Lipid Aldehydes 4-Hydroxynonenal and 4-Hydroxyhexenal Exposure Differentially Impact Lipogenic Pathways in Human Placenta.

Long chain polyunsaturated fatty acids (LCPUFAs), such as the omega-6 (n-6) arachidonic acid (AA) and n-3 docosahexanoic acid (DHA), have a vital role in normal fetal development and placental function. Optimal supply of these LCPUFAs to the fetus is critical for improving birth outcomes and preventing programming of metabolic diseases in later life. Although not explicitly required/recommended, many pregnant women take n-3 LCPUFA supplements. Oxidative stress can cause these LCPUFAs to undergo lipid peroxidation, creating toxic compounds called lipid aldehydes. These by-products can lead to an inflammatory state and negatively impact tissue function, though little is known about their effects on the placenta. Placental exposure to two major lipid aldehydes, 4-hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE), caused by peroxidation of the AA and DHA, respectively, was examined in the context of lipid metabolism. We assessed the impact of exposure to 25 µM, 50 µM and 100 µM of 4-HNE or 4-HHE on 40 lipid metabolism genes in full-term human placenta. 4-HNE increased gene expression associated with lipogenesis and lipid uptake (ACC, FASN, ACAT1, FATP4), and 4-HHE decreased gene expression associated with lipogenesis and lipid uptake (SREBP1, SREBP2, LDLR, SCD1, MFSD2a). These results demonstrate that these lipid aldehydes differentially affect expression of placental FA metabolism genes in the human placenta and may have implications for the impact of LCPUFA supplementation in environments of oxidative stress.

How the placenta-brain lipid axis impacts the nutritional origin of child neurodevelopmental disorders: Focus on attention deficit hyperactivity disorder and autism spectrum disorder.

Dietary fish is a rich source of omega-3 (n-3) fatty acids, and as such, is believed to have played an important role in the evolution of the human brain and its advanced cognitive function. The long chain polyunsaturated fatty acids, particularly the n-3 docosahexanoic acid (DHA), are critical for proper neurological development and function. Both low plasma DHA and obesity in pregnancy are associated with neurodevelopmental disorders such as attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in childhood, and n-3 supplementation has been shown to improve symptoms, as reviewed herein. The mechanisms underlying the connection between maternal obesity, n-3 fatty acid levels and offspring's neurological outcomes are poorly understood, but we review the evidence for a mediating role of the placenta in this relationship. Despite promising data that n-3 fatty acid supplementation mitigates the effect of maternal obesity on placental lipid metabolism, few clinical trials or animal studies have considered the neurological outcomes of offspring of mothers with obesity supplemented with n-3 FA in pregnancy.

Placental Impact of Dietary Supplements: More Than Micronutrients.

PURPOSE: Maternal nutrition is a key modifier of fetal growth and development. However, many maternal diets in the United States do not meet nutritional recommendations. Dietary supplementation is therefore necessary to meet nutritional goals. The effects of many supplements on placental development and function are poorly understood. In this review, we address the therapeutic potential of maternal dietary supplementation on placental development and function in both healthy and complicated pregnancies. METHODS: This is a narrative review of original research articles published between February 1970 and July 2020 on dietary supplements consumed during pregnancy and placental outcomes (including nutrient uptake, metabolism and delivery, as well as growth and efficiency). Impacts of placental changes on fetal outcomes were also reviewed. Both human and animal studies were included. FINDINGS: We found evidence of a potential therapeutic benefit of several supplements on maternal and fetal outcomes via their placental impacts. Our review supports a role for probiotics as a placental therapeutic, with effects that include improved inflammation and lipid metabolism, which may prevent preterm birth and poor placental efficiency. Supplementation with omega-3 fatty acids (as found in fish oil) during pregnancy tempers the negative effects of maternal obesity but may have little placental impact in healthy lean women. The beneficial effects of choline supplementation on maternal health and fetal growth are largely attributable to its placental impacts. l-arginine supplementation has a potent provascularization effect on the placenta, which may underlie its fetal growth-promoting properties. IMPLICATIONS: The placenta is exquisitely sensitive to dietary supplements. Pregnant women should consult their health care practitioner before continuing or initiating use of a dietary supplement. Because little is known about impacts of many supplements on placental and long-term offspring health, more research is required before robust clinical recommendations can be made.

Maternal obesity is not associated with placental lipid accumulation in women with high omega-3 fatty acid levels.

