Microorganisms in the Placenta: Links to Early-Life Inflammation and Neurodevelopment in Children

Prenatal exposure to various stressors can influence both early and later life childhood health. Microbial infection of the intrauterine environment, specifically within the placenta, has been associated with deleterious birth outcomes, such as preterm birth, as well as adverse neurological outcomes later in life.

SUMMARY

Prenatal exposure to various stressors can influence both early and later life childhood health. Microbial infection of the intrauterine environment, specifically within the placenta, has been associated with deleterious birth outcomes, such as preterm birth, as well as adverse neurological outcomes later in life. The relationships among microorganisms in the placenta, placental function, and fetal development are not well understood. Microorganisms have been associated with perinatal inflammatory responses that have the potential for disrupting fetal brain development. Microbial presence has also been associated with epigenetic modifications in the placenta, as well other tissues. Here we review research detailing the presence of microorganisms in the placenta and associations among such microorganisms, placental DNA methylation, perinatal inflammation, and neurodevelopmental outcomes.

INTRODUCTION

The developmental origins of health and disease (DOHaD) hypothesis proposes that the prenatal environment, through fetal reprogramming, can influence the risk of adult disease and other later-life outcomes (1, 2), such as neurocognitive function and mental health (3–5). Epigenetic modifications are one proposed biological mechanism for early-life reprogramming (6). Supporting the DOHaD hypothesis, intrauterine infection and inflammation are associated with adverse birth outcomes, such as preterm birth (PTB), and neurodevelopmental outcomes later in life (5, 7–9). Based on its critical role in regulating the fetus’ exposure to nutrients, hormones, and other molecular signals, as well as to environmental exposures, the placenta might play an important role in early-life programming.

Microorganisms in the placenta constitute an intrauterine environmental exposure that has been associated with a variety of adverse birth outcomes (7, 10, 11). It is generally accepted that pathogenic bacteria can colonize the placenta by hematogenous spread or invasion from the vagina (7). More controversial is the concept that the placenta typically is colonized by nonpathogenic commensal bacteria that constitute a placental microbiome (12–14). Disagreement about the existence of a nonpathogenic placental microbiome arises, in part, from methods used to detect bacteria (15–17). Traditional methods depend on culturing organisms in media optimized for detection of pathogenic organisms (18) and thus might be less sensitive to detection of commensal organisms. Newer culture-independent techniques, such as 16S rRNA gene sequencing, can reveal more microbially diverse populations and detect organisms of low abundance in clinical samples (19), but these techniques do not differentiate between living and dead bacteria and are susceptible to contamination from dust or commercial reagents (15, 17). Notwithstanding this methodological concern, 16S rRNA sequencing has enabled the detection in the placenta of vaginal microorganisms, as well as microorganisms represented in the oral microbiome (12, 20). Nonpathogenic bacteria have been detected in the placenta using conventional culture techniques, but these studies involved extremely preterm births, so the results might not apply to normal pregnancies (21, 22). Since the presence of microorganisms in the placenta has been associated with PTB and other deleterious birth outcomes (7, 23), studies of these bacterial species and their relationship to the placenta and outcomes in the offspring could inform efforts to prevent PTB and its effects on the child.

In this review, we focus on the association between placental microorganisms and neurocognitive outcomes and examine potential biological mechanisms underlying this association (Fig. 1). Multiple lines of evidence support an association between intrauterine infection and inflammation (7, 24) and prenatal inflammation and neurodevelopmental impairment (25–29). Here, we summarize evidence that bacteria in the placenta may induce inflammation-related responses through epigenetic modifications, specifically via DNA methylation, that is associated with neurodevelopment and neurological functioning later in life.

FIG 1.

Schematic of the biological mechanisms underlying the association between placental microorganism and later life neurological outcomes. The arrows indicate the different associations that are discussed in the article. (a to c) The presence of microorganisms in the placenta is associated with the production of inflammatory proteins in placental cells (51, 52) (a), a sustained systemic inflammatory response in newborns (61) (b), and the placental methylome (75) (c). (d) The DNA methylation profile of the placenta has been associated with different neurodevelopmental outcomes in infants (82). (e) Exposure to in utero inflammation leads to a greater risk of neurocognitive disorders (122, 139). (f and g) The presence of inflammatory proteins in newborn blood has been associated with a variety of neurodevelopmental outcomes at 2 years of age (119, 131–133) (f) and at 10 years of age (134) (g).

