, and Small Guinea Pig Littermates

Summary: Placental blood flow in the maternal side and transfer of [14C]-α-amino isobutyric acid (AIB) and [3H]methylglucose (MG) were measured in 22 pregnant guinea pigs at various gestational ages. The fetuses were divided in three groups according to their body weights: small, average, and large. Body weight was 85.25% of average values in the small fetuses and 114.12% in the large fetuses. Placental weight was 121.73% of average in the large fetuses and 84.42% in the small fetuses. Placental blood flow was 134.48% of average in large fetuses and 73.18% in small fetuses. AIB and MG transfers were significantly lower in the small fetuses (80.33% and 86.06%, respectively, of average values). In contrast, in large fetuses, AIB transfer was 123.43%, and MG transfer was 113.96% of average. Significant correlations were found between fetal and placental weight and placental blood flow and transfer of AIB and MG in the various groups. Placental transfer of AIB and placental blood flow were significantly correlated in the small (r = 0.59) and average weight fetuses (r = 0.37). In addition, the slope of the regression curve for AIB was significantly steeper in the small fetuses when compared with the slope of average and large fetuses. Placental blood flow and transfer of MG were significantly correlated only in the large fetuses (r = 0.48). In the small fetuses, the rate of AIB transfer was proportionally more reduced than that of MG transfer as the rate of placental blood flow decreased.The results demonstrate that spontaneous fetal growth retardation in the guinea pig is associated with a smaller placenta, a reduced placental blood flow, and a reduced transfer of AIB and MG. Inasmuch as in the small fetuses AIB transfer was proportionally more reduced than MG transfer, it is suggested that in addition to the reduced blood flow limited availability of certain essential ammo acids may be a cause of fetal growth retardation.Speculation: A reduced placental transfer of certain essential amino acids may further aggravate the fetal growth retardation associated with low placental blood flow.

Changes in ascorbic acid metabolism of the offspring following high maternal intake of this vitamin in the pregnant guinea pig

Guinea pigs were fed a control (0.05%) or a high (0.5%) ascorbic acid diet during the last half of pregnancy. When the pups were tested at 5 and 10 days of life the ones from the high-ascorbic-acid group demonstrated a marked increase in 14CO2 excretion, compared with the control pups, following an intraperitoneal injection of 14C-labeled ascorbic acid. When the animals were weaned to an ascorbic-acid-deficient diet signs of scurvy appeared earlier in the pups from the high vitamin C group and their survival was shorter. When excretion of labeled CO2 in both groups was correlated with the day of onset of scurvy signs, a linear correlation was found between these two parameters, suggesting that the earlier appearance of signs of scurvy in the experimental pups is secondary to an increased rate of ascorbic acid catabolism.

Maternal Hyperglycemia and its Effect on the Placental Transport of Ascorbic acid

Summary: This report explored the possibility that maternal hyperglycemia during pregnancy might produce a competition between glucose (G) and ascorbic acid (AA) and reduce the transfer of AA to the fetus using an in vivo single-pass placental perfusion technique in the guinea pig. Levels of G in maternal plasma increased from 104 ± 4 mg/dl (x ± S.E.) before AA + G infusion to 370 ± 19 mg/dl at the end of each study (P < 0.001). Preinfusion levels of AA in maternal and fetal plasma were 0.29 ± 0.02 mg/dl and 0.46 ± 0.03 mg/dl, respectively. Maternal infusion of AA or AA + G produced significant increases in maternal plasma AA (P < 0.025) and fetal plasma AA (P < 0.001); however, fetal plasma AA from dams infused with AA + G were significantly below fetal plasma values obtained when only AA was infused (P < 0.005) suggesting that when maternal plasma G is increased, the placental transport of AA to the fetus is reduced. Preinfusion levels of AA in placental tissue were 10.8 ± 0.5 mg/dl and infusion of AA or AA + G produced significant increases in AA in this organ (P < 0.001). Comparison of the AA in placental tissue from fetuses of dams infused with either solution demonstrates that significantly less AA was present after AA + G infusion (P < 0.005). Additionally, when AA + G was infused a significant decrease in AA transferred across the placenta was found (P < 0.001) as maternal plasma G increased beyond 200 mg/dl. The data suggest that in the guinea pig glucose may compete with ascorbic acid transfer across the placenta and that maternal hyperglycemia may reduce the bioavailability of AA to the fetus.Speculation: An acute episode of maternal hyperglycemia interferes with the placental transfer of ascorbic acid. Therefore, maternal hyperglycemia during gestational diabetes may result in a decreased supply of ascorbic acid to the fetus.

Nutrition and Pregnancy

Fetal growth largely depends on an adequate supply of oxygen and nutrients. The changes that occur in the maternal organism during pregnancy, the so-called maternal adaptive mechanisms, are the most part directly or indirectly involved with the oxygen and nutrient needs of the fetus. The control of the maternal adaptive changes is not well understood. It seems clear, however, that to a large extent they are not under the direct influence of the fetus. Experiments have shown that both the rat and human placentae may remain attached to the uterus and, apparently, maintain an adequate secretion of hormones even after removal of the fetus (Bourdel and Jacquot, 1959; Friedman et al., 1969). The sequence of the maternal adaptive changes also suggest the influence of placental hormones rather than fetal needs. For example, the maximum rate of expansion of blood volume and maternal weight gain takes place during midgestation, 10 weeks before maximum placental growth and 15 weeks before maximum fetal growth (Fig. 1). Thus, pregnancy seems to have two phases: a “maternal phase,” which occurs during the first half of gestation and prepares the maternal organism for future fetal demands, and a “fetal phase” of maximum fetal requirements, occurring during the second half of gestation.

Effects of Malnutrition on Brain Development

During the past 15 years, it has become increasingly clear that severe malnutrition imposed during certain critical periods of development will affect brain growth and function. Because infantile malnutrition still constitutes one of the greatest health problems in the world, since even by conservative estimates 300 million people may have been afflicted by malnutrition in infancy, it would seem important to examine, critically, the evidence upon which this statement is based. The purpose of this chapter is to review normal brain growth, to examine the data leading up to the “critical periods” hypothesis, and to document the effects of undernutrition during these critical periods.