Melissa Suter

BackgroundZika virus congenital infection evades double-stranded RNA detection and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. Understanding how viruses can persist and replicate in the placenta without causing overt cellular or tissue damage is fundamental to deciphering mechanisms of maternal-fetal vertical transmission.ObjectivePlacenta-specific microRNAs are believed to be a tenet of viral resistance at the maternal-fetal interface. We aimed to test the hypothesis that the Zika virus functionally disrupts placental microRNAs, enabling viral persistence and fetal pathogenesis.Study DesignTo test this hypothesis, we used orthogonal approaches in human and murine experimental models. In primary human trophoblast cultures (n=5 donor placentae), we performed Argonaute high-throughput sequencing ultraviolet-crosslinking and …

ObjectiveInhalation and ingestion of millions of microplastics (particles< 20 μm) occur annually in people. Microplastic exposures have been linked to increased levels of inflammatory markers in experimental animal models. Given the putative role of disrupted inflammatory pathways in preterm birth risk, we hypothesized that microplastics quantitatively differ in human placentae.Study DesignWe visualized and quantified cumulative microplastics (Fig. 1A) by Fourier-transformed infrared microscopy (FTIR; n= 31), quantified microplastics species by pyrolysis followed by quantitative time of flight gas chromatography-mass spectrometry (pyro-qTOF/GC-MS; n= 10), and quantified polycyclic aromatic hydrocarbons (PAHs; n= 70) BaP, BbF, and DBA by GC/MS. We then applied machine learning algorithms correlating environmental toxicants (n= 24 with PAH and microplastics data) with social deprivation scores and …

ObjectiveAlthough Lactobacillus spp. are prevalent members of the vaginal and gut microbiomes, their role in birth outcomes has received little attention. Recently, L. crispatus has been associated with decreased risk of spontaneous PTB. Lactoplantibacillus plantarum has also been implicated in attenuating the somatotropic axis, indicating a potential role in PTB outcomes. We sought to determine the role of the six most prevalent Lactobacilli spp. of the microbiome on birth outcomes in a large, prospective, longitudinal cohort (BaBs, Bacteria and Birth study).Study DesignThe BaBs study prospectively enrolled gravidae (n= 585) at risk for preterm birth at 11-19 6/7 wks, and longitudinally sampled maternal and applicable neonatal infant sites to 1mo postpartum. Sampling timepoints included enrollment, early 3 rd trimester (27-28wks), delivery (term or preterm), and within 6wks postpartum. A total of 52116 maternal …

ObjectiveTraditional maternal drug toxicity studies focus on fetal malformations, overlooking potential childhood outcomes not recognized at birth. Metformin evades 1st pass liver metabolism & crosses the placenta. Based on its pharmacodynamics & limited clinical studies suggesting risk for childhood obesity & insulin resistance, we hypothesized that metformin initiated periconception would lead to fetal bioaccumulation with aberrant fetal growth. We developed a highly novel primate model and applied triple-quadruple pole LC mass spectrometry (UHPLC-QQQ) for direct quantitation of maternal and fetal metformin levels with detailed fetal biometry & histopathology.Study DesignWithin 30d of confirmed conception, n= 19 Rhesus macaque dams fed a control chow or Western style diet (mWSD) were initiated on twice daily, human dose-equivalent (10mg/kg) metformin or vehicle control (dose weight-adjusted Q …

Introduction The Maternal and Infant Environmental Health Riskscape (MIEHR) Center was established to address the interplay among chemical and non-chemical stressors in the biological, physical, social, and built environments that disproportionately impact perinatal health among Black pregnant people in a large and diverse urban area with documented disparities in the U.S. Methods The MIEHR cohort is recruiting non-Hispanic Black and non-Hispanic white pregnant people who deliver their infants at major obstetric hospitals in Houston, Texas. At enrollment, all participants are asked to provide urine samples for chemical [metals, cotinine, and polycyclic aromatic hydrocarbons (PAHs)] analyses and blood samples. A subset of the cohort is asked to provide oral and vaginal swabs, and fecal samples. Questionnaire and electronic health record data gather information about residential address history during pregnancy, pregnancy history and prenatal care, sociodemographic and lifestyle factors, experiences of discrimination and stress, and sources of social support. Using information on where a participant lived during their pregnancy, features of their neighborhood environment are characterized. We provide summaries of key individual- and neighborhood-level features of the entire cohort, as well as for Black and white participants separately. Results Between April 2021 and February 2023, 1,244 pregnant people were recruited. Nearly all participants provided urine samples and slightly less than half provided blood samples. PAH exposure patterns as assessed on 47% of participants thus far showed varying levels depending on …

