Maternal Preconception Omega-6, Omega-3, and Omega-6:Omega-3 Intake and Uterine Artery Indices in Mid-Gestation.

OBJECTIVE: Maternal preconception diet influences pregnancy health and fetal outcomes. We examined the relationship between preconception fatty acid (FA) intake and uterine artery indices in mid-gestation in a large, heterogeneous cohort of nulliparous individuals. STUDY DESIGN: This is a secondary analysis of the nuMom2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be) study. Dietary ω-6 and ω-3 FA intake was assessed with food frequency questionnaires and uterine artery indices were obtained via Doppler studies in the second trimester. For our primary outcome of pulsatility index (PI) > 1.6, we compared proportions by each dichotomous FA exposure and tested differences with chi-square test. RESULTS: For PI > 1.6, odds ratio for the unfavorable FA quartile compared with remaining quartiles for the exposures were 0.96 to 1.25, p = 0.157 (ω-6 FA); 0.97 to 1.26, p = 0.124 (ω-3 FA); 0.87 to 1.14, p = 1.00 (ω-6:ω-3 FA ratio). CONCLUSION: No significant associations between self-reported maternal preconception ω-6 and ω-3 FA intake and uterine artery Doppler indices measured during the second trimester were observed. KEY POINTS: · Maternal diet impacts pregnancy health/fetal outcomes.. · ω-3 and ω-6 FA intake influences cardiovascular health.. · FA intake may affect blood flow to fetoplacental unit.. · Results are limited by inadequate adherence to dietary recommendations..

Maternal high-fat diet up-regulates type-1 cannabinoid receptor with estrogen signaling changes in a sex- and depot- specific manner in white adipose tissue of adult rat offspring.

PURPOSE: Obesity and high-fat (HF) diet are associated with over activation of the endocannabinoid system (ECS). We have demonstrated that maternal HF diet induces early obesity and modulates cannabinoid signaling in visceral (VIS) and subcutaneous (SUB) white adipose tissue (WAT) in weanling rat offspring. We hypothesized that perinatal maternal HF diet would program the expression of ECS in adipose tissue in a long-term way in parallel to alterations in epigenetic markers and sex hormone signaling. METHODS: Progenitor female rats received control diet (C, 9% fat) or isocaloric high-fat diet (HF, 28% fat) for 8 weeks before mating, gestation, and lactation. All pups were weaned to C diet and they were euthanized at 180 days old. RESULTS: Maternal HF diet induced overweight and increased SUB WAT mass of male and female adult offspring. Maternal HF diet induced hypertrophy of VIS and SUB adipocytes only in female offspring associated with increased type 1 cannabinoid receptor protein (CB1) and mRNA (Cnr1) levels. These changes were associated with increased estrogen receptor α binding to Cnr1 promoter in SUB WAT of adult female offspring, which may contribute to higher expression of Cnr1. CONCLUSION: Increased CB1 signaling in adipose tissue might contribute to higher adiposity programmed by maternal HF diet because endocannabinoids stimulate the accumulation of fat in the adipose tissue. Our findings provide molecular insights into sex-specific targets for anti-obesity therapies based on the endocannabinoid system.

Former-preterm lambs have persistent alveolar simplification at 2 and 5 months corrected postnatal age.

Preterm birth and mechanical ventilation (MV) frequently lead to bronchopulmonary dysplasia, the histopathological hallmark of which is alveolar simplification. How developmental immaturity and ongoing injury, repair, and remodeling impact completion of alveolar formation later in life is not known, in part because of lack of suitable animal models. We report a new model, using former-preterm lambs, to test the hypothesis that they will have persistent alveolar simplification later in life. Moderately preterm lambs (~85% gestation) were supported by MV for ~6 days before being transitioned from all respiratory support to become former-preterm lambs. Results are compared with term control lambs that were not ventilated, and between males (M) and females (F). Alveolar simplification was quantified morphometrically and stereologically at 2 mo (4 M, 4 F) or 5 mo (4 M, 6 F) corrected postnatal age (cPNA) compared with unventilated, age-matched term control lambs (4 M, 4 F per control group). These postnatal ages in sheep are equivalent to human postnatal ages of 1-2 yr and ~6 yr, respectively. Multivariable linear regression results showed that former-preterm lambs at 2 or 5 mo cPNA had significantly thicker distal airspace walls ( P < 0.001 and P < 0.009, respectively), lower volume density of secondary septa ( P < 0.007 and P < 0.001, respectively), and lower radial alveolar count ( P < 0.003 and P < 0.020, respectively) compared with term control lambs. Sex-specific differences were not detected. We conclude that moderate preterm birth and MV for ~6 days impedes completion of alveolarization in former-preterm lambs. This new model provides the opportunity to identify underlying pathogenic mechanisms that may reveal treatment approaches.

