Vulnerability of the fetal primate brain to moderate reduction in maternal global nutrient availability

Abstract

Moderate maternal nutrient restriction during pregnancy occurs in both developing and developed countries. In addition to poverty, maternal dieting, teenage pregnancy, and uterine vascular problems in older mothers are causes of decreased fetal nutrition. We evaluated the impact of global 30% maternal nutrient reduction (MNR) on early fetal baboon brain maturation. MNR induced major cerebral developmental disturbances without fetal growth restriction or marked maternal weight reduction. Mechanisms evaluated included neurotrophic factor suppression, cell proliferation and cell death imbalance, impaired glial maturation and neuronal process formation, down-regulation of gene ontological pathways and related gene products, and up-regulated transcription of cerebral catabolism. Contrary to the known benefits from this degree of dietary reduction on life span, MNR in pregnancy compromises structural fetal cerebral development, potentially having an impact on brain function throughout life.oderate malnutrition during pregnancy is widespread in both developing and industrialized countries. Worldwide, 852 million people experienced food insecurity in 2004 (1) and 35-40% of children experience moderate malnutrition (2). In industrialized countries, maternal lifestyle, in which dieting (including global food reduction) is used for cosmetic reasons, is a common cause of moderate malnutrition. Recently, one study has shown that most women do not improve their dietary and lifestyle patterns in pregnancy (3). Decreased nutrient delivery to the fetus also occurs in teenage pregnancy (4) and during pregnancy in women over 35 y of age (5). Severe global reduction in nutrition during pregnancy has long been known to result in fetal growth restriction and to cause permanent brain dysfunction, especially cognitive and behavior deficits (6-10). In rodents, these deficits are accompanied by alterations of neuronal excitability as well as structural changes in the developing and adult brain (11,12). In contrast, effects of moderate maternal global reduction in nutrition on the fetus have been poorly examined. It is often assumed that moderate degrees of maternal nutrient reduction (MNR) are without unwanted consequences because it has generally been considered that the mother prioritizes fetal nutrient supply at the expense of her own needs, and brain growth is assumed to be spared from the other fetal effects of moderate decreases in fetal nutrient availability. This concept no longer appears to be tenable. Several rodent studies have demonstrated significant changes in fetal body and brain composition, often in the absence of major reduction of birth weight following poor maternal nutrition during pregnancy (11,12). In relation to the changes in brain development that we report here in a nonhuman primate species, evidence is accumulating that birth weight at the lower end of the normal range is associated with impaired higher mental function in later life (5,13,14).We addressed effects of 30% global moderate MNR on early fetal cereb...

Prenatal growth in humans and postnatal brain maturation into late adolescence

“…Similarly, the proper incorporation of new neurons and incoming afferents into the developing cortical sheet is thought to rely heavily on the subplate, a transient structure that becomes most prominent during the second trimester of primate pregnancy, and especially so under nascent associative cortices (23). Although speculative, the notion that SVZ and subplate processes might be particularly vulnerable to alterations of the prenatal environment capable of modifying BW has been lent support by a recently published study that provides experimental data on in utero adversity and brain development in primates (37). In this landmark study, modest maternal calorie restriction not only altered the balance between rates of cell birth and apoptosis in midgestation baboon SVZ but also reduced subplate neuronal network density.…”

“…In keeping with this notion, most studies of the mechanisms underlying BW differences between MZ twins have focused on the placenta as the chief determinant of the in utero environment, linking withintwin differences in prenatal growth to inequitable access to placental tissue (35). The capacity of placental mechanisms for BW variation to also impact brain development has been established through experimental modification of effective placental transfer in animal models of placental insufficiency (1) and maternal undernutrition (36,37). In humans, ultrasonographic markers of placental insufficiency have been shown to predict neurobehavioral outcomes during fetal and early postnatal life (38,39).…”

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

“…Given that brain methylation cannot be studied in vivo in humans, and that epigenetic changes relevant for developmental programming can be part of a general response of the entire organism, 20,37 we used pyrosequencing to analyze rs6265 methylation in peripheral blood mononuclear cells (PBMCs) of 259 healthy humans. This site is differentially methylated in human PBMCs and, as predictable, methylation was affected by rs6265 genotype, given that only the Val allele has a CpG in this position (ANOVA: ND259; F 2,256 D1601.2; P < 0.001 ÃÃÃ ; ValVal > ValMet > MetMet; Fig.…”

“…17 However, BDNF has not been associated with schizophrenia in recent large scale genome wide association studies. 18 BDNF expression is sensitive to early-life environment [19][20][21] and specifically hypoxic-stressors, 22,23 which, in turn, are critical factors involved in the pathophysiology of schizophrenia. [24][25][26][27] The failure to find association between BDNF and schizophrenia in large-scale case control studies may conceivably reflect a complex interaction of genotype and environmental experience that alters methylation status.…”

Maternal cortisol over the course of pregnancy and subsequent child amygdala and hippocampus volumes and affective problems

“…Intrauterine conditions that affect these structures and also are associated with increased risk for neuropsychiatric disorders include infection (9), maternal undernutrition (10,11), unhealthy maternal behaviors such as smoking or alcohol or drug use (12)(13)(14), and excessive maternal stress exposure (15). We and others have suggested that glucocorticoids (cortisol in humans) may play a salient role in this process (16)(17)(18).…”