Effects of maternal nutrient restriction during the periconceptional period on placental development in the mouse

Abstract

Maternal undernutrition has detrimental effects on fetal development and adult health. Total caloric restriction during early pregnancy followed by adequate nutrition for the remainder of gestation, is particularly linked to cardiovascular and metabolic disease risks during adulthood. The placenta is responsible for transport of nutrients from the maternal to fetal circulation, and the efficiency with which it does so can be adjusted to the maternal nutrient supply. There is evidence that placental adaptations to nutrient restriction in early pregnancy may be retained even when adequate nutrition is restored later in pregnancy, leading to a potential mismatch between placental efficiency and maternal nutrient supplies. However, in the mouse, 50% caloric restriction from days 1.5–11.5 of gestation, while temporarily altering placental structure and gene expression, had no significant effect on day 18.5. The periconceptional period, during which oocyte maturation, fertilization, and preimplantation development occur may be especially critical in creating lasting impact on the placenta. Here, mice were subjected to 50% caloric restriction from 3 weeks prior to pregnancy through d11.5, and then placental structure, the expression of key nutrient transporters, and global DNA methylation levels were examined at gestation d18.5. Prior exposure to caloric restriction increased maternal blood space area, but decreased expression of the key System A amino acid transporter Slc38a4 at d18.5. Neither placental and fetal weights, nor placental DNA methylation levels were affected. Thus, total caloric restriction beginning in the periconceptional period does have a lasting impact on placental development in the mouse, but without changing placental efficiency.

Placental adaptations supporting fetal growth during normal and adverse gestational environments

“…However, in mice a 25% reduction in maternal caloric intake from mid-gestation can result in increased Slc2a3 expression and glucose transport, but this is associated with a secondary reduction in placental system L transport and fetal growth restriction (Ganguly et al, 2012(Ganguly et al, , 2016. In undernourished mice, there is also a report of placental Slc38a4 expression being less, but fetal weight unchanged compared to normally nourished controls (Van Gronigen Case et al, 2021). Last, findings relying on the expression or abundance of nutrient transporters in sheep have suggested that placental glucose and lipid transport capacity may be increased in early pregnancy by maternal undernutrition, as informed by Slc2a1 and Fatp4 expression levels, respectively, and these may relate to normal fetal growth in the model near term (Ma et al, 2011).…”

“…For instance, other work has found Igf2 to be stably expressed in the placenta even when there are environmentally mediated changes in placental phenotype with reduced placental perfusion in guinea pigs (Carter et al, 2005), or undernutrition in sheep (McMullen et al, 2005). Further, changes in the placental expression of additional imprinted genes, including Igf2r, H19, Dlk1, Grb10 and Slc38a4, have been reported in different animal models subject to unfavourable gestational environments (Coan et al, 2008(Coan et al, , 2011Cuffe et al, 2014;Lesage et al, 2002;Lin et al, 2012;Sferruzzi-Perri et al, 2013;Van Gronigen Case et al, 2021). Thus, imprinted genes are important for mediating adaptive responses in placental physiology, in response to both developmental and environmental cues.…”

“…In sheep, a graded reduction in food intake across pregnancy (McMullen et al., 2005 ) or 15% reduction in food intake just in the first half of pregnancy (Steyn et al., 2001 ) also results in the formation of more mature placentas and preserved fetal weight. In mice, a 50% reduction in maternal food intake from prior to pregnancy is associated with no change in placental weight, preserved labyrinthine zone size, expanded placental–maternal blood spaces and fetal growth maintenance until term (Chen et al., 2013 ; Ganguly et al., 2012 , 2016 ; Harper et al., 2015 ; Schulz et al., 2012 ; Van Gronigen Case et al., 2021 ). Also in mice, a 20% reduction in maternal food intake from the start of pregnancy is also accompanied by maintenance of labyrinthine zone size and fetal weight, at least until late gestation (Coan et al., 2010 ; Sferruzzi‐Perri et al., 2011 ).…”

Evaluating different models of maternal stress on stress-responsive systems in prepubertal mice

“…Two frequent models of maternal stress include nutritional stress by high fat diet (HFD) or caloric restriction (CR) ( Cortes-Albornoz et al, 2021 ; Van Gronigen Case et al, 2021 ). These exposures have been linked to behavioral alterations indicative of attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), anxiety, and depression ( Cortes-Albornoz et al, 2021 ; Wen et al, 2022 ; Castillo et al, 2023 ).…”

Early life programming of neurodevelopment and growth: understanding nutritional, inflammatory, and placental contributions in complex pregnancies

“…Importantly, understanding nutrient-sensitive dysregulation in the placenta may not explain whether, or which, nutrient-related mechanisms drove improper neural tube closure earlier in pregnancy, and thus, may not directly inform preventative efforts for NTDs. However, maternal undernutrition, even when limited to the periconceptional and early gestational periods, can have a lasting impact on placental phenotype 51,468 , and changes in the placenta may reflect earlier environments, thus provide clues of key developmental programming phenomena. For clear ethical reasons, investigation of neural tube closure in the human embryo in vivo is not possible, however, our analysis pipeline could be applied as a first step towards characterising the nutrient-sensitive functions of the human yolk sac (YS).…”