Alveolar formation is dysregulated by restricted nutrition but not excess sedation in preterm lambs managed by noninvasive support.

BACKGROUND: Preterm birth and respiratory support with invasive mechanical ventilation frequently leads to bronchopulmonary dysplasia (BPD). A hallmark feature of BPD is alveolar simplification. For our preterm lamb model of BPD, invasive mechanical ventilation is associated with postnatal feeding intolerance (reduced nutrition) and sedation. In contrast, preterm lambs managed by noninvasive support (NIS) have normal alveolar formation, appropriate postnatal nutrition, and require little sedation. We used the latter, positive-outcome group to discriminate the contribution of reduced nutrition vs. sedation on alveolar simplification. We hypothesized that, restricted nutrition, but not sedation with pentobarbital, contributes to impaired indices of alveolar formation in preterm lambs managed by NIS. METHODS: Preterm lambs managed by NIS for 21d were randomized into three groups: NIS control, NIS plus restricted nutrition, and NIS plus excess sedation with pentobarbital. We quantified morphological and biochemical indices of alveolar formation, as well as mesenchymal cell apoptosis and proliferation. RESULTS: Restricted nutrition impaired morphological and biochemical indices of alveolar formation, and reduced mesenchymal cell apoptosis and proliferation. Excess sedation with pentobarbital did not alter these indices, although mesenchymal cell apoptosis was less. CONCLUSION: Our results demonstrate that restricted nutrition, but not excess sedation, contributes to impaired alveolar formation during the evolution of BPD in chronically ventilated preterm lambs.

Epigenetic contributions to the developmental origins of adult lung disease.

Perinatal insults, including intrauterine growth restriction, preterm birth, maternal exposure to toxins, or dietary deficiencies produce deviations in the epigenome of lung cells. Occurrence of perinatal insults often coincides with the final stages of lung development. The result of epigenome disruptions in response to perinatal insults during lung development may be long-term structural and functional impairment of the lung and development of lung disease. Understanding the contribution of epigenetic mechanisms to life-long lung disease following perinatal insults is the focus of the developmental origins of adult lung disease field. DNA methylation, histone modifications, and microRNA changes are all observed in various forms of lung disease. However, the perinatal contribution to such epigenetic mechanisms is poorly understood. Here we discuss the developmental origins of adult lung disease, the interplay between perinatal events, lung development and disease, and the role that epigenetic mechanisms play in connecting these events.

Maternal tobacco smoke increased visceral adiposity and serum corticosterone levels in adult male rat offspring.

BACKGROUND: Maternal tobacco smoke (MTS) predisposes human and rat offspring to visceral obesity in early adulthood. Glucocorticoid excess also causes visceral obesity. We hypothesized that in utero MTS would increase visceral adiposity and alter the glucocorticoid pathway in young adult rats. METHODS: We developed a novel model of in utero MTS exposure in pregnant rats by exposing them to cigarette smoke from E11.5 to term. Neonatal rats were cross-fostered to control dams and weaned to standard rat chow through young adulthood (postnatal day 60). RESULTS: We demonstrated increased visceral adiposity (193%)*, increased visceral adipose 11-ß hydroxysteroid dehydrogenase 1 mRNA (204%)*, increased serum corticosterone (147%)*, and no change in glucocorticoid receptor protein in adult male MTS rat offspring. Female rats exposed to MTS in utero demonstrated no change in visceral or subcutaneous adiposity, decreased serum corticosterone (60%)*, and decreased adipose glucocorticoid receptor protein (66%)*. *P < 0.05. CONCLUSION: We conclude that in utero MTS exposure increased visceral adiposity and altered in the glucocorticoid pathway in a sex-specific manner. We speculate that in utero MTS exposure programs adipose dysfunction in adult male rat offspring via alteration in the glucocorticoid pathway.

Combination of intrauterine growth restriction and a high-fat diet impairs cholesterol elimination in rats.

