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The PROTECT Center studies exposure to environmental contamination in Puerto Rico and its contribution to adverse pregnancy outcomes, including preterm birth. Rates of preterm birth and infant mortality in Puerto Rico are among the highest of all US states and territories.
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Toxicant-Stimulated Disruption of Gestational Tissues with Implications for Adverse Pregnancy Outcomes (Project 2)
Toxicant-Stimulated Disruption of Gestational Tissues with Implications for Adverse Pregnancy Outcomes (Project 2)
The Harris research team contributes to the mission of PROTECT Project 2 with toxicological studies of disruption of the placenta and the membranes as potential mechanisms of preterm birth and decreased birth weight. Our studies use tissue cultures of human placenta and fetal membranes from healthy pregnancies as experimental models that allow manipulation for toxicity assessment.
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Supported with funding from the National Institute of Environmental Health Sciences' Superfund Research Program Grant # P42 ES017198
Recent Research Highlights
A Data Mining Approach Reveals Chemicals Detected at Higher Levels in Non-Hispanic Black Women Target Preterm Birth Genes and Pathways
A Data Mining Approach Reveals Chemicals Detected at Higher Levels in Non-Hispanic Black Women Target Preterm Birth Genes and Pathways
Abstract: Preterm birth occurs disproportionately in the USA non-Hispanic Black population. Black women also face disproportionate exposure to certain environmental chemicals. The goal of this study was to use publicly available toxicogenomic data to identify chemical exposures that may contribute to preterm birth disparities. We tested 19 chemicals observed at higher levels in the blood or urine of non-Hispanic Black women compared to non-Hispanic White women. We obtained chemical-gene interactions from the Comparative Toxicogenomics Database and a list of genes involved in preterm birth from the Preterm Birth Database. We tested chemicals for enrichment with preterm birth genes using chi-squared tests. We then conducted pathway enrichment analysis for the preterm birth genes using DAVID software and identified chemical impacts on genes involved in these pathways. Genes annotated to all 19 chemicals were enriched with preterm birth genes (FDR-adjusted p value < 0.05). Preterm birth enriched chemicals that were detected at the highest levels in non-Hispanic Black women included methyl mercury, methylparaben, propylparaben, diethyl phthalate, dichlorodiphenyldichloroethylene, and bisphenol S. The preterm birth genes were enriched for pathways including "inflammatory response" (FDR-adjusted p value = 3 × 10-19), "aging" (FDR-adjusted p value = 4 × 10-8) and "response to estradiol" (FDR-adjusted p value = 2 × 10-4). Chemicals enriched with preterm birth genes impacted genes in all three pathways. This study adds to the body of knowledge suggesting that exposures to environmental chemicals contribute to racial disparities in preterm birth and that multiple chemicals drive these effects. These chemicals affect genes involved in biological processes relevant to preterm birth such as inflammation, aging, and estradiol pathways.
Exposure to Trichloroethylene Metabolite S-(1,2-Dichlorovinyl)-L-cysteine Causes Compensatory Changes to Macronutrient Utilization and Energy Metabolism in Placental HTR-8/SVne0 Cells
Exposure to Trichloroethylene Metabolite S-(1,2-Dichlorovinyl)-L-cysteine Causes Compensatory Changes to Macronutrient Utilization and Energy Metabolism in Placental HTR-8/SVne0 Cells
Abstract: Trichloroethylene (TCE) is a widespread environmental contaminant following decades of use as an industrial solvent, improper disposal, and remediation challenges. Consequently, TCE exposure continues to constitute a risk to human health. Despite epidemiological evidence associating exposure with adverse birth outcomes, the effects of TCE and its metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) on the placenta remain undetermined. Flexible and efficient macronutrient and energy metabolism pathway utilization is essential for placental cell physiological adaptability.
Abstract: Trichloroethylene (TCE) is a widespread environmental contaminant following decades of use as an industrial solvent, improper disposal, and remediation challenges. Consequently, TCE exposure continues to constitute a risk to human health. Despite epidemiological evidence associating exposure with adverse birth outcomes, the effects of TCE and its metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) on the placenta remain undetermined. Flexible and efficient macronutrient and energy metabolism pathway utilization is essential for placental cell physiological adaptability.
Because DCVC is known to compromise cellular energy status and disrupt energy metabolism in renal proximal tubular cells, this study investigated the effects of DCVC on cellular energy status and energy metabolism pathways in placental cells. Human extravillous trophoblast cells, HTR-8/SVneo, were exposed to 5-20 uM for 6 or 12 h. After establishing concentration and exposure duration thresholds for DCVC-induced cytotoxicity, targeted metabolomics was used to evaluate overall energy status and metabolite concentrations from energy metabolism pathways.
Because DCVC is known to compromise cellular energy status and disrupt energy metabolism in renal proximal tubular cells, this study investigated the effects of DCVC on cellular energy status and energy metabolism pathways in placental cells. Human extravillous trophoblast cells, HTR-8/SVneo, were exposed to 5-20 uM for 6 or 12 h. After establishing concentration and exposure duration thresholds for DCVC-induced cytotoxicity, targeted metabolomics was used to evaluate overall energy status and metabolite concentrations from energy metabolism pathways.