The exponential increase in global plastic usage has led to the emergence of nano- and microplastic (NMP) pollution as a pressing environmental issue due to its implications for human and other mammalian health. We have developed methodologies to extract solid materials from human tissue samples by saponification and ultracentrifugation, allowing for highly specific and quantitative analysis of plastics by pyrolysis-gas chromatography and mass spectrometry (Py-GC-MS). As a benchmark, placenta tissue samples were analyzed using fluorescence microscopy and automated particle count, which demonstrated the presence of > 1-micron particles and fibers, but not nano-sized plastic particles. Analyses of the samples (n = 10) using Attenuated Total Reflectance—Fourier Transformed Infrared spectroscopy indicating presence of rayon, polystyrene, polyethylene, and unclassified plastic particles. By …

ObjectiveWe have previously reported that increased placental levels of the ubiquitous PAH benzo [a] pyrene (BaP) is significantly associated with preterm birth (PTB). Furthermore, we have shown that increased levels of placental BaP are positively correlated with histone methylation, and acetylation. These epigenetic modifications can contribute to alterations in placental gene expression. In this study we aimed to determine if the enzymes responsible for establishment and maintenance of these modifications were altered in association with BaP levels.Study DesignProtein extracts were derived from 77 placentae samples and were utilized for Reverse Phase Protein Array analyses of 38 proteins involved in the post-translational modification of histones or chromatin remodeling. Data was normalized to total histone protein levels. Absolute levels of BaP were measured from the same samples using GC-MS …

Ozone (O3) is a criteria air pollutant with the most frequent incidence of exceeding air quality standards. Inhalation of O3 is known to cause lung inflammation and consequent systemic health effects, including endothelial dysfunction. Epidemiologic data have shown that gestational exposure to air pollutants correlates with complications of pregnancy, including low birth weight, intrauterine growth deficiency, preeclampsia, and premature birth. Mechanisms underlying how air pollution may facilitate or exacerbate gestational complications remain poorly defined. The current study sought to uncover how gestational O3 exposure impacted maternal cardiovascular function, as well as the development of the placenta. Pregnant mice were exposed to 1PPM O3 or a sham filtered air (FA) exposure for 4 h on gestational day (GD) 10.5, and evaluated for cardiac function via echocardiography on GD18.5 …

Although the earth's climate has been continuously changing over billions of years, human influence has accelerated that rate of change. While high latitudes suffer the greatest increase in incremental temperature, moderate latitudes are highly vulnerable due to their temperate/tropical rain storms and hurricanes that bring about extreme flooding events. We and others have shown that there is a link between the occurrence and severity of these climate events and risk of adverse perinatal outcomes. In this review, we will discuss the data and consider interacting near and intermediate sequelae of worsening natural disasters–including food scarcity, disrupted or compromised built environments and infrastructure, and loss of communities with human migration. While certainly tackling these and other proximal mediators of adverse perinatal outcomes will benefit maternal and child health, a failure to meaningfully …

ObjectivePolycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental toxins resulting from carbon combustion, and found in air, vehicle exhaust, drinking water, soil and cigarette smoke (including 2 nd hand smoke). We and others have reported that exposure to harmful PAH derivatives via vehicle emissions and smoking are associated with sPTB. We have previously shown significant differences in the accumulated absolute levels of these harmful PAHs in placentae from sPTB vs term births, as measured by mass spectrometry. In this study we aimed to determine if trophoblasts gene expression patterns vary with exposure to harmful PAHs.Study DesignWithin 1 hour from delivery, trophoblasts were isolated and cultured for 48 hours from term placentae. Trophoblast cultures were treated for 24 hours with DMSO (vehicle control), 10M Benzo [a] pyrene (BaP), 10M Benzo [b] fluoranthene (BbF), 10M …