BACKGROUND: Intrauterine growth restriction (IUGR) increases the risk of adult-onset hypercholesterolemia. High-fat diet (HFD) consumption potentiates IUGR-induced increased cholesterol. Cholesterol is converted to bile acids by Cyp7a1 in preparation for excretion. We hypothesized that IUGR rats fed a HFD will have increased cholesterol, decreased Cyp7a1 protein levels, and decreased bile acids compared to control rats fed a HFD. METHODS: At day 21, IUGR and control pups were placed on one of three diets: a regular chow or one of two HFDs containing 1% or 2% cholesterol. Cholesterol levels and hepatic Cyp7a1 protein levels were quantified a postnatal week 28. RESULTS: Both HFDs increased serum cholesterol levels in control rats, and HFD fed IUGR rats had further increased serum cholesterol up to 35-fold. Both HFDs increased hepatic cholesterol levels, and IUGR further increased hepatic cholesterol levels up to fivefold. IUGR decreased hepatic Cyp7a1 protein up to 75%, and hepatic bile acids up to 54%. CONCLUSION: IUGR increased cholesterol and bile acids and decreased Cyp7a1 protein in rats fed a HFD without changing food intake. These findings suggest that IUGR increases the vulnerability of HFD fed rats to hypercholesterolemia via decreased cholesterol conversion to bile acids.

Umbilical artery systolic to diastolic ratio is associated with growth and myocardial performance in infants with hypoplastic left heart syndrome.

OBJECTIVE: Despite standardization in care, heterogeneity in outcomes persists for infants with hypoplastic left heart syndrome (HLHS). One potential factor is in utero stressors. Uteroplacental insufficiency (UPI) induces systemic vascular and myocardial adaptations in the absence of structural heart disease. The effect of UPI in HLHS is unknown. METHODS: We retrospectively analyzed infants undergoing Norwood palliation for HLHS from 2007 to 2012. We compared the umbilical artery systolic to diastolic (SD) ratio to growth outcomes and postoperative right ventricular function. RESULTS: Forty three infants met our inclusion criteria. Fetuses without a declining SD ratio with advancing gestational age had asymmetric birth biometry, defined as birth weight minus head circumference z scores (-0.9 vs -0.05, p < 0.01). The SD ratio near the end of gestation negatively correlated with asymmetric birth biometry (R = -0.521, p < 0.01) and interstage growth (R = -0.49, p = 0.04). Males with higher SD ratios had a greater postoperative incidence of abnormal right ventricular function. CONCLUSIONS: A higher umbilical artery SD ratio was associated with asymmetric prenatal growth, poor weight gain, and decreased myocardial performance in infants with HLHS. Better understanding of UPI's effects on cardiovascular development and metabolism in HLHS will help identify new strategies for targeting morbidity in this high risk population.

Abnormal abdominal aorta hemodynamics are associated with necrotizing enterocolitis in infants with hypoplastic left heart syndrome.

The risk of necrotizing enterocolitis (NEC) in association with congenital heart disease is highest in patients with hypoplastic left heart syndrome (HLHS). Within the HLHS population, however, risk factors for NEC remain debated. We hypothesized that some infants with HLHS have vascular changes that contribute to gut hypoperfusion independent of diastolic runoff and low cardiac output. We analyzed the abdominal aorta pulsatility index and right-ventricular function on routine preoperative and postoperative echocardiograms for all infants who underwent stage I palliation for HLHS from January 2007 to January 2012. The echocardiography findings and clinical course were compared between those with and those without an episode of NEC. Of the 61 cases reviewed, 11 (18 %) developed NEC during a mean follow-up of 3.8 ± 1.3 years. Those with NEC had a lower abdominal aorta pulsatility index compared with those without NEC both on stage I preoperative (3.38 ± 0.15 vs. 3.89 ± 0.09, p < 0.05) and postoperative echocardiograms (2.21 ± 0.28 vs. 3.05 ± 0.78, p = 0.01) despite similar ventricular function and operative risk. Abdominal aorta Doppler pulsations are lower in patients with HLHS whose clinical course is complicated by NEC. This finding suggests that the systemic vasculature in a subset of neonates with HLHS may be inherently abnormal. Further investigation is warranted to determine if this is secondary to structural changes in the mesenteric and/or systemic vasculature.

Intrauterine growth restriction transiently delays alveolar formation and disrupts retinoic acid receptor expression in the lung of female rat pups.