MICROORGANISMS IN THE PLACENTA

The presence of pathogenic bacteria in the placenta is associated with adverse birth outcomes, including prematurity (7, 23), stillbirth (10, 23), and fetal inflammatory response syndrome (11, 30). Until recently, the placenta has typically been considered sterile, serving as a barrier to bacterial infections while providing nutrition to a growing fetus. Any bacterial presence is assumed to have originated from invasion from the lower genital tract (7). Consistent with this, many of the bacteria identified in the uterus were of vaginal origin (31–33). However, recently developed metagenomics methods for detection of bacteria have identified bacterial species in the placenta that are not typically found in the vagina.

A single metagenomic study of sterilely collected placenta samples identified a low-abundance (but metabolically rich) community of microorganisms, the profile of which was associated with PTB (12). Another supporting study used staining methods to detect bacteria in 195 sterilely collected placenta tissue specimens from the basal plate. Bacteria was detected in more than 25% of the placentas, and there was no significant difference in bacterial detection when comparing preterm and term placentas (13). Based on these results the researchers hypothesize that a placental microbiome exists both in pregnancies that end prematurely, as well as those that proceed to term (12, 13). The concept of a placental microbiome suggests the possibility that some bacteria in the placenta exert no pathogenic effect and possibly could contribute to normal development of the fetal immune system (34–37), whereas the presence of other microbes in the placenta might initiate an inflammatory response. However, there is disagreement as to whether a placental microbiome exists, and recent studies using similar metagenomic methods have found no evidence of a placental microbiome in term or preterm placentas (38) or placentas delivered by cesarean section (39). Potential limitations of studies on which the concept of a placental microbiome is based include limited sensitivity for the detection of low-abundance microbial communities, lack of appropriate controls for detecting contamination from dust or the commercial reagents, and lack of evidence of the viability of the microorganisms (15–17).

In addition to vaginal organisms, oral microorganisms have also been reported from placental samples (12). While the source of these microorganism could be blood within the samples (15), periodontal disease has been associated with PTB (40–44), and there is evidence that oral bacteria can translocate to the placenta (20). Hematogenous transmission, or transmission through the bloodstream, is a proposed explanation for how oral bacteria reach the placenta. Isolates of Enterococcus, Streptococcus, Staphylococcus, and Propionibacterium spp. have been isolated from umbilical cord blood, supporting hematogenous transmission (45). Hematogenous infection of Fusobacterium nucleatum, a bacterium present in the oral cavity, has been associated with colonization of the mouse placenta and was associated with PTB and stillbirth (46). In fact, a variety of oral bacteria have the ability to translocate to the placenta following hematogenous infection (20).

In summary, the placental microbiome is a recently proposed and controversial concept. Several studies provide preliminary evidence of a placental microbiome (12–14). In one of these studies, microscopic examination of sectioned and stained basal plates revealed bacteria in placenta from both preterm and term pregnancies, even in the absence of clinical or pathological infection (13). While these observations suggest that commensal nonpathogenic bacteria exist in the placenta, the microbiological techniques used in these studies are contested (15–17), and other studies using similar metagenomic methods have failed to detect a placental microbiome (38, 39).

PLACENTAL MICROORGANISMS AND INFLAMMATION

Microorganisms in the intrauterine environment can induce an inflammatory response, thereby initiating preterm labor and delivery (24, 47–50). Two studies have examined how trophoblasts, cells that form the outer layer of the blastocyst and develop into the placenta, respond to specific microorganisms. First, in cell culture, exposure of trophoblasts isolated from human placentas to a variety of microorganisms induced a release of interleukin-1β (IL-1β), IL-6, and IL-8, all of which are proinflammatory, and IL-10, which is anti-inflammatory (51). Separately, in a mouse model, placental trophoblasts were shown to play a role in the innate immune response to placental infection with Listeria monocytogenes, consisting of increased production of IL-12, IL-18, tumor necrosis factor alpha (TNF-α), and gamma interferon (52).

