Aline Andres

Maternal obesity is associated with a lipotoxic placental environment.

Maternal obesity is associated with placental lipotoxicity, oxidative stress, and inflammation, where MAPK activity may play a central role. Accordingly, we have previously shown that placenta from obese women have increased activation of MAPK-JNK. Here, we performed RNA-sequencing on term placenta from twenty-two subjects who were dichotomized based on pre-pregnancy BMI into lean (BMI 19-24 kg/m(2); n = 12) and obese groups (BMI, 32-43 kg/m(2); n = 12). RNA-seq revealed 288 genes to be significantly different in placenta from obese women by ≥ 1.4-fold. GO analysis identified genes related to lipid metabolism, angiogenesis, hormone activity, and cytokine activity to be altered in placenta from obese women. Indicative of a lipotoxic environment, increased placental lipid and CIDEA protein were associated with decreased AMPK and increased activation of NF-κB (p65) in placenta from obese women. Furthermore, we observed a 25% decrease in total antioxidant capacity and increased nuclear FOXO4 localization in placenta from obese women that was significantly associated with JNK activation, suggesting that maternal obesity may also be associated with increased oxidative stress in placenta. Maternal obesity was also associated with decreased HIF-1α protein expression, suggesting a potential link between increased inflammation/oxidative stress and decreased angiogenic factors. Together, these findings indicate that maternal obesity leads to a lipotoxic placental environment that is associated with decreased regulators of angiogenesis and increased markers of inflammation and oxidative stress.

The health implications of soy infant formula

Soy formula (SF) has been fed to millions of infants worldwide. It has been shown to promote growth and development as well as milk-based formula (MF). Controversy has developed over the adequacy and safety of SF. Most concerns are based on in vivo and in vitro data that raise the possibility of estrogenic effects of isoflavones contained in SF. There are few studies of children who were fed SF, and thus insufficient data are available to judge if SF feeding results in clinically significant developmental effects and if there are any long-term health consequences (adverse or beneficial). However, the Arkansas Childrens Nutrition Center is conducting a prospective longitudinal study comparing growth, development, and health of breastfed children with formula-fed (SF and MF) children from birth through age 6 y. After 5 y of study, children in all 3 groups (n > 300) are growing and developing within normal limits, and there are no indications of adverse effects in the soy-fed children. Neonatal pig studies comparing SF, MF, and breast milk (BM) have shown diet-specific gene expression profiles in various target tissues. Therefore, although SF differed significantly from BM, MF also differed from BM, and SF differed from MF. Nonetheless, these animals grew and developed normally, and SF piglets had several health benefits (eg, increased bone quality) and no observable adverse effects. Thus, to date, our results suggest that SF supports normal growth and may have advantages in promoting bone development.

Soy isoflavones and virus infections.

Abstract Isoflavones and their related flavonoid compounds exert antiviral properties in vitro and in vivo against a wide range of viruses. Genistein is, by far, the most studied soy isoflavone in this regard, and it has been shown to inhibit the infectivity of enveloped or nonenveloped viruses, as well as single-stranded or double-stranded RNA or DNA viruses. At concentrations ranging from physiological to supraphysiological (3.7–370 μM), flavonoids, including genistein, have been shown to reduce the infectivity of a variety of viruses affecting humans and animals, including adenovirus, herpes simplex virus, human immunodeficiency virus, porcine reproductive and respiratory syndrome virus, and rotavirus. Although the biological properties of the flavonoids are well studied, the mechanisms of action underlying their antiviral properties have not been fully elucidated. Current results suggest a combination of effects on both the virus and the host cell. Isoflavones have been reported to affect virus binding, entry, replication, viral protein translation and formation of certain virus envelope glycoprotein complexes. Isoflavones also affect a variety of host cell signaling processes, including induction of gene transcription factors and secretion of cytokines. The efficacy of isoflavones and related flavonoids in virus infectivity in in vitro bioassays is dependent on the dose, frequency of administration and combination of isoflavones used. Despite promising in vitro results, there is lack of data confirming the in vivo efficacy of soy isoflavones. Thus, investigations using appropriate in vivo virus infectivity models to examine pharmacological and especially physiological doses of flavonoids are warranted.

Developmental Status of 1-Year-Old Infants Fed Breast Milk, Cow’s Milk Formula, or Soy Formula