BACKGROUND: We showed that intrauterine growth restriction (IUGR) increases distal airspace wall thickness at birth (postnatal age 0; P0) in rat pups (saccular stage of lung development). However, that report did not assess whether the saccular phenotype persisted postnatally or occurred in males or females, nor did the report identify a potential molecular pathway for the saccular phenotype at P0. We hypothesized that IUGR persistently delays alveolar formation and disrupts retinoic acid receptor (RAR) mRNA and protein levels in the lung of rat pups in a postnatal age- and sex-specific manner. METHODS: IUGR was induced in pregnant rats by bilateral uterine artery ligation. Alveolar formation and expression of RARα, -ß, and -γ were quantified at P0, P6 (alveolar stage), and P21 (postalveolarization). RESULTS: IUGR increased distal airspace wall thickness in female pups at P0 only. IUGR did not affect male pups at any age. IUGR transiently increased lung RAR-ß protein abundance, which inhibits alveolar formation, at P0 in female pups. Serum retinol concentration was normal at all ages. CONCLUSION: IUGR alone is not sufficient to persistently delay postnatal alveolar formation or disrupt expression of RARs. We speculate that for IUGR to delay alveolar formation postnatally, a second insult is necessary.

Postnatal growth restriction impairs rat lung structure and function.

The negative impact of nutritional deficits in the development of bronchopulmonary dysplasia is well recognized, yet mechanisms by which nutrition alters lung outcomes and nutritional strategies that optimize development and protect the lung remain elusive. Here, we use a rat model to assess the isolated effects of postnatal nutrition on lung structural development without concomitant lung injury. We hypothesize that postnatal growth restriction (PGR) impairs lung structure and function, critical mediators of lung development, and fatty acid profiles at postnatal day 21 in the rat. Rat pups were cross-fostered at birth to rat dams with litter sizes of 8 (control) or 16 (PGR). Lung structure and function, as well as serum and lung tissue fatty acids, and lung molecular mediators of development, were measured. Male and female PGR rat pups had thicker airspace walls, decreased lung compliance, and increased tissue damping. Male rats also had increased lung elastance, increased lung elastin protein abundance, and lysol oxidase expression, and increased elastic fiber deposition. Female rat lungs had increased conducting airway resistance and reduced levels of docosahexaenoic acid in lung tissue. We conclude that PGR impairs lung structure and function in both male and female rats, with sex-divergent changes in lung molecular mediators of development.

Perinatal Research Society's Young Investigator Workshop Prepares the Next Generation of Investigators.

Sustaining impactful research within the field of perinatal biology requires training and retention of the next generations of physician-scientists and basic-scientists. Professional societies such as the Perinatal Research Society (PRS) have a unique role to play in training and retention of perinatal biologists. Here we report outcomes for an innovative Young Investigator Training Workshop created for the PRS. The PRS Workshop uses immersive, active-writing, and active-oral presentation design, with one-on-one feedback from NIH-funded faculty-mentors drawn from the PRS membership. Young investigator data were collected by anonymous surveys of young investigators, NIH RePORTER, and individual young investigator follow-up. Ninety-seven young investigators attended the Workshops over the period 2013-2018. Young investigators were physician- (73%) and PhD- (27%) scientists at the rank of clinical fellow/postdoctoral fellow (27%) or instructor/assistant professor (73%). Participation by underrepresented minority (URM) young investigators was 14%. Young investigators received NIH and non-NIH funding, with 80% of young investigators receiving new funding since the Workshop that they attended. NIH funding was received by 31% of young investigators in the form of K-series awards, R01 equivalents, and other NIH awards. In conclusion, our PRS young investigator Workshop serves as a model to facilitate training of emerging physician- and basic-scientists by scientific societies.

Antenatal Steroids and Cord Blood T-cell Glucocorticoid Receptor DNA Methylation and Exon 1 Splicing.

