The following summarizes the presentations given during the Symposium Session “Placenta as a Target of Environmental Exposures: From Bench to Society” that was held as part of the 2023 SOT Annual Meeting and ToxExpo.
Importance of the Placenta in Toxicological Studies
Presenter: Thaddeus Schug, PhD
The placenta is a sexually dimorphic organ that is essential for pregnancy. Central to the developmental origins of health and disease (DoHaD), the placenta functions as a liver, kidney, respiratory, and immune system and can provide vital information on the health and history of the pregnancy. Its job is to transport molecules, train the fetal immune system, and signal labor, among other things. In order to perform these functions, it is necessary to have a healthy placenta. An unhealthy placenta is associated with stillbirth, low birthweight, and preterm birth. However, assessment of the placenta during pregnancy is difficult because it is inaccessible, and thus, it is difficult to determine placental health until after birth. The Human Placenta Project is National Institute of Child Health and Human Development–led initiative with which the National Institute of Environmental Health Sciences is responsible for the development of the Environmental Influences on Placental Origins of Development (ePOD) program. The goal of ePOD is to develop models that assess placental health and aim to understand the effects of early-stage physiology and environmental exposures and how they influence health.
Phthalate Exposure and Longitudinal Ultrasound Measures of Placental Function in the Human Placenta Project Cohort
Presenter: Emma Rosen, PhD candidate, on behalf of Kelly Ferguson, PhD
Phthalates are non-persistent endocrine-disrupting chemicals found in a plethora of everyday products. Humans are easily exposed through a variety of sources like shampoo and food packaging; metabolism and excretion are quick. Phthalates are concerning in pregnancy because they are associated with poor birth outcomes, such as low birthweight and preterm birth. Studies indicate that this association may be mediated by placental function. Because the rodent placenta is not optimal for modeling the human placenta, an epidemiologic study was conducted to investigate whether phthalate exposure across pregnancy was associated with placental health. The study evaluated exposure to 18 metabolites and assessed a total of 10 exposures, which were a mixture of single metabolites and molar sums of phthalates like di(2-ethylhexyl) phthalate (DEHP). To assess placental health, several measures were used: placental microvasculature, count of arteries, and the ratio of uterine artery pulsatility index/fetal-placental arteriole count, placental calcification, and placental elasticity. A high pulsatility index indicated impeded blood flow, and high fetal-placental arteriole count indicated increased nutrient flow. All exposures and outcomes (except placental calcification) were averaged across pregnancy. In covariate-adjusted general linear models, the study found that several phthalates were associated with poorer placental microvasculature and increased odds of placental calcification. In the future, the lab will investigate mixtures of phthalates and aims to identify windows of susceptibility.
Placental Glucose Transfer after Gestational Particulate Matter Exposure
Presenter: Phoebe Stapleton, PhD
Epidemiological and experimental evidence suggests that particulate matter exposure may impact fetal growth. Though proper fetal growth is imperative for lifelong health, the role of the placenta has not yet been evaluated. Given the presence of particulate matter, the Stapleton lab set out to investigate whether inhalation of aerosolized titanium dioxide nanoparticles impairs the ability of glucose to pass through the placenta, thereby inhibiting fetal growth. Occupation-relevant doses of titanium oxide nanoparticles were used. To determine if nanoparticles translocate the placental barrier, the lab developed a placental perfusion technique to allow for cross-perfusion of blood through the placenta and permit the collection of effusion that would enter the fetal compartment. Using this ex vivo model, they found that the placenta did not act as a barrier, and nanosized particles were detected in umbilical vein effluent. The next goal was to investigate whether titanium dioxide reduced glucose transport to the fetus, using rats as a model. Gestational exposure to titanium dioxide in rats did not result in any decrease in fetal weight or placental efficiency. However, there was a large reduction in successful pregnancies. Additionally, though there was no change in blood glucose or insulin, hexokinase was decreased in the male placenta, and GLUT1 localization was decreased. Overall, results indicate that placental metabolism may be reduced in a sex-specific manner.
Environmental Modulator of Placental Tryptophan Catabolism and Influence on Maternal-Fetal Immune Cells
Presenter: Martha Susiarjo, PhD
Nearly 15% of clinically recognized pregnancies end in miscarriage due to aneuploidy, immunological complications, and hormonal abnormalities. Bisphenol A (BPA) is an endocrine-disrupting chemical that is detected in over 90% of human serum samples and is associated with an increased risk of miscarriage, though the mechanism of action is poorly understood. Similarly, tetrabromobisphenol A (TBBPA)—a flame retardant—is a BPA analog with similar reproductive toxicity with relatively unknown mechanisms. Currently, one proposed mechanism is disruption in indoleamine 2,3-deoxygenase 1 (IDO1)–mediated tryptophan catabolism that impairs expansion of regulatory T cells (Tregs) and creates excessive proinflammatory responses against the semiallogeneic fetus. In rodents, tryptophan plays a role in pregnancy maintenance and declines as pregnancy progresses. BPA is associated with elevated tryptophan in mice, and those exposed to BPA and TBBPA in pregnancy had higher rates of conceptus hemorrhaging than those unexposed; these effects were associated with a lower number of maternal Tregs. IDO1 is a tryptophan-depleting enzyme and IDO1 mRNA expression in the placenta begins at E7.5 and peaks at E9.5 and is localized to trophoblast giant cells in the placenta. BPA and TBBPA exposure in mice resulted in lower protein expression of IDO1 in the placenta. The results suggest that maternal exposure to BPA and TBBPA disrupts tryptophan catabolism, which adversely impacts IDO1 protein expression.
