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.

Fig. 1.

Fetal baboon brain cortical development at 0.5 gestation. Immunohistochemical distribution of glial (GFAP, S-100β) and neuronal (DCX, NeuN) marker proteins (brown precipitate) is shown. The brain at this stage of development consists of the ventricular zone and SVZ (where cells are born), the intermediate zone (through which cells migrate to target regions, such as the cortical plate), the subplate (a transient structure essential in cortical network formation), and the cortical plate and marginal zone that form the presumptive cerebral cortex. GFAP⁺ radial glia are highly concentrated in the SVZ. Their processes span the entire width of the cerebral wall. Sporadic GFAP⁺ cells with few astral branches represent mature astrocytes with growing processes. Immature S-100β+ astrocytes and DCX+ neurons are abundant in all layers. The extracellular appearance of S-100β reflects its function as a neurotrophic factor. Mature NeuN+ neurons are most prominent in the cortical plate. Their more dense occurrence in the inner than in the outer cortical plate reflects inside-out layering.

Fig. 2.

Effects of MNR in the proliferative SVZ and in the cortical plate. SVZ: MNR reduced SVZ thickness (arrowheads), increased the density of proliferative Ki-67⁺ cells (brown precipitate, arrowheads mark the SVZ), increased apoptotic TUNEL⁺ cells (dark cells marked by arrows), and reduced glial S-100β IR (brown precipitate, arrows). Cortical plate: MNR decreased local IGF-I and BDNF IR (brown precipitate), density of the neuronal network (Golgi silver impregnation, arrowheads), and O4⁺ preoligodendrocytes (brown precipitate, arrows) reflecting impaired cerebral myelinogenesis.

Fig. 3.

Effects of MNR on proteins that participate in regulation of brain development. MNR decreased MHC-B IR in the SVZ, PSA-NCAM IR in the intermediate zone, and EphB2 and β-actin IR in the cortical plate (brown precipitate). In contrast, antiapoptotic Bcl-2 increased (brown precipitate), probably in response to increased proliferative cell death.