In order for inflammatory proteins to be produced, the initiating stimulus (e.g., microorganisms) must be identified by the host. Toll-like receptors (TLRs) recognize molecules derived from microbes, and TLR binding of these molecules initiates an innate immune response, including inflammation (53). The TLR signaling pathway activates NF-κB (54), which controls transcription for IL-1β, TNF-α, and other proinflammatory cytokines (8). Researchers have analyzed the human placenta for the presence and regulation of TLR2 and TLR4, specifically. TLR4 recognizes Gram-negative bacteria by its endotoxin lipopolysaccharide (LPS) (55, 56). TLR2 recognizes a wide variety of pathogens, including yeast (57), mycobacteria (58), and Gram-positive bacteria (59). Immunohistochemical staining of placentas from normal pregnancies identifies TLR2 and TLR4 in the trophoblasts of the placenta (60).

Microbes in the placenta not only are associated with a localized inflammatory response but also a sustained systemic inflammatory response in newborns. In a study of 527 placentas from the Extremely Low Gestational Age Newborn (ELGAN) study, the recovery of bacteria from the placenta, using culture techniques, was associated with an increased expression of inflammatory proteins in the neonate’s blood (61). A notable exception was Lactobacillus sp., which was associated with lower levels of inflammatory proteins (61). Other evidence that Lactobacillus sp. could have an anti-inflammatory influence is the inhibition of NF-κB, a proinflammatory pathway, by Lactobacillus in the intrauterine environment of a mouse model (62), and the increased production of IL-10, an anti-inflammatory cytokine, by Lactobacillus in trophoblast cells (63). These findings suggest that not all microbes in the placenta induce a proinflammatory response.

Although the studies above suggest that bacterial colonization of the placenta induces a fetal and/or neonatal inflammatory response that could adversely affect the infant, few studies have focused specifically on the relationship between microbes in the human placenta and an inflammatory response. Since bacterial presence in the fetal membranes does not always induce an inflammatory response (64), the species of bacteria in the placenta might influence whether an inflammatory response is induced. Given the role of TLR4 binding in the initiation of inflammation, Gram-negative bacteria could be of more consequence then other types of bacteria, and the cellular expression of TLR4 could influence the magnitude of the inflammatory response.

MICROORGANISMS AND DNA METHYLATION

Epigenetic mechanisms control gene expression but do not change base pair sequences (65). Epigenetic modifications include DNA methylation, histone modification, and microRNAs. DNA methylation involves the addition of methyl groups to the nucleotide cytosine. The methyl group is added to DNA by the enzyme DNA methyltransferase (DNMT). Hypermethylation reflects an increase in methyl groups at a specific site, while hypomethylation refers to a decrease in methyl groups. Hypomethylation in promoter regions of DNA often leads to gene upregulation, with some exceptions (66).

We hypothesize that bacteria can lead to altered DNA methylation in a gene-specific or non-gene-specific pattern (Fig. 2). The presence of bacteria can induce the production of reactive oxygen species (ROS) by phagocytes (67), and ROS-induced oxidative stress has been shown to modulate DNA methylation that alters gene expression (68). ROS can damage DNA and cause structural modifications through base modifications, base deletions, and chromosomal breakages (69). These structural modifications interfere with the activity of DNMT and lead to genomewide, non-gene-specific hypomethylation (68). On the other hand, the transcription factor occupancy theory proposes that transcription factors are drivers of gene-specific DNA methylation patterns (70). The transcription factor binding to the DNA either prevents or allows the DNA methylation machinery access to the DNA sequences, and therefore this binding influences gene-specific methylation. In the context of bacterium-induced inflammation, increased activity of inflammation-related transcription factors would lead to altered methylation of inflammatory genes.

FIG 2.

Proposed mechanisms for non-gene-specific and gene-specific mechanisms of altered DNA methylation. Microbial presence may trigger the production of ROS and inflammation-associated transcription factors as a mechanism of cellular defense. ROS damages DNA, which may render DNMT unable to access the DNA leading to genome-wide hypomethylation. On the other hand, transcription factors may bind to the DNA at specific inflammatory-related promoter regions. This binding may prevent or allow DNMT access to the DNA and lead to gene-specific differential methylation.

