Malformation rates in humans range from 2-16% of live births. Craniofacial birth defects arising from first and second branchial arch defects occur in 1 of 4000 live births. Of the full spectrum of human malformations, 7-11% are thought to have an identifiable external factor (including xenobiotics); but 55-70% are due to unknown etiologies. Preliminary data presented herein indicate that dietary supplementation during gestation with ellagic acid, a naturally occurring plant phenolic with demonstrated anticarcinogenic, antimutagenic, and in vitro embryoprotectant qualities, is capable of at least partial protection of rat embryos from the craniofacial teratogenic effects of alkylating agents. The broad significance of these studies revolves around the potential to protect the conceptus from craniofacial chemical teratogenesis in utero via maternal dietary modification. If some portion of craniofacial birth defects are the result of in utero exposure to chemical teratogens, the ability of naturally occurring dietary chemopreventives such as ellagic acid could be harnessed to raise the threshold of susceptibility of the conceptus to teratogenic insult. The studies proposed herein would evaluate the ability of ellagic acid to provide teratogenic embryoprotection utilizing models of craniofacial teratogenicity with which the P.I. has demonstrated experience. Two experiments are proposed: a developmental toxicity evaluation of dietary ellagic acid; and a feeding trial utilizing established models of teratogenicity. The developmental toxicity evaluation is requisite to any potential utilization of ellagic acid as a dietary chemopreventive and is also needed to pick concentrations of ellagic acid for the second study. The concentration of elIagic acid in maternal rat liver at the conclusion of the feeding study will also be determined as a marker of dietary absorption In order to determine if an absorption maximum exists for ellagic acid. Although numerous teratogenicity models are available, the second study utilizes 3,3-dimethyl-1-phenyltriazene and N-methyl-N- nitrosourea rat models with which the P.I. has demonstrated experience. These models induce an extremely high and uniform rate of craniofacial and brain malformations. In summary, evidence of in vivo embryoprotection in the proposed studies would be of significance in the implication that human maternal dietary manipulation could potentially decrease the incidence of certain craniofacial birth defects.
