Maternal selenium (Se) deficiency is associated with decreased neonatal Se levels, which increases the risk for neonatal morbidities. There is a hierarchy to selenoprotein expression after Se deficiency in adult rodents, depending on the particular protein and organ evaluated. However, it is unknown how limited Se supply during pregnancy impacts neonatal selenoprotein expression. We used an Se-deficient diet to induce perinatal Se deficiency (SeD), initiated 2–4 weeks before onset of breeding and continuing through gestation. Neonatal plasma, liver, heart, kidney, and lung were collected on the day of birth and assessed for selenoproteins, factors required for Se processing, and non-Se containing antioxidant enzymes (AOE). Maternal SeD reduced neonatal circulating and hepatic glutathione peroxidase (GPx) activity, as well as hepatic expression of Gpx1 and selenophosphate synthetase 2 (Sps2). In contrast, the impact of maternal SeD on hepatic thioredoxin reductase 1, hepatic non-Se containing AOEs, as well as cardiac, renal, and pulmonary GPx activity, varied based on duration of maternal exposure to SeD diet. We conclude that the neonatal liver and circulation demonstrate earlier depletion in selenoenzyme activity after maternal SeD. Our data indicate that prolonged maternal SeD may escalate risk to the neonate by progressively diminishing Se-containing AOE across multiple organs.

Intrauterine growth restriction (IUGR) is a relevant predictor for higher rates of neonatal sepsis worldwide and is associated with an impaired neonatal immunity and lower immune cell counts. During the perinatal period, the liver is a key immunological organ responsible for the nuclear factor kappa B (NF-κB)-mediated innate immune response to inflammatory stimuli, but whether this role is affected by IUGR is unknown. Herein, we hypothesized that the newborn liver adapts to calorie-restriction IUGR by inducing changes in the NF-κB signaling transcriptome, leading to an attenuated acute proinflammatory response to intraperitoneal lipopolysaccharide (LPS). We first assessed the hepatic gene expression of key NF-κB factors in the IUGR and normally grown (NG) newborn mice. Real-time quantitative PCR (RT-qPCR) analysis revealed an upregulation of both IκB proteins genes (Nfkbia and Nfkbib) and the NF-κB subunit Nfkb1 in IUGR vs. NG. We next measured the LPS-induced hepatic expression of acute proinflammatory genes (Ccl3, Cxcl1, Il1b, Il6, and Tnf) and observed that the IUGR liver produced an attenuated acute proinflammatory cytokine gene response (Il1b and Tnf) to LPS in IUGR vs. unexposed (CTR). Consistent with these results, LPS-exposed hepatic tumor necrosis factor alpha (TNF-α) protein concentrations were lower in IUGR vs. LPS-exposed NG and did not differ from IUGR CTR. Sex differences at the transcriptome level were observed in the IUGR male vs. female. Our results demonstrate that IUGR induces key modifications in the NF-κB transcriptomic machinery in the newborn that compromised the acute proinflammatory cytokine gene and protein response to LPS. Our results bring novel insights in understanding how the IUGR newborn is immunocompromised due to fundamental changes in NF-κB key factors.

Acetaminophen (APAP) overdose results in high morbidity and mortality, with limited treatment options. Increased understanding of the cellular signaling pathways activated in response to toxic APAP exposure is needed to provide insight into novel therapeutic strategies. Toxic APAP exposure induces hepatic nuclear factor kappa B (NFκB) activation. NFκB signaling has been identified to mediate the pro-inflammatory response, but also induces a pro-survival and regenerative response. It is currently unknown whether potentiating NFkB activation would be injurious or advantageous after APAP overdose. The NFκB inhibitory protein beta (IκBβ) dictates the duration and degree of the NFκB response following exposure to oxidative injuries. Thus, we sought to determine whether IκBβ/NFκB signaling contributes to APAP-induced hepatic injury. At late time points (24 hours) following toxic APAP exposures, mice expressing only IκBβ (AKBI mice) exhibited increased serologic evidence of hepatic injury. This corresponded with increased histologic injury, specifically related to sinusoidal dilatation. Compared to wild-type (WT) mice, AKBI mice demonstrated sustained hepatic nuclear translocation of the NFκB subunits p65 and p50, and enhanced NFκB target gene expression. This included increased expression of interleukin-6 (Il-6), a known contributor to hepatic sinusoidal dilation. This transcriptional response corresponded with increased plasma protein content of Il-6, as well as increased activation of signal transducer and activator of transcription 3 (STAT3). Impact Statement: IκBβ/NFκB signaling is associated with a pro-inflammatory response, exacerbated Il-6 and STAT3 activation, and this was associated with late development of sinusoidal dilatation. Thus, targeting sustained IκBβ/NFκB signaling may represent a novel therapeutic approach to attenuate late hepatic injury following toxic APAP exposure.

Objectives Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity. Selenium (Se) deficiency increases the risk for oxygen requirement at 28 days and BPD and thus may be a modifiable nutritional intervention. Se is an essential trace mineral that is incorporated into Se-containing antioxidant enzymes (AOE). An infant's Se status at birth is regulated by the mother's Se supply during pregnancy, however, it is unknown if any neonatal Se-containing AOE in the lung are decreased by antenatal Se deficiency. We hypothesize that antenatal Se deficiency will decrease neonatal pulmonary expression of Se-containing AOE. Methods C57Bl/6 mice were allocated to sufficient (SeS, 0.4 ppm Se) or deficient (SeD, < 0.01 ppm Se) diets before breeding. Breeding pairs were allowed to serially breed, and pups from the 1st-4th pregnancies were evaluated. Pups were sacrificed at PN0. Glutathione peroxidase (GPx) activity was measured in the lung by enzyme activity assay. Pulmonary GPx1, GPx3, thioredoxin reductase 1 (Trxrd1) and selenoprotein N (SelenoN) protein content were measured by Western blot. F and M pups were analyzed as separate groups. Results Weights were similar at postnatal day 0 (PN0) and PN4 for SeS and SeD pups, but by PN7 through adulthood, both male and female SeD mice weighed less then SeS mice. At PN0, pulmonary GPx activity was decreased in all SeD pups, with similar decreases in the protein content of both GPx1 and GPx3 (n = 6–10). We observed a progressive impact of SeD on the pups based on the dam's pregnancy. GPx activity and protein contents were more significantly decreased in pups born after a dam's 3rd or 4th pregnancy than the 1st or 2nd (n = 4–6). Trxrd1 and SelenoN protein content were not decreased in pups born after a dam's 1st or 2nd pregnancy (n = 4–6). However, both were decreased in the lungs of pups born to a dam's 3rd or 4th gestation (n = 6). Conclusions Neonatal pups exposed to antenatal SeD demonstrate decreased pulmonary GPx protein content and activity level without sex differences. Pups born to a SeD dam's third or fourth gestation exhibited a further decline in pulmonary Trxrd1 and SelenoN content. We speculate that SeD neonates may be vulnerable to pulmonary oxidative stresses secondary to low antioxidant enzymatic defense. Impaired ability to respond to oxidative challenge in the lung may predispose SeD infants to BPD. Funding Sources NIH/NHLBI.