Multiple studies have examined the presence of microorganisms in a variety of tissue types in relation to alterations of epigenetic mechanisms. The presence of Escherichia coli in uroepithelial cells significantly increased the expression of DNMT and the promoter region of cyclin-dependent kinase inhibitor 2A, a tumor suppressor, was hypermethylated, while its expression was downregulated (71). There is also evidence that Helicobacter pylori, which is associated with ulcers and stomach cancer, affects CpG methylation patterns in the gastric mucosae. Eight sites that are known to be methylated in gastric cancer were found to be hypermethylated in the presence of H. pylori (72). This is evidence that the presence of microorganisms can influence the methylation state of DNA and alter epigenetic machinery.

In examining the effects of bacteria on placental tissue methylation, a mouse model was used to determine the association between Campylobacter rectus and methylation of the insulin-like growth factor 2 (IGF2) gene in the placenta. The promoter region of IGF2 was hypermethylated when C. rectus was present in the placenta (73). IGF2 plays a critical role in placental growth, as well as growth of the developing fetus (74). In one of our recent studies conducted within the ELGAN cohort, placental microorganisms were analyzed in relation to genome-wide DNA methylation in the human placenta. Genes that were differentially methylated in the presence of placental microorganisms were enriched for growth and transcription factors, the immune response, and the inflammatory response, specifically the NF-κB pathway (75). Activation of NF-κB has been associated with initiation labor (76, 77) and also plays a role in inflammation-related disease (27). These observations provide a basis for the hypothesis that microorganisms in the placenta affect fetal development, birth outcomes, and later life disease through epigenetic changes in the placenta. However, in order to support this, it is necessary to examine gene expression of inflammatory-associated proteins in placental tissues in the presence of microorganisms. As discussed in the previous section, these relationships have been studied in cell culture and a mouse model but not in the human placenta.

PLACENTAL DNA METHYLOME AND NEURODEVELOPMENT

Since the DOHaD hypothesis proposes epigenetic modifications as a mechanism by which prenatal exposures can contribute to later life disease (6), there is considerable interest in the relationship of the placental DNA methylome to health and developmental disorders later in life. Similarities have been shown between neuronal and placental DNA methylation profiles in genes that are associated with neuronal development (78); thus, DNA methylation in the placenta could contribute to neurodevelopment and neurocognitive outcomes later in life. Multiple studies have examined the association between the DNA methylation patterns of specific genes in the placenta and neurological outcomes in infants, primarily using the NICU Network Neurobehavioral Scales (NNNS). The NNNS evaluates neurologic measures, behavioral measures, and signs of stress in infants to determine neurobehavioral performance (79). In addition to its value as an early-life assessment, the NNNS is predictive of neurodevelopmental and cognitive performance, as well as school readiness in children (80, 81).

Multiple epigenetic studies have been conducted using the Rhode Island Child Health Study (RICHS), a birth cohort of term pregnancies delivered at Women and Infants’ Hospital in Providence, Rhode Island, and the findings have been consistent across the different approaches and neurobehavioral outcomes (82). The methylation status of two target genes, hydroxysteroid 11-β dehydrogenase 2 (HSD11B2) and nuclear receptor subfamily 3 group C member 1 (NR3C1), have been analyzed in relation to NNNS measures. These genes were selected because HSD11B2 is involved in cortisol regulation in the placenta and in the hypothalamic-pituitary-adrenocortical (HPA) axis. Previous studies have shown that reduced HSD11B2 expression in the placenta leads to the fetus being exposed to increased levels of cortisol and dysregulation of the infant’s HPA axis and neurodevelopment (83, 84). NR3C1 is the gene for the glucocorticoid receptor, which binds cortisol. Analysis of placentas of 185 newborn infants indicated that the promoter region of HSD11B1 was hypermethylated in infants who had reduced scores for quality of movement (85). Similar analyses showed an association between the methylation pattern in the promoter region of NR3C1 and the quality of infant movement (86), infant attention (86, 87), self-regulation (87), and lethargy (87). The interaction of DNA methylation of HSD11B2 and NR3C1 is associated with distinct neurobehavioral phenotypes (88). For example, when methylation was high for both genes the children had higher habituation scores (88).

