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

Project-Specific Links

Final Progress Reports

Year:   2014  2008 

The health consequences of environmental toxicants are likely to have critical effects during in utero fetal development because of the complex signaling cascades, high cellular proliferation rates, and differentiation events. Although the hormonal milieu, metabolic changes, and placental microenvironment are programmed in a pregnancy compatible manner, pregnancy presents itself as an immunological and hormonal paradox. The role of steroid hormones is well known in uterine receptivity, implantation, local immune modulation, and pregnancy success. If not temporally produced and regulated, their dysfunction lead to infertility or pregnancy loss. Man-made chemicals like polychlorinated biphenyls (PCBs) act like hormones and interfere with their cognate receptor functions impacting normal biological processes. Although the genotoxic effects of PCBs have been investigated intensively and epidemiological studies have highlighted their health risks, the mechanisms responsible for reproductive and neuro-developmental effects still remain enigmatic. The overarching goal of the studies carried out by Dr. Surendra Sharma’s team is to identify unknown pathways and targets that impart adverse effects on pregnancy. In this study, the Sharma group has directed its efforts toward establishing an experimental system to evaluate in utero gene-environment effects of PCBs using wild type mice and their counterparts deficient in pregnancy compatible anti-inflammatory cytokines such as IL-10.

Despite serious health risks in humans and wild life, the underlying mechanisms that explain gene-environment effects of chemical toxicants are largely unknown. PCBs are one of the most ubiquitous environmental toxicants worldwide, with reported epidemiological evidence for reproductive and neurocognitive anomalies in humans. Dr. Sharma and colleagues have recently shown that Aroclor 1254, a mixture of structurally distinct PCBs, causes preterm birth in IL-10-/- mice at a dose that does not show any effects in wild type mice, highlighting the significance of IL-10 as an anti-toxicant cytokine. Aroclor 1254-treated IL-10-/- mice demonstrated increased amniotic fluid, intrauterine growth restriction, and reduced litter size with postnatal neuromotor defects. Most importantly, Dr. Sharma’s group identified aquaporin 1 (AQP1), a potent effector of fluid volume regulation and angiogenic activity, as a novel placental target of PCBs.  In vivo or in vitro exposure to Aroclor 1254 coupled with IL-10 deficiency significantly reduced the protein content of AQP1. Reduced uterine AQP1 levels were associated with defective spiral artery transformation. These data demonstrate for the first time that the IL-10-AQP1 axis is a novel regulator of PCB-induced in utero effects.