BACKGROUND AND OBJECTIVE: Although soy formula has been reported to support normal development, concerns exist regarding potential adverse developmental effects of phytochemicals associated with soy protein. This study characterized developmental status (mental, motor, and language) of breastfed (BF), milk-based formula–fed (MF), or soy protein–based formula–fed (SF) infants during the first year of life. METHODS: Healthy infants (N = 391) were assessed longitudinally at ages 3, 6, 9, and 12 months. Development was evaluated by using the Bayley Scales of Infant Development and the Preschool Language Scale-3. Mixed effects models were used while adjusting for socioeconomic status, mother’s age and IQ, gestational age, gender, birth weight, head circumference, race, age, and diet history. RESULTS: No differences were found between formula-fed infants (MF versus SF). BF infants scored slightly higher than formula-fed infants on the Mental Developmental Index (MDI) score at ages 6 and 12 months (P < .05). Infants who were breastfed also had higher Psychomotor Development Index scores than SF infants at age 6 months and slightly higher Preschool Language Scale-3 scores than MF infants at ages 3 and 6 months (P < .05). In addition, BF infants had a lower probability to score within the lower MDI quartile compared with MF infants and a higher likelihood to score within the upper quartile for the MDI and Psychomotor Development Index compared with SF infants. CONCLUSIONS: This unique study showed that all scores on developmental testing were within established normal ranges and that MF and SF groups did not differ significantly. Furthermore, this study demonstrated a slight advantage of BF infants on cognitive development compared with formula-fed infants.

Ultrasonographic Patterns of Reproductive Organs in Infants Fed Soy Formula: Comparisons to Infants Fed Breast Milk and Milk Formula

OBJECTIVE To determine if differences exist in hormone-sensitive organ size between infants who were fed soy formula (SF), milk formula (MF), or breast milk (BF). STUDY DESIGN Breast buds, uterus, ovaries, prostate, and testicular volumes were assessed by ultrasonography in 40 BF, 41 MF, and 39 SF infants at age 4 months. RESULTS There were no significant feeding group effects in anthropometric or body composition. Among girls, there were no feeding group differences in breast bud or uterine volume. MF infants had greater (P < .05) mean ovarian volume and greater (P < .01) numbers of ovarian cysts per ovary than did BF infants. Among boys, there were no feeding group differences in prostate or breast bud volumes. Mean testicular volume did not differ between SF and MF boys, but both formula-fed groups had lower volumes than BF infants. CONCLUSIONS Our data do not support major diet-related differences in reproductive organ size as measured by ultrasound in infants at age 4 months, although there is some evidence that ovarian development may be advanced in MF-fed infants and that testicular development may be slower in both MF and SF infants as compared with BF. There was no evidence that feeding SF exerts any estrogenic effects on reproductive organs studied.

Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity

Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine (IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters (IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling.

A comprehensive analysis of the human placenta transcriptome

As the conduit for nutrients and growth signals, the placenta is critical to establishing an environment sufficient for fetal growth and development. To better understand the mechanisms regulating placental development and gene expression, we characterized the transcriptome of term placenta from 20 healthy women with uncomplicated pregnancies using RNA-seq. To identify genes that were highly expressed and unique to the placenta we compared placental RNA-seq data to data from 7 other tissues (adipose, breast, hear, kidney, liver, lung, and smooth muscle) and identified several genes novel to placental biology (QSOX1, DLG5, and SEMA7A). Semi-quantitative RT-PCR confirmed the RNA-seq results and immunohistochemistry indicated these proteins were highly expressed in the placental syncytium. Additionally, we mined our RNA-seq data to map the relative expression of key developmental gene families (Fox, Sox, Gata, Tead, and Wnt) within the placenta. We identified FOXO4, GATA3, and WNT7A to be amongst the highest expressed members of these families. Overall, these findings provide a new reference for understanding of placental transcriptome and can aid in the identification of novel pathways regulating placenta physiology that may be dysregulated in placental disease.

Brain gray and white matter differences in healthy normal weight and obese children

To compare brain gray and white matter development in healthy normal weight and obese children.

Longitudinal body composition of children born to mothers with normal weight, overweight, and obesity.

The longitudinal trajectories of body composition of children born to mothers with normal weight, overweight, and obesity have not been evaluated using precise body composition methods. This study investigated the relationship between maternal prepregnancy BMI and offspring body composition trajectories during the first 6 years of life.

Quantitative Nuclear Magnetic Resonance to Measure Fat Mass in Infants and Children

Quantitative nuclear magnetic resonance (QMR) is being used in human adults to obtain measures of total body fat mass (FM) with high precision. The current study assessed a device specially designed to accommodate infants and children between 3 and 50 kg (EchoMRI‐AH). Body composition of 113 infants and children (3.3–49.9 kg) was assessed using dual‐energy X‐ray absorptiometry (DXA), air displacement plethysmography (ADP, PeaPod for infants ≤8 kg and BodPod for children ≥6 years) and QMR. Results were compared with the deuterium oxide dilution technique (D2O) and a four‐compartment model (4‐C). The percentages of compliance were: 98% QMR; 75% DXA; 94% BodPod; and 95% PeaPod. Although QMR precision was high (coefficient of variation = 1.42%), it overestimated FM ∼10% compared to the 4‐C model and underestimated FM by ∼4% compared to the deuterium method in children ≥6 years. QMR was less concordant with 4‐C or D2O models for infants ≤8 kg. Thus, a piece‐wise defined model for mathematically fitting the QMR data to the D2O data was employed and this adjustment improved the accuracy relative to D2O and 4‐C for infants. Our results suggest that the pediatric QMR with appropriate mathematical adjustment provides a fast and precise method for assessing FM longitudinally in infants and in children weighing up to 50 kg.