Superfund Research Program
Genetic Stress and Toxicant-Induced Pregnancy Disruption
Project Leader: Surendra Sharma (Women & Infants Hospital of Rhode Island)
Grant Number: P42ES013660
Funding Period: 2005-2014
Final Progress Reports
Year: 2014 2008
Studies and Results
The intrauterine microenvironment is particularly vulnerable to environmental exposures and pathogens because of temporal organogenesis and development. In humans, epidemiological studies suggest that exposure to polychlorinated biphenyls (PCBs) is associated with reproductive health consequences and neurological anomalies in the offspring. In this regard, researchers previously established a mouse model that provided evidence for a two-hit gene-environment interaction hypothesis for adverse pregnancy outcomes and neurological defects. Data suggested that IL-10 deficiency coupled with exposure to Aroclor 1254, a mixture of more than 100 PCB congeners, during pregnancy led to preterm birth associated with fetal growth restriction, placental insufficiency, and righting reflex defects in newborns. Researchers also identified the water channel protein aquaporin 1 (AQP1) as a unique placental target of PCBs. Since AQP1 has been linked with angiogenesis and since PCB exposure resulted in placental insufficiency, they hypothesized that PCBs acted as regulators of anti-angiogenesis at the placenta level. However, understanding of the mechanisms underlying such observations is limited. Researchers hypothesized that PCBs targeted the vascular endothelial growth factor (VEGF) machinery by activating the Notch-delta-like ligand (dll) signaling pathways. Recent results support this hypothesis. Exposure of pregnant IL-10-/- mice or human trophoblast cells to Aroclor 1254 or PCB126 resulted in activation of the Notch-dll pathway in the mouse placenta as well as in human trophoblast cells resulting in inhibition of VEGF receptor 2 (VEGF R2). These results were confirmed by a combination of complementary techniques. Using human trophoblast cells, researchers also demonstrated that inhibition of AQP1 by Aroclor 1254 or PCB126 was aryl hydrocarbon receptor (AhR)-dependent as blockade of AhR rescued AQP1 expression. Importantly, recent data also provide evidence for PCB126-mediated multi-generational effects on pregnancy outcome, obesity of pregnant dams and their offspring, and placental anomalies. All of these observations are currently being prepared for publication.
Observations provide strong evidence for a role of co-planar PCBs in programming pregnancy-associated hypertension, preterm birth, intrauterine growth restriction (IUGR), and obesity in dams and in offspring. Since angiogenesis and fluid regulation across gestation are critical for normal placental and fetal growth, these results are novel in that PCB exposure, particularly co-planar congeners, can program hypertension, preterm birth, and obesity in a transgenerational manner. Researchers also would like to explore the Notch1-dll4 pathways for anti-angiogenic activities of PCB congeners. Recent results on PCB-induced hypertension during pregnancy and obesity post-pregnancy and postnatally are intriguing. Unraveling novel pathways underlying these poorly understood effects of PCB exposure will be a major step forward in addressing PCB-associated environmental disease.