Legacy and Replacement Per- and Polyfluoroalkyl Substances (PFAS) Target the Placenta
Presenter: Suzanne Fenton, PhD
Per- and polyfluoroalkyl substances (PFAS) are endocrine-disrupting “forever” chemicals that persist in the environment and bioaccumulate, and they are currently being replaced with congeners, about which little is known. Experimental and epidemiologic studies indicate that PFAS, specifically perfluorooctanoic acid (PFOA), is associated with increased risk of poor birth outcomes and sets the stage for a lifetime of increased disease susceptibility. Unfortunately, PFAS are known to cross the placenta. Thus, the goal of the Fenton lab was to characterize the ways in which PFOA and its replacement, HFPO-DA or GenX, affect placental function. Initial studies were conducted utilizing CD-1 mice that were exposed to PFOA (at doses with known effects) and GenX (at levels of unknown consequence). Briefly, placental lesions were observed in mice exposed to PFOA and GenX, and PFOA remodeled the decidual spiral artery in placentas of male pups. Delving further, the Fenton lab utilized JEG-3 human placental trophoblasts to evaluate a panel of 42 varied family members in a multiplexed high-throughput screen for proliferation, cytotoxicity, and mitochondrial membrane potential changes. Overall, GenX-exposed cells exhibited reduced IGF2 and EGFR expression and increased CTNNB1 expression. Exposure to either GenX or PFOA resulted in upregulated ABCG2 expression, as well as upregulation of estradiol-related genes. In summary, findings suggest that exposure to PFOA and GenX has implications for placental health, and sex-specific associations may need to be explored.
Single Cell and Cell Type–Specific Analyses in Human Placental Tissues: Implications for Chemical Exposures and Adverse Birth Outcomes
Presenter: Kelly Bakulski, PhD
The placenta is a heterogeneous tissue with unique and specialized cells. Environmental exposures have been linked to differential gene expression in bulk placenta tissue. Cells are differentiated by epigenetic and RNA patterns, which can be altered by environmental stressors. Interpretation of placental gene expression and epigenetic measures in the placenta are difficult given this variety of cells; however, the Bakulski lab utilized single-cell RNA sequencing to generate term placental cell type–specific gene expression profiles. To test this method, the lab set out to answer the question, “Is cell composition associated with gestational age?” Using available data, the Bakulski lab observed changes in placental cell composition throughout pregnancy and that the composition differed by fetal sex in the third trimester. Furthermore, the lab demonstrated that preeclampsia was associated with overexpression of the FLT1 gene in the placenta, and this was mediated by overabundance of extravillous trophoblast cells. The next step was to apply these models to toxicology. Specifically, the group set out to evaluate exposure to cadmium. Overall, exposure in the first trimester was associated with changes in levels of trophoblasts, and exposure in the third trimester was associated with endothelial cells; there also were general changes in immune cell proportions. In short, gene expression and DNA methylation patterns can be utilized to estimate bulk placental cell composition, which changes throughout pregnancy and may differ by fetal sex in the later trimesters.
Placenta Transcriptomic Alterations Underlie Neurodevelopmental Effects of Pesticide Exposure
Presenter: Carmen Marsit, PhD
Organophosphates and pyrethroid pesticides remain heavily used throughout the globe to control insects and maintain agriculture. Unfortunately, pyrethroids have been linked to adverse health outcomes in epidemiologic and experimental studies, including neurodevelopmental effects. Adverse neurodevelopmental deficits occur because pyrethroids block acetylcholinesterase, thus increasing acetylcholine, but also through mechanisms involving serotonin and dopamine. In pregnancy, the placenta produces neuroendocrine hormones and neurotransmitters. Using rodent models and a cohort of farm-working pregnant women, the Marsit lab set out to investigate the role of the placenta in the association between prenatal pyrethroid exposure and postnatal neurodevelopment. In mice, the lab observed that chlorpyrifos exposure during pregnancy reduces differential gene expression in the brain and placenta, as did deltamethrin exposure. Interestingly, there was very little overlap between genes in the brain that were dysregulated by both chlorpyrifos and deltamethrin but over 200 genes overlapped in the placenta. Most notably, both pesticides resulted in overexpression of the Max transcription factor in both tissues. In the cohort of farm-working women, the lab observed that pesticide exposure was associated with differential gene expression in the placenta, with implications for late-pregnancy health. Given that there are common genes and pathways in the brain and placenta that are disrupted by pesticide exposure, the placenta may serve as a tool for developing tailored cognitive interventions.
This blog reports on the Symposium Session titled “Placenta as a Target of Environmental Exposures: From Bench to Society” that was held during the 2023 SOT Annual Meeting and ToxExpo. An on-demand recording of this session is available for meeting registrants on the SOT Online Planner and SOT Event App.
This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email SOT Headquarters.
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