Antenatal administration of glucocorticoids such as betamethasone (BMZ) during the late preterm period improves neonatal respiratory outcomes. However, glucocorticoids may elicit programming effects on immune function and gene regulation. Here, we test the hypothesis that exposure to antenatal BMZ alters cord blood immune cell composition in association with altered DNA methylation and alternatively expressed Exon 1 transcripts of the glucocorticoid receptor (GR) gene in cord blood CD4+ T-cells. Cord blood was collected from 51 subjects in the Antenatal Late Preterm Steroids Trial: 27 BMZ, 24 placebo. Proportions of leukocytes were compared between BMZ and placebo. In CD4+ T-cells, methylation at CpG sites in the GR promoter regions and expression of GR mRNA exon 1 variants were compared between BMZ and placebo. BMZ was associated with an increase in granulocytes (51.6% vs. 44.7% p = 0.03) and a decrease in lymphocytes (36.8% vs. 43.0% p = 0.04) as a percent of the leukocyte population vs. placebo. Neither GR methylation nor exon 1 transcript levels differed between groups. BMZ is associated with altered cord blood leukocyte proportions, although no associated alterations in GR methylation were observed.

IUGR decreases elastin mRNA expression in the developing rat lung and alters elastin content and lung compliance in the mature rat lung.

Complications of intrauterine growth restriction (IUGR) include increased pulmonary morbidities and impaired alveolar development. Normal alveolar development depends upon elastin expression and processing, as well as the formation and deposition of elastic fibers. This is true of the human and rat. In this study, we hypothesized that uteroplacental insufficiency (UPI)-induced IUGR decreases mRNA levels of elastin and genes required for elastin fiber synthesis and assembly, at birth (prealveolarization) and postnatal day 7 (midalveolarization) in the rat. We further hypothesized that this would be accompanied by reduced elastic fiber deposition and increased static compliance at postnatal day 21 (mature lung). We used a well characterized rat model of IUGR to test these hypotheses. IUGR decreases mRNA transcript levels of genes essential for elastic fiber formation, including elastin, at birth and day 7. In the day 21 lung, IUGR decreases elastic fiber deposition and increases static lung compliance. We conclude that IUGR decreases mRNA transcript levels of elastic fiber synthesis genes, before and during alveolarization leading to a reduced elastic fiber density and increased static lung compliance in the mature lung. We speculate that the mechanism by which IUGR predisposes to pulmonary disease may be via decreased lung elastic fiber deposition.

Epigenetics and the developmental origins of lung disease.

The developmental origins of disease hypothesis have recently been expanded to include the early origins of lung disease, particularly early events that alter lung development. Intrauterine growth restriction (IUGR), preterm birth with the need for prolonged mechanical ventilation, and maternal tobacco smoke (MTS) or nicotine exposure produce neonatal and adult lung disease. These perinatal insults are characterized by alterations in alveolar formation and changes in the expression of genes that regulate alveolarization, including IGF1 and PPARγ. A potential mechanism for such changes in gene expression is epigenetics. IGF1 and PPARγ have altered epigenetic states in response to these perinatal insults. Identification of the specific epigenetic mechanisms involved in the developmental origin of lung disease may facilitate identification of molecular biomarkers with the potential to personalize respiratory disease risk assessment and treatment. The purpose of this review is to summarize what is known about the developmental origins of lung disease, the epigenetic contributions to lung disease, and areas that need further investigation.

Intrauterine growth restriction alters T-lymphocyte cell number and dual specificity phosphatase 1 levels in the thymus of newborn and juvenile rats.

Intrauterine growth restricted (IUGR) infants have increased susceptibility to infection associated with higher risk of illness and death. Dual specificity phosphatase 1 (DUSP1), which is transcribed in the thymus, increases in quantity as T cells mature and differentiate into CD4+ cells. Little is known about how IUGR affects DUSP1 levels and T-cell subpopulations over time. We hypothesized that IUGR would decrease cell count, CD4+ and CD8+ subpopulations of T lymphocytes, and DUSP1 levels in IUGR rat thymus and spleen. Bilateral uterine artery ligation produced IUGR rats. Thymus and spleen were harvested at P0 and P21. Flow cytometry was used to compare CD4+ and CD8+ lymphocyte populations. Real-time RT-PCR and Western blotting were used to determine DUSP1 quantity. IUGR significantly decreased total cell count in P0 and P21 IUGR male and female thymus. IUGR significantly increased CD4+ cells in IUGR P0 males and females, significantly decreased CD4+ cells in P21 female thymus, and significantly altered DUSP1 levels in the IUGR female thymus at P0 and P21, although it is not yet known whether the change in DUSP1 levels is due to a change in the level per cell or to a change in cellular composition of the thymus.

IUGR differentially alters MeCP2 expression and H3K9Me3 of the PPARγ gene in male and female rat lungs during alveolarization.

