Reproductive epidemiology is a newly-developing area, and much of our work continues to be in the exploration of fundamental problems of reproductive epidemiology (publications #3,4,5,7). Much of our applied work is directed toward using genetic susceptibility as a tool for identifying reproductive toxins. We made major progress this year in designing a case-control study of cleft palate in collaboration with the Norwegian National Institute of Health. We plan to enroll all babies with cleft lip or palate born in Norway over the next 5 years (an estimated 750 affected babies). This innovative project will incorporate DNA markers for allelic variants of key metabolic genes, and of genes that regulate early embryonic development of the craniofacial region. Combined with data on nutrition, infection and other environmental exposures, we will search for gene-environment interactions that contribute to this common birth defect. In another study of genetic susceptibility, we are collaborating with the Laboratory of Biochemical Risk Analysis in an exploration of metabolic genes associated with risk of spontaneous abortion. We completed our collection of data on 493 adult sons and 598 adult daughters of women who had been exposed to DES during their pregnancies in the early 1950's. In an earlier analysis we had seen evidence suggesting that DES daughters may be experiencing premature ovarian failure. However, after obtaining medical records, we found that most such cases had been misreported. We find no evidence at this time for premature onset of menopause among DES exposed daughters. Also, contrary to expectation, our preliminary analyses show no effect of prenatal DES exposure on fertility of DES sons. We are continuing to look for evidence of problems in female reproduction (in addition to those already well established), and for possible problems of immune function in these offspring.