ObjectiveSingle-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics have identified novel cell subtypes and microenvironments which compartmentalize diverse functions at the maternal-fetal interface. We aimed to combine these high-resolution technologies with a rigorous classification of transcription alterations associated with diabetes subtypes in pregnancy. We hypothesized characteristic transcriptome profiles in specific cell populations would be linked to these classifications.Study DesignWe clinically validated gestational diabetes mellitus type 1 (GDMA1), GDMA2, and type 2 diabetes (T2DM) classes within a cohort of placentae and compared them to healthy controls by bulk RNA-seq (N= 53). We then integrated our non-diabetic term placentae spatial transcriptomics data (N= 12) with 273,944 publicly available transcriptomes from term placenta scRNA-seq or single-nuclei RNA-seq (snRNA-seq …

Objective Obesity in pregnancy bears unique maternal and fetal risks. Obesity has also been associated with chronic inflammation, including elevated serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher serum lipopolysaccharide (LPS) levels have been implicated in driving this inflammation, a phenomenon called metabolic endotoxemia (ME). GLP-2, a proglucagon-derived peptide, is believed to be integral in maintaining the integrity of the intestine in the face of LPS-mediated endotoxemia. We hypothesized that obesity and/or excess weight gain in pregnancy would be associated with an increase in maternal and neonatal markers of ME, as well as GLP-2. Study Design Paired maternal and neonatal (cord blood) serum samples (n = 159) were obtained from our pregnancy biobank repository. Serum levels of LPS, endotoxin core antibody-immunoglobulin M (EndoCAb-IgM), and …

ObjectiveHuman studies and experimental primate models have demonstrated that a maternal high-fat diet (mHFD) during pregnancy leads to persistent changes in her offspring's immunologic, metabolic, and microbiome profiles. Herein, we utilized our primate model to investigate how this occurs in utero. We hypothesized that impaired metabolic transcriptomic and epigenomic signatures would be detectible in the fetal liver tissue by the beginning of the 3 rd trimester.Study DesignAfter conception, Japanese macaques were fed a control diet (N= 3), mHFD (N= 8), mHFD with resveratrol, an HDAC inhibitor at 480 mg/day (mHFRes; n= 8), or switched from mHFD to control diet just before conception (mHFRev; N= 3). At gestational day 130 (the human equivalent of 32 weeks), fetal livers were dissected and processed for both bulk RNA-seq and ChIP-seq.ResultsDifferential expression revealed 154 fetal gene …

ObjectiveFetal exposure to environmental toxins, such as polycyclic aromatic hydrocarbons (PAHs), is associated with the development of later-in-life disease, including asthma and obesity. However, the mechanisms for this increased risk remain largely unknown. We and others have shown that gut microbiota are major players in xenobiotic metabolism, and that the maternal microbiome strongly influences development of the infant microbiome. In this study we sought to determine if there are significant changes to the maternal and offspring gut microbiome with exposure to benzo [a] pyrene (BaP), a toxic and ubiquitous PAH.Study DesignFemale mice (C57BL7, n= 7) were orally gavaged with BaP (30 mg/kg) within 12 hours of mating (Fig 1a). Oral administration of BaP (or corn oil control) was repeated on gestational days 11, 12, 16 & 19, and stool samples were collected daily. Total microbial DNA from stool and …

Introduction Given limited evidence of previous studies, we evaluated the role of environmental justice (EJ) burden (i.e., a neighborhood characterized by both increased environmental burden and socioeconomic deprivation) in Black-White disparities in spontaneous preterm birth (sPTB) in Harris County, Texas and compared results that evaluated neighborhood-level socioeconomic deprivation alone. Methods We conducted a retrospective analysis using PeriBank, a database and biospecimen repository of gravidae giving birth at two hospitals in the Texas Medical Center. We included 3,703 non-Hispanic Black and 5,475 non-Hispanic white gravidae who were U.S.-born, delivered from August 2011-December 2020, and resided in Harris County, TX. We used data from the U.S. EPA EJScreen to characterize the EJ burden of participant's zip code of residence from fine particulate matter (PM2.5), ozone, and proximity to National Priorities List (NPL) sites and calculated zip-code level Area Deprivation Index (ADI). We assessed the contribution of neighborhood-level variables to the Black-White disparity in sPTB by evaluating attenuation of the odds ratio (OR) representing the effect of race in multivariable logistic regression models, controlling for individual-level characteristics. We also conducted race-stratified analyses between each neighborhood variable and sPTB. Exposure indices were treated as continuous variables; in stratified models, ORs and 95% Confidence Intervals (CIs) are presented per 10-unit increase in the neighborhood variable. Results Accounting for individual-level variables, Black gravidae had 79% higher odds of sPTB …