More recent studies employed genome-wide methylation of the placenta instead of examining specific candidate genes. An epigenome-wide study of 335 infants found that an increase in methylation of a CpG site in the fragile histidine triad (FHIT) gene was associated with increased infant attention, whereas the inverse was true for a CpG site in the ankyrin repeat domain 11 (ANKRD11) gene (89). FHIT is a tumor suppressor gene that has been linked to autism spectrum disorder (90), and ANKRD11 acts as a nuclear coregulator in the developing brain (91) and has been associated with KBG syndrome (92), which is associated with developmental delays and intellectual deficiencies (93). Gene ontology analysis indicated that CpG sites associated with NNNS outcomes were located within genes enriched for biological pathways involved in both brain development and placental physiology (89).

In one of the first studies that directly analyzes the association of placental CpG methylation and neurocognitive outcomes later in life, genome-wide placental methylation was analyzed in relation to neurocognitive function in a cohort of individuals born extremely preterm. Genes related to neuronal development and function were hypermethylated (94), which typically suppresses gene expression. Hypermethylation of 16 genes involved in both neuronal development and function was associated with moderate to severe cognitive impairment at 10 years of age (94). Additional studies that attempt to replicate these findings are needed.

INFLAMMATION AND NEURODEVELOPMENT

Preclinical (26, 95–99) and epidemiologic studies in humans (9, 25, 100–105) suggest that inflammation and cytokines can disrupt fetal and neonatal brain development. In the placenta, an inflammatory response, with activation of a cytokine cascade, could transmit inflammatory signals between maternal and fetal tissues (106). Inflammation of fetal membranes is associated with the upregulation and shedding of cell adhesion molecules (107, 108) and elevation of IL-6 levels (109, 110). These proteins activate fetal leukocytes (111, 112) which appear to have a role in the pathogenesis of white matter damage (113). Cytokines and other large molecules have access to the brain through circumventricular organs, areas in the brain that are devoid of the blood-brain barrier (9). Cells in the circumventricular organs contain TLR4 and IL-1 receptors (114, 115) and thus have the potential to initiate the NF-κB signaling cascade, a release of cytokine and chemokines that can transmit inflammatory signals to other cells in the central nervous system, resulting in prolonged neuroinflammation (116, 117).

Both prenatal (103, 104) and postnatal (118–120) inflammation have been associated with neurodevelopment impairment. In a mouse model, increased maternal IL-17a, a proinflammatory cytokine, promotes abnormal cortical development in the offspring (121). Elevated levels of IL-6 and IL-8 in the amniotic fluid have been associated with cerebral palsy (CP) at age three (122). In the Providence cohort from the Collaborative Perinatal Project, increased levels of TNF-α in the maternal serum were associated with increased odds of schizophrenia and other psychoses in the offspring (123). TNF-α has been shown to irreversibly alter synaptic transmission and impair cognition in adult inflammation models (124–126). Interestingly, in a mouse model study, maternal inflammation led to an increase in placental serotonin output (127). Maternal serotonin from the placenta reaches the fetal brain and modulates key neurodevelopmental processes (128–130).

The ELGAN study has provided additional evidence of a relationship between early-life inflammation and adverse neurodevelopment. The concentrations of inflammation-related proteins were measured in neonatal blood samples from study participants, who were then evaluated at 2 years of age with the Bayley Scales of Infant and Toddler Development II and the Child Behavior Check List (CBCL) (119, 131–133). Of the 25 inflammation-related proteins evaluated, the elevated levels of 17 of them were associated with early cognitive impairment (131). Persistent or sustained elevation of at least four or more of the inflammation-related proteins was associated with the risk of early cognitive impairment, microcephaly, and attention problems defined by CBCL (132). Similar findings were obtained when neonatal levels of inflammation-related proteins were studied in relation to outcomes at 10 years of age (134).

