Superfund Research Program
PCB Effects on Uterine Muscle
Project Leader: Rita Loch-Caruso (University of Michigan)
Grant Number: P42ES004911
Funding Period: 1995 - 2006
Polychlorinated biphenyls (PCBs) are widespread environmental contaminants. Previous epidemiologic and laboratory studies indicate that some PCBs alter gestation length. Because PCBs accumulate in uterus and placenta during pregnancy, these tissues may be direct targets of PCBs. In 2005, Dr. Loch-Caruso began investigating polybrominated diphenyl ethers (PBDEs), which share some structural similarities with PCBs. PBDEs are emerging toxicants of concern due to their widespread commercial use as flame retardants and their pervasive contamination of environmental media, wildlife and humans. Although no study has yet examined PBDE effects on gestation length, previous studies showed that PBDEs cross the human placenta and decrease gestation length in rabbits. The overall objective of this work is to identify plausible biological pathways by which PCBs and PBDEs could stimulate premature birth. Current experiments are focusing on the prostaglandin pathway, a key pathway for parturition.
In pregnant women, the amnion is the most abundant source of stimulatory prostaglandins for induction of labor. Dr. Loch-Caruso’s group found that several ortho-substituted PBDEs and PCBs increased prostaglandin (PG) release from rat and human amnion cells. The greatest response was observed with the PBDE congener BDE-47, with a maximal response exceeding a 10-fold increase after 4 h of exposure to 60 mM BDE-47.
To initiate prostaglandin synthesis, phospholipases release arachidonic acid from membrane phospholipids. They found that several ortho-substituted PCBs and PBDEs significantly stimulated release of arachidonic acid from rat and human amnion cells. Furthermore, they identified a previously uncharacterized 50-kDa iPLA2 isoform in human term, non-laboring amnion and chorio-decidua membranes and in rat myometrium. In rat myometrium, expression of the 50-kDa iPLA2 increased about 7.5-fold near-term (gestation day 20) compared with midgestation (gestation day 10). Ongoing experiments are examining how PCBs and PBDEs modify expression of this and other PLA2 isoforms in human gestational membranes.
Dr. Loch-Caruso’s group showed that the PBDE congeners BDE-47 (40 mM) and BDE-153 (25 mM) induced expression of COX-2 in human amnion cells. Similarly, PCB 153, which shares structural similarities with BDE-153, increased COX-2 mRNA expression in rat amnion cells. Because COX-2 is critical for prostaglandin synthesis and because increased expression of COX-2 is associated with parturition, PBDE induction of COX-2 may contribute to increased synthesis of PGE2. Furthermore, a hydroxylated PCB congener decreased prostaglandin dehydrogenase (PGDH) activity in human chorion trophoblast cells. Because PGDH activity in the chorion metabolically inactivates amnion-produced prostaglandins, inhibition of PGDH would effectively elevate prostaglandin availability and stimulation of uterine contractions.
Pro-inflammatory cytokines have been linked previously with increased prostaglandin release from gestational membranes and with onset of labor. They found that PBDEs (BDE-47 and BDE-100) increased IL-6 release from human amnion cells and TNFa from human chorion trophoblast cells, and that TNFa increased expression of COX-2 in rat amnion cells. These data suggest that PBDEs may increase prostaglandin synthesis through a cytokine-related mechanism.
In summary, these results suggest that PCBs and PBDEs activate prostaglandin signaling in gestational tissues. If subsequent work supports initial findings, this provides a biological pathway by which these toxicants could promote preterm parturition.