INTRODUCTION: Placentas of obese women have higher lipid content compared to lean women. We have previously shown that supplementation of overweight and obese women with omega-3 fatty acids decreases placental esterification pathways and total lipid content in a mid-western population (Ohio). We hypothesized that placental lipid accumulation and inflammation would be similar between lean and obese women living in a region of high omega-3 intake, such as Hawaii. METHODS: Fifty-five healthy, normal glucose tolerant women from Honolulu Hawaii, dichotomized based on pre-pregnancy BMI into lean (BMI <25 kg/m2, n = 29) and obese (BMI >30 kg/m2, n = 26), were recruited at scheduled term cesarean delivery. Maternal plasma DHA levels were analyzed by mass spectrometry. Expression of key genes involved in fatty acid oxidation and esterification were measured in placental tissue using qPCR. Total lipids were extracted from placental tissue via the Folch method. TNF-α concentration was measured by enzyme-linked immunosorbent assay in placental lysates. RESULTS: DHA levels were higher in lean women compared to obese women (P = 0.02). However, DHA levels in obese women in Hawaii were eight times higher compared to obese Ohioan women (P=<0.0001). Placental lipid content and expression of key genes involved in fatty acid oxidation and esterification were similar (P > 0.05) between lean and obese women in Hawaii. Furthermore, TNF-α placental lysates were not different between lean and obese women. CONCLUSIONS: Though obese women in Hawaii have lower DHA levels compared to their lean counterparts, these levels remain over eight times as high as obese Ohioan women. These relatively high plasma omega-3 levels in obese women in Hawaii may suppress placental lipid esterification/storage and inflammation to the same levels of lean women, as seen previously in vitro.

Maternal Weight Gain Regulates Omega-3 Fatty Acids in Male, Not Female, Neonates.

The fetus largely depends on maternal supply and placental transport for its source of long-chain polyunsaturated fatty acids (LCPUFAs), which are essential for proper neurological and cardiovascular development. Pregnancy complications such as diabetes reduces neonatal LCPUFA supply, but little is known of how fatty acid delivery is affected by maternal body type or weight gain in uncomplicated pregnancies. In a cross-sectional study of maternal-neonatal pairs at term, we sought to determine the effect of gestational weight gain on neonatal LCPUFA supply. Forty maternal-neonatal pairs of uncomplicated (no gestational hypertension or diabetes) term pregnancies were recruited upon admission to Oregon Health & Science University Labor & Delivery for scheduled cesarean section. Maternal and umbilical cord plasma fatty acid profiles were measured using gas chromatography-mass spectrophotometry. First trimester weight gain was negatively correlated with maternal n-3 LCPUFA ( r = -0.80, P = .0002), and this was not affected by fetal sex. High maternal weight gain in the first trimester was negatively associated with cord n-3 polyunsaturated fatty acid levels ( r = -0.70, P = .03) and placental thickness ( r = -0.69, P = .03) in male, but not female, offspring. High maternal weight gain in the first trimester is associated with a thinner placenta and low levels of n-3 LCPUFA in male offspring. Further study is required to confirm that male offspring are at a higher risk of poor outcomes associated with high maternal weight gain early in pregnancy.

Effect of ω-3 supplementation on placental lipid metabolism in overweight and obese women.

BACKGROUND: The placentas of obese women accumulate lipids that may alter fetal lipid exposure. The long-chain omega-3 fatty acids (n­3 FAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) alter FA metabolism in hepatocytes, although their effect on the placenta is poorly understood. OBJECTIVE: We aimed to investigate whether n­3 supplementation during pregnancy affects lipid metabolism in the placentas of overweight and obese women at term. DESIGN: A secondary analysis of a double-blind randomized controlled trial was conducted in healthy overweight and obese pregnant women who were randomly assigned to DHA plus EPA (2 g/d) or placebo twice a day from early pregnancy to term. Placental FA uptake, esterification, and oxidation pathways were studied by measuring the expression of key genes in the placental tissue of women supplemented with placebo and n­3 and in vitro in isolated trophoblast cells in response to DHA and EPA treatment. RESULTS: Total lipid content was significantly lower in the placentas of overweight and obese women supplemented with n­3 FAs than in those supplemented with placebo (14.14 ± 1.03 compared with 19.63 ± 1.45 mg lipid/g tissue; P < 0.05). The messenger RNA expression of placental FA synthase (FAS) and diacylglycerol O-acyltransferase 1 (DGAT1) was negatively correlated with maternal plasma enrichment in DHA and EPA (P < 0.05). The expression of placental peroxisome proliferator­activated receptor γ (r = −0.39, P = 0.04) and its target genes DGAT1 (r = −0.37, P = 0.02) and PLIN2 (r = −0.38, P = 0.04) significantly decreased, with an increasing maternal n­3:n­6 ratio (representing the n­3 status) near the end of pregnancy. The expression of genes that regulate FA oxidation or uptake was not changed. Birth weight and length were significantly higher in the offspring of n­3-supplemented women than in those in the placebo group (P < 0.05), but no differences in the ponderal index were observed. Supplementation of n­3 significantly decreased FA esterification in isolated trophoblasts without affecting FA oxidation. CONCLUSION: Supplementing overweight and obese women with n­3 FAs during pregnancy inhibited the ability of the placenta to esterify and store lipids. This trial was registered at clinicaltrials.gov as NCT00957476.