Neonatal Selenoenzyme Expression Is Variably Susceptible to Duration of Maternal Selenium Deficiency

Research background: effects of in-utero selenium deficiency on neonatal mortality

If a mother is malnourished before and during pregnancy, the fetus may not receive enough macro- and micro-nutrients and could experience poor outcomes after birth. Deficiencies of the micronutrient selenium (Se) have been linked to neonatal conditions including sepsis, impaired neurodevelopment, poor postnatal growth, bronchopulmonary dysplasia and retinopathy of prematurity.

Se is essential for redox homeostasis and response to oxidative stress – an impaired response to oxidative stress can result in illness or death in neonates – and a decrease in Se-associated antioxidant enzymes (AOE) could disrupt organ development.

The regulation of Se processing has been depicted using preclinical mouse models, but its unknown how limited Se supply during pregnancy impacts neonatal selenoprotein expression and contributes to worse outcomes in neonates. A study led by the Perinatal Research Center at Children’s Hospital Colorado sought to determine:

They hypothesized, like the adult liver, that the neonatal liver responds to maternal Se deficiency by decreasing hepatic expression of GPx1 and Txnrd1 expression, and by increasing expression of non-Se containing AOE.

Research methods: characteristics of mice used for maternal Se analysis

Model of perinatal Se deficiency:

Two groups of six female and male mice, 3 to 4 weeks old were created:

• One group fed Torula yeast-based Se sufficient (SeS) diet
• One group fed Se-deficient diet (SeD)

The diet was fed to the mice two to four weeks before breeding and continued through gestation. Subsequent studies repeated the process, with mice from 10 sufficient litters and 10 deficient litters ultimately being assessed. In total, 20 SeS neonatal pups and 32 SeD pups were assessed on day of birth. The neonatal plasma, liver, heart, kidney and lung were collected for study.

Research results: neonate liver response to maternal Se deficiency 

Adult breeding age mice exposed to Se-deficient diet demonstrate decrease in circulating and hepatic selenoproteins:

Gpx3, Plasma Senop, and Hepatic GPx1 protein content decreased in male and female SeD mice. Hepatic Txnrd1 decreased after SeD, with males presenting with less Txnrd1 protein content than females. Female SeS mice had higher hepatic GPx than males, with GPx decreasing in the liver for both males and females. 

Antenatal Se-deficiency decreases litter size and circulating GPx activity in neonatal mice

The impact of Se deficiency on neonatal pups was evaluated on the day of birth. Litter size was lower in SeD pregnancies than SeS pregnancies, and all pups appeared phenotypically normal. Plasma GPx activity significantly decreased in SeD pups. 

Neonatal hepatic factors for Se processing and transport are decreased after antenatal Se deficiencies 

Selenophosphate synthetase 2 (Sephs2) was not reduced by maternal Se deficiency, but a significant decrease was noticed in phosphoryl-tRNA kinase (Pstk) and selenocysteine synthase (Sepsecs). SelenoP mRNA levels decreased in newborn mice from SeD dams, along with the expression of selenophosphate synthetase (Sps2).

Neonatal hepatic glutathione peroxidase 1 (Gpx1) is decreased after antenatal Se deficiency 

Hepatic Gpx1 mRNA levels and protein content decreased when an antenatal Se deficiency was present. No sex differences were found in Gpx1 mRNA, protein, or activity. 

Prolonged duration of maternal Se deficiency decreases neonatal hepatic thioredoxin reductase 1

An initial analysis of neonatal Trxrd1 showed high variability relating to the duration of maternal Se deficiency. Hepatic Txnrd1 mRNA decreased in the short and prolonged duration group, with Txnrd2 decreasing in the prolonged duration group. Txnrd1 protein content decreased in the prolonged SeD duration group, but Txnrd2 was unchanged. These results indicate that neonatal Txnrd1 content is initially sustained following exposure to maternal Se deficiency but eventually decreases in pups born in the longer duration of SeD group. 

Prolonged maternal Se deficiency was associated with increased expression of superoxide dismutase 2 and heme oxygenase 1 

Superoxide dismutase 2 (SOD) levels were greater in pups in the prolonged SeD dam group compared to the SeS or short SeD exposure group.

Neonatal GPx activity in the heart, kidney and lung is variable decreased Depending on Duration of Antenatal Se Deficiency 

GPx activity was significant in the liver and heart, with the kidney and lung also showing activity. Cardiac and renal GPx activity were lower in the prolonged SeD maternal group, with decreased pulmonary GpX activity showing in both groups. 

Research discussion: analyzing the impact of maternal Se deficiency on a neonate 

Maternal Se deficiency leads to decreased neonatal Se status, increasing an infant’s risk for various neonatal morbidities. This study was the first to create a neonatal hepatic selenoprotein hierarchy after exposure to decreased maternal Se supply. 

Key findings

• Selenoproteins in the neonatal circulation and liver were decreased by maternal Se deficiency. 
• Neonatal pups born to Se-deficient mothers are at risk for depletion in multiple Se-containing antioxidant enzymes. 
• The duration or severity of maternal Se deficiency may have a cumulative impact on an infant. 
• Decreased neonatal circulating and hepatic GPx may be maladaptive if the infant is exposed to high oxidant stress, common in modern neonatal intensive care units (ICUs). 
• The varied response noted in the duration of maternal Se deficiency for hepatic Txnrd1 suggests that it could be a confounding factor of maternal age.
• Increased hepatic GPx activity was higher at baseline for female adult rodents, consistent with past research. 

Research conclusions/clinical implication: maternal Se deficiency can significantly impact the health of an infant 

Overall, maternal periconception and antenatal Se deficiency are correlated with decreased circulating and organ-specific selenoproteins in offspring. Infants may be at a higher risk for morbidity after oxidative challenge if they have neonatal circulating and hepatic GPx1, both related to maternal Se deficiency.

The duration and degree of said deficiency also impacts the infant. Infants can experience many oxidative challenges that cause the insufficient selenoenzyme defense, which may increase the risk for morbidity or mortality. Future studies should look at Se deficiency on the hepatic redox state under normal physiologic conditions and when infants experience oxidative stress. They should also control for the degree of selenoprotein depletion in the neonate.