To summarize, preclinical and epidemiologic studies indicate that early-life inflammation could influence the risk of neurological impairments later in life. The placenta plays a functional role in fetal neurodevelopment and can pass inflammatory signals from mother to fetus; hence, inflammation in the placenta could have deleterious effects on the fetus. Postnatal inflammation, arising from neonatal illnesses or prenatal exposures, is associated with neurodevelopmental impairment later in life. Although a large body of evidence supports a relationship between inflammation in utero and neurodevelopmental impairment later in life, mechanisms that mediate this relationship are not fully understood.

PLACENTAL MICROORGANISMS AND NEURODEVELOPMENT

Indicators of infection in the placenta, such as chorioamnionitis and fetal vasculitis, have been associated with adverse brain structural (28) and functional disorders (103, 135). However, few studies focusing on neurodevelopment have directly tested the placenta for the presence of microorganisms and instead have used indicators of inflammation as a proxy for microbial presence. One study that did directly test the placenta detected infectious agents using in situ hybridization or reverse transcriptase PCR and found an association between in utero infection of the placenta and neurodevelopmental abnormalities (136). In the ELGAN cohort, placentas were analyzed for multiple microorganisms and infants underwent ultrasound scans shortly after birth and were assessed for CP at 24 months. The presence of microorganisms in the placenta were predictive of ultrasound lesions of the brain and diparetic CP (137), specifically the presence of Ureaplasma urealyticum was associated with increased risk of intraventricular hemorrhage and echolucent brain lesions in the white matter of the brain (138). Clearly, more study is needed of the relationship between placental microorganisms and neurodevelopment, including assessments of the children beyond 24 months of life, when neurodevelopmental outcomes are more meaningful.

CONCLUSION

This review summarizes studies of the relationship between placental microorganisms and neurodevelopment and neurocognitive outcomes. Much of the evidence for this relationship is based on indirect markers of infection, such as clinical and/or placenta histological evidence of chorioamnionitis. Thus, more studies are needed to better characterize the relationship of specific microbial species in the placenta and neurodevelopmental outcomes. Here, we propose two processes, placental DNA methylation and inflammation, that could mediate a relationship between placental microbes and neurodevelopmental outcomes. From published studies of this relationship some major themes emerge. First, the presence of microorganisms in the placenta could play an important role in placental function and fetal growth and development. Second, noncommensal bacteria could induce an inflammatory response in the placenta that may impact fetal development in utero or be sustained in the newborn. Third, microorganisms have the potential to influence epigenetic machinery and cause differential DNA methylation in the human placenta. Fourth, alterations to the placental DNA methylome have been associated with neurological outcomes in infants using the NNNS assessment. Fifth, inflammatory signals can be transmitted from mother to fetus and have major impacts on fetal development.

There are a number of knowledge gaps in the understanding of the relationship between placental microorganisms and later life neurological outcomes. First, the concept of a placental microbiome remains under debate and needs to be further investigated. Evaluation of microbial presence in the placenta from “normal” pregnancies, as well as from pregnancies with complications, is critical to understanding whether commensal bacteria are normally present in the placenta and which bacterial communities contribute to health and disease. Second, more research is needed to characterize how specific bacterial species in the placenta affect placental functions, including inflammatory responses. Third, further investigations are necessary to determine how placental microorganisms impact the placental methylome. Most of the research on microorganisms and DNA methylation has been done in other tissue types. Fourth, analysis of the placental methylome in relation to neurodevelopment should include studies that assess neurocognitive outcomes at school age and beyond. Finally, placental inflammation that accompanies microorganisms in the placenta should be studied in relation to neurological outcomes later in life. Gaining a better understanding of which microorganisms in the placenta are associated with neurological disorders and the biological mechanisms driving this association could lead to improved identification, prevention, and treatment for these disorders.

Biographies

Martha Scott Tomlinson, Ph.D., is a postdoctoral researcher in the Department of Environmental Sciences and Engineering at the Gillings School of Global Public Health at UNC–Chapel Hill and the Assistant Director of the Community Engagement Core in the Institute for Environmental Health Solutions (IEHS). Dr. Tomlinson received a B.S. in Biological Sciences with an emphasis in Toxicology from Clemson University and holds a Ph.D. from UNC–Chapel Hill in Environmental Sciences and Engineering where she worked under the advisement of Dr. Rebecca Fry. Her doctoral research focused on how the presence of microorganisms alter biological mechanisms within intrauterine environment and how these modifications may contribute to later life disease, specifically neurological outcomes. Her future research interests include exploring how environmental exposures influence health and disease and working with exposed communities to assist them in better understanding and preventing exposure.