The data revealed glucose metabolism perturbations including a time-dependent accumulation of glucose-6-phosphate+frutose-6-phosphate (G6P+F6P) as well as independent shunting of glucose intermediates that diminished with time, with modest energy status decline but in the absence of significant changes in ATP concentrations. Furthermore, metabolic profiling suggested that DCVC stimulated compensatory utilization of glycerol, lipid, and amino acid metabolism to provide intermediate substrates entering downstream in the glycolytic pathway or the tricarboxylic acid cycle. Lastly, amino acid deprivation increased susceptibility to DCVC-induced cytotoxicity. Taken together, these results suggest that DCVC caused metabolic perturbations necessitating adaptations in macronutrient and energy metabolism pathway utilization to maintain adequate ATP levels.
The data revealed glucose metabolism perturbations including a time-dependent accumulation of glucose-6-phosphate+frutose-6-phosphate (G6P+F6P) as well as independent shunting of glucose intermediates that diminished with time, with modest energy status decline but in the absence of significant changes in ATP concentrations. Furthermore, metabolic profiling suggested that DCVC stimulated compensatory utilization of glycerol, lipid, and amino acid metabolism to provide intermediate substrates entering downstream in the glycolytic pathway or the tricarboxylic acid cycle. Lastly, amino acid deprivation increased susceptibility to DCVC-induced cytotoxicity. Taken together, these results suggest that DCVC caused metabolic perturbations necessitating adaptations in macronutrient and energy metabolism pathway utilization to maintain adequate ATP levels.
Elana R Elkin, Dave Bridges, Sean M Harris, Rita Karen Loch-Caruso
Elana R Elkin, Dave Bridges, Sean M Harris, Rita Karen Loch-Caruso
Identification of environmental chemicals targeting miscarriage genes and pathways using the comparative toxicogenomics database
Identification of environmental chemicals targeting miscarriage genes and pathways using the comparative toxicogenomics database
Abstract: Miscarriage is a prevalent public health issue and many events occur before women are aware of their pregnancy, complicating research design. Thus, risk factors for miscarriage are critically understudied. Our goal was to identify environmental chemicals with a high number of interactions with miscarriage genes, based on known toxicogenomic responses.
Abstract: Miscarriage is a prevalent public health issue and many events occur before women are aware of their pregnancy, complicating research design. Thus, risk factors for miscarriage are critically understudied. Our goal was to identify environmental chemicals with a high number of interactions with miscarriage genes, based on known toxicogenomic responses.
Sean M. Harris, Yuan Jin, Rita Loch-Caruso, Ingrid Y. Padilla, John D. Meeker, Kelly M. Bakulski
Sean M. Harris, Yuan Jin, Rita Loch-Caruso, Ingrid Y. Padilla, John D. Meeker, Kelly M. Bakulski
The trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine induces progressive mitochondrial dysfunction in HTR-8/SVneo trophoblasts
The trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine induces progressive mitochondrial dysfunction in HTR-8/SVneo trophoblasts
Abstract: Trichloroethylene is an industrial solvent and common environmental pollutant. Despite efforts to ban trichloroethylene, its availability and usage persist globally, constituting a hazard to human health. Recent studies reported associations between maternal trichloroethylene exposure and increased risk for low birth weight. Despite these associations, the toxicological mechanism underlying trichloroethylene adverse effects on pregnancy remains largely unknown. The trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) induces mitochondrial-mediated apoptosis in a trophoblast cell line.
Abstract: Trichloroethylene is an industrial solvent and common environmental pollutant. Despite efforts to ban trichloroethylene, its availability and usage persist globally, constituting a hazard to human health. Recent studies reported associations between maternal trichloroethylene exposure and increased risk for low birth weight. Despite these associations, the toxicological mechanism underlying trichloroethylene adverse effects on pregnancy remains largely unknown. The trichloroethylene metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) induces mitochondrial-mediated apoptosis in a trophoblast cell line.
To gain further understanding of mitochondrial-mediated DCVC placental toxicity, this study investigated the effects of DCVC exposure on mitochondrial function using non-cytolethal concentrations in placental cells. Human trophoblasts, HTR-9/SVneo, were exposed in vitro to a maximun of 20 uM DCVC for up to 12 h. Cell-based oxygen consumption and extracellular acidification assays were used to evaluate key aspects of mitochondrial function. Following 6 h of exposure to 20 uM DCVC, elevated oxygen consumption, mitochondrial proton leak and sustained energy coupling deficiency were observed. Similarly, 12 h of exposure to 20 uM DCVC decreased mitochondrial-dependent basal, ATP-linked and maximum oxygen consumption rates.