Intrauterine growth restriction (IUGR) increases the risk of postnatal lung disease, with males more affected. In rat lungs, IUGR impairs alveolarization in conjunction with altered expression of peroxisome proliferator-activated receptor gamma (PPARγ). In non-lung cells, PPARγ transcription is regulated in part by the epigenetic modifying enzyme, and the methyl CpG binding protein 2 (MeCP2). However, it is unknown if IUGR affects MeCP2 expression or its interaction with PPARγ in the rat lung during alveolarization. In this study, we hypothesized that the rat lung would be characterized by the presence of MeCP2 short and long mRNA transcripts, MeCP2 protein isoforms, and the MeCP2 regulatory micro RNA, miR132. We further hypothesized that IUGR would, in a gender-specific manner, alter the levels of MeCP2 components in association with changes in PPARγ mRNA, MeCP2 occupancy at the PPARγ promoters, and PPARγ histone 3 lysine 9 trimethylation (H3K9Me3). To test these hypotheses, we used a well-characterized rat model of uteroplacental insufficiency-induced IUGR. We demonstrated the presence of MeCP2 mRNA, protein, and miR132 in the rat lung throughout alveolarization. We also demonstrated that IUGR alters MeCP2 expression and its interaction with PPARγ in a gender-divergent manner. We conclude that IUGR induces gender-specific alterations in the epigenetic milieu in the rat lung. We speculate that in the IUGR rat lung, this altered epigenetic milieu may predispose to gender-specific alterations in alveolarization.

Uteroplacental Insufficiency with Hypoxia Upregulates Placental PPARγ-KMT5A Axis in the Rat.

The placenta represents a critical node in fetal lipid acquisition, yet the mechanisms by which the placenta handles lipids under normal and pathologic conditions are incompletely understood. A key player in placental lipid handling is peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ influences global gene expression via its regulation of the epigenetic modifier lysine methyltransferase 5A (KMT5A), which places a methyl group on histone 4 lysine 20 (H4K20me) of target genes. Here we test the hypothesis that KMT5A is present in both the human and rat placentas and is affected by uteroplacental insufficiency (UPI) in the rat in association with increased placental lipid accumulation. We assessed levels and localization of KMT5A, as well as lipid droplet accumulation, in human placental tissue collected from maternal donors after delivery by planned cesarean section. Using a rat model of UPI, we also evaluated the effects of UPI on lipid accumulation, PPARγ, KMT5A, and H4K20me in the rat placenta. In this study, we show for the first time the presence and activity of KMT5A, in human and in rat placentas. We also demonstrate that in the rat placenta, UPI increases hypoxia, KMT5a expression, and activity in association with increased lipid accumulation in placenta supporting male fetuses. Placental PPARγ-KMT5A axis may be an important mediator of placental lipid handling.

Maternal Tobacco Smoke Exposure Causes Sex-Divergent Changes in Placental Lipid Metabolism in the Rat.

Maternal tobacco smoke exposure (MTS) affects fetal acquisition of long-chain polyunsaturated fatty acids (LCPUFA) and increases the risk of obesity and cardio-metabolic disease in the offspring. Alterations in fetal LCPUFA acquisition in maternal smoking are mediated by the placenta. The handling of LCPUFA by the placenta involves protein-mediated transfer and storage. Molecular mediators of placental LCPUFA handling include PPARγ and the fatty acid transport proteins. We previously demonstrated, in a rat model, that MTS results in programming of adult-onset obesity and metabolic disease in male, but not female, offspring. In this study, we test the hypothesis that in utero MTS exposure alters placental structure, placental LCPUFA handling, and fetal fatty acid levels, in a sex-divergent manner. We exposed pregnant rats to tobacco smoke from embryonic day 11 to term gestation. We measured placental and fetal fatty acid profiles, the systolic/diastolic ratio (SD ratio), placental histology, and expression of molecular mediators in the placenta. Our primary finding is that MTS alters fatty acid profiles in male, but not female fetuses and placenta, including increasing the ratio of omega-6 to omega-3 fatty acids. MTS also increased SD ratio in male, but not female placenta. In contrast, the expression of PPARγ and FATPs was upregulated in female, but not male placenta. We conclude that MTS causes sex-divergent changes in placental handling of LCPUFA in the rat. We speculate that our results demonstrate an adaptive response to MTS by the female placenta.