Kun Lu, Ph.D., is an associate professor in the Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill. The overarching goal of Dr. Lu’s research is to better understand health effects of environmental exposure and individual response. He has strong technical background and expertise in analytical chemistry, microbiome, exposome, omics profiling, and biomarker development. Dr. Lu studies how gut microbiome interacts with environmental exposure, how microbiome affects disease susceptibility, and how host factors crosstalk with microbiome to influence its response. Another focus of Dr. Lu’s research is to map exposome for human disease to characterize exposures over the lifespan via high-resolution mass spectrometry, understand the health impact of the exposome, and design strategies to reduce exposure-associated adverse effects.

Jill R. Stewart, Ph.D., is an Associate Professor in the UNC Gillings School of Global Public Health. She is also Deputy Director of the UNC Center for Galápagos Studies, a Faculty Fellow in the Carolina Population Center, and the co-Lead for the Global Health Concentration of the Gillings MPH degree program. She previously served as the chair (2012–2013) and councilor (2013–2014) for ASM Division Q: Environmental and General Applied Microbiology, and as an ASM Distinguished Lecturer (2015–2016). Her research focuses on environmental health microbiology, including the development of novel tools to detect and track microbes of public health concern. Recent research also includes studies to evaluate the evolution and dissemination of antibiotic-resistant bacteria in the environment and in human and animal populations. Overall, this research is leading to a greater understanding of how environmental conditions can affect human health and how humans themselves influence this process.

Carmen J. Marsit, Ph.D., is Professor in the Department of Environmental Health and the Department of Epidemiology in the Emory University Rollins School of Public Health. He is also the Director of the Emory Exposome Research Center and NIEHS-funded P30 Core Center dedicated to developing and supporting environmental health research. Carmen leads a multidisciplinary research program focused on defining biological mechanisms underlying the role of the environment on human health and disease, particularly focused on the developmental origins of children’s health and disease. He incorporates state-of-the-art high-dimensional genomic and epigenomic tools to define how environmental factors ranging from toxic trace metals to adversity and psychosocial stress use unique and shared biological responses to affect health and may provide insights into novel prevention and intervention strategies.

T. Michael O’Shea, M.D., M.P.H., completed undergraduate, graduate (epidemiology), and medical training at the University of North Carolina, and neonatology training at Duke University. For more than three decades, his research focus has been the epidemiology and prevention of chronic health and developmental disorders among survivors of very preterm birth. He is the Principal Investigator for the third phase of the Extremely Low Gestational Age Newborn Study (4UH3OD023348-01) and has been a coinvestigator on that study since its inception in 2001. He currently serves as the C. Richard Morris Distinguish Professor of Pediatrics and Division Chief for Neonatology at the University of North Carolina. He is actively involved in mentoring researchers at many levels, including medical students, neonatology fellows, graduate students, and postdoctoral fellows. In his leisure time he most enjoys spending time with his three children and four grandchildren.

Rebecca C. Fry, Ph.D., is the Carol Remmer Angle Distinguished Professor in Children’s Environmental Health and Associate Chair in the Department of Environmental Sciences and Engineering at the Gillings School of Global Public Health at UNC-Chapel Hill. Dr. Fry is the founding Director of the Institute for Environmental Health Solutions (IEHS) at UNC-Chapel Hill. She is the Principal Investigator of the third phase of the Extremely Low Gestational Age Newborn Study which is funded through the Environmental Influences on Child Health Outcomes (ECHO) program. Dr. Fry holds a Ph.D. in biology with postdoctoral training in toxicogenomics and environmental health sciences. A primary goal of Dr. Fry’s research is to better understand the deleterious impacts of toxic exposures during the prenatal period with a focus on the epigenome and developmental origins of health and disease. Her group has identified epigenetic mechanisms that relate toxic substances to children’s health.