ObjectivePAHs are toxic byproducts of the incomplete combustion of fossil fuel, and classified under EPA as prevalent hazardous pollutants. We and others have established that exposure to certain environmental chemicals (such as PAHs) during pregnancy is significantly associated with PTB, SGA, and other adverse pregnancy outcomes. Specifically, we have previously reported that increased placental levels of the ubiquitous PAH benzo [a] pyrene (BaP) is significantly associated with PTB. However, no studies to-date have provided a mechanistic link between elevated PAHs and molecular changes (such as epigenomic modifications) which would give rise to preterm delivery. We hypothesized that exposure to PAHs, as determined by measuring absolute levels of placental BaP, is associated with altered levels of epigenomic histone modifications.Study DesignHistones were acid extracted from 24 placental …

ObjectiveThere has been recent controversy as to whether mammalian fetuses normally develop in sterile intrauterine environments, or rather amidst sparse & low-abundance/low-diversity beneficial microbial communities. Despite supportive evidence from cultivation, metagenomics, molecular tagging & functional immune experiments, this controversy has persisted because of (1) presumptive contaminants, and (2) a lack of identifiable intrauterine substrates which could support beneficial microbial growth. Milk oligosaccharides are evolutionarily preserved complex glycans which are indigestible by mammals which produce them, but provide a growth advantage to beneficial microbes & promote a healthy infant gut. Based on initial detection in an unbiased AF metabolomics screen, we hypothesized that HMOs may be ubiquitous & serve as intrauterine beneficial microbial substrates. Our aims were to use …

Widespread public health campaigns have reduces the prevalence of tobacco and nicotine exposures during pregnancy in the United States. However, tobacco and nicotine exposures during pregnancy persist as a common modifiable perinatal risk exposure. Furthermore, declines in tobacco use have been accompanied by parallel rises in both the prevalence and incidence of marijuana use in pregnancy. This is worrisome, as the macromolecules which comprise tobacco and marijuana smoke affect placental function. In this chapter we summarize the decades of evidence contributing to our understanding of the placental molecular pathophysiology accompanying these chemical exposures, thereby rendering risk of adverse perinatal outcomes.

ObjectiveHMOs (and their mammalian equivalents) are evolutionarily exceptional. Despite the substantial metabolic investment into their production, they are indigestible by mammals. Rather than nutrition, their purpose resides in the curation and selective proliferation of microbes that are beneficial to the gut and protective of infection. Given recent detection of sparse microbes in the fetal meconium and gut in every mammal examined to date, we set out to characterize the full spectrum of HMOs that are detected in utero in a large population-based cohort of second trimester gravidae.Study DesignCollection of amniotic fluid at genetic amniocentesis (GA 16-29, mean 17.5 weeks) was undertaken for n= 610 samples. Oligosaccharides were measured using an in house developed LC-MS analysis. Quantified metabolites were normalized by Z-scores and assessed using a combination of least squares linear …

ObjectiveHarris County, Houston, has 15 active and 11 remediated Superfund sites and has a preterm birth (PTB) rate that significantly exceeds the US rate (11.4% vs. 9.6%). In addition to racial disparities, exposure to environmental chemicals has been hypothesized as being a potential underlying cause of increased occurrence of PTB. Since biochemical and molecular activities of the placenta respond to and are modified by environmental insults, our aim was to conduct an initial multi’omic analysis of the placenta from women who resided proximal or distal to Superfund sites to identify and compare all/any molecular footprint in the placenta.Study Design22 placenta samples were used, of which 11 individuals resided in zip codes corresponding to Superfund sites and was matched with other 11 who resided away from these sites. Heavy metals were estimated, untargeted LC-MS metabolomics was performed on …