To gain further understanding of mitochondrial-mediated DCVC placental toxicity, this study investigated the effects of DCVC exposure on mitochondrial function using non-cytolethal concentrations in placental cells. Human trophoblasts, HTR-9/SVneo, were exposed in vitro to a maximun of 20 uM DCVC for up to 12 h. Cell-based oxygen consumption and extracellular acidification assays were used to evaluate key aspects of mitochondrial function. Following 6 h of exposure to 20 uM DCVC, elevated oxygen consumption, mitochondrial proton leak and sustained energy coupling deficiency were observed. Similarly, 12 h of exposure to 20 uM DCVC decreased mitochondrial-dependent basal, ATP-linked and maximum oxygen consumption rates.
Using the fluorochrome TMRE, dissipation of mitochondrial membrane potential was detected after a 12-h exposure to 20uM DCVC, and (+-)-a-tocopherol, a known suppressor of lipid peroxidation, attenuated DCVC-stimulated mitochondrial membrane depolarization but failed to rescue oxygen consumption perturbations. Together, these results suggest that DCVC caused progressive mitochondrial dysfunction, resulting in lipid peroxidation-associated mitochondrial membrane depolarization. Our findings contribute to the biological plausibility of DCVC-induced placental impairment and provide new insights into the role of the mitochondria in DCVC-induced toxicity.
Using the fluorochrome TMRE, dissipation of mitochondrial membrane potential was detected after a 12-h exposure to 20uM DCVC, and (+-)-a-tocopherol, a known suppressor of lipid peroxidation, attenuated DCVC-stimulated mitochondrial membrane depolarization but failed to rescue oxygen consumption perturbations. Together, these results suggest that DCVC caused progressive mitochondrial dysfunction, resulting in lipid peroxidation-associated mitochondrial membrane depolarization. Our findings contribute to the biological plausibility of DCVC-induced placental impairment and provide new insights into the role of the mitochondria in DCVC-induced toxicity.
Elana R Elkin, Dave Bridges, Rita Loch-Caruso
Elana R Elkin, Dave Bridges, Rita Loch-Caruso
Group B streptococcus activates transcriptomic pathways related to premature birth in human extraplacental membranes in vitro
Group B streptococcus activates transcriptomic pathways related to premature birth in human extraplacental membranes in vitro
Abstract: Streptococcus agalactiae (group B streptococcus [GBS]) infection in pregnant women is the leading cause of infectious neonatal morbidity and mortality in the United States. Although inflammation during infection has been associated with preterm birth, the contribution of GBS to preterm birth is less certain. Moreover, the early mechanisms by which GBS interacts with the gestational tissue to affect adverse pregnancy outcomes are poorly understood. We hypothesized that short-term GBS inoculation activates pathways related to inflammation and premature birth in human extraplacental membranes.
Abstract: Streptococcus agalactiae (group B streptococcus [GBS]) infection in pregnant women is the leading cause of infectious neonatal morbidity and mortality in the United States. Although inflammation during infection has been associated with preterm birth, the contribution of GBS to preterm birth is less certain. Moreover, the early mechanisms by which GBS interacts with the gestational tissue to affect adverse pregnancy outcomes are poorly understood. We hypothesized that short-term GBS inoculation activates pathways related to inflammation and premature birth in human extraplacental membranes.
We tested this hypothesis using GBS-inoculated human extraplacental membranes in vitro. In agreement with our hypothesis, a microarray-based transcriptomics analysis of gene expression changes in GBS-inoculated membranes revealed the GBS activated pathways related to inflammation and preterm birth with significant gene expression changes occurring as early as 4 hr postinoculation. In addition, pathways related to DNA replication and repair were downregulated with GBS treatment. Conclusions based on our transcriptomics data were further supported by responses of prostaglandin E2 (PGE2), and matrix metalloproteinases 1 (MMP1) and 3 (MMP3), all of which are known to be involved in parturition and premature rupture of membranes. These results support our initial hypothesis and provide new information on molecular targets of GBS infection in human extraplacental membranes.
We tested this hypothesis using GBS-inoculated human extraplacental membranes in vitro. In agreement with our hypothesis, a microarray-based transcriptomics analysis of gene expression changes in GBS-inoculated membranes revealed the GBS activated pathways related to inflammation and preterm birth with significant gene expression changes occurring as early as 4 hr postinoculation. In addition, pathways related to DNA replication and repair were downregulated with GBS treatment. Conclusions based on our transcriptomics data were further supported by responses of prostaglandin E2 (PGE2), and matrix metalloproteinases 1 (MMP1) and 3 (MMP3), all of which are known to be involved in parturition and premature rupture of membranes. These results support our initial hypothesis and provide new information on molecular targets of GBS infection in human extraplacental membranes.
Hae-Ryung Park, Sean M Harris, Erica Boldenow, Richard C McEachin, Maureen Sartor, Mark Chames, Rita Loch-Caruso
Hae-Ryung Park, Sean M Harris, Erica Boldenow, Richard C McEachin, Maureen Sartor, Mark Chames, Rita Loch-Caruso
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