MS34. TESTICULAR DYSGENESIS SYNDROME (TDS) AND ENVIRONMENT: A POSSIBLE ROLE OF ENDOCRINE DISRUPTORS. Skakkebaek, Niels E.¹, ¹ University Department of Growth & Reproduction, Copenhagen, Denmark
     Male infertility has become a major health problem in many Western countries. In Denmark more than 6% of all children are now born after assisted reproduction. Unfortunately the causes are not known in most cases, although spermatogenic failure can be due to Y microdeletions and other rare genetic causes. In addition, testicular cancer, which is a disease of young adults, is becoming more common in industrialized countries. We propose that male infertility, undescended testis, hypospadias and testicular cancer may all be symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS). The most severe form of the syndrome is gonadal dysgenesis in intersex patients and the less severe phenotype may present itself as subfertility due to decreased sperm count. We assume that not only genetic abnormalities cause maldevelopment of the male gonad, but also environmental factors may contribute to an increasing occurrence of TDS. In fact, it has been repeatedly shown that TDS-like symptoms can be produced in rats exposed to phthalates in utero. Our preliminary data from an ongoing study suggests that phthalate exposure via breast milk may lead to decreased Leydig cell function in newborn boys. However, current research raises more questions than answers: Is there a biologically significant chemical exposure of the unborn child through placenta and breast milk. May it affect reproductive function during puberty and adult life? Are we, in the industrialized world, currently witnessing a process, where human fecundity is declining due to adverse environmental exposures?

MS35. WHAT CAN WE LEARN FROM THE TRANSCRIPTOME PROFILING? - PROMISES AND CAVEATS. Shioda, Toshi¹, Coser, Kathryn¹, Chesnes, Jessica¹, Dean, Kathleen¹, Hur, Jingyung¹, Isselbacher, Kurt¹, ¹ Massachusetts General Hospital Center for Cancer Research, Charlestown, MA
     Recent advancements in the DNA microarray technology have provided a wide variety of biomedical research fields with reliable methods to evaluate the transcriptome profile: the quantitative measurement of expression of the mRNA transcripts for all protein-coding genes found in the genome. This technology has been becoming more accessible and affordable in the past couple of years, and it is now considered as one of the key approaches that are to be applied to many biological questions. Attempts to apply the transcriptome profiling to monitor human diseases are about migrating from the proof-of-concept stage to practical applications. The DNA microarray data offer a unique opportunity to perform the unsupervised data analysis, which reasonably classifies the samples and/or the genes without using other information; this approach often provides unexpected, important insights into the physiological and pathological processes. The more classical, supervised data analysis, which finds marker genes for given conditions, is also a powerful approach to obtain the initial insights into the genomic basis of the biological phenomena. However, even when performed by skilled hands, DNA microarray tends to generate large numbers of false positive results, and sometimes such experimentally false positives, which do not relate to the biological phenomena in question, are generated somewhat reproducibly. When DNA microarray is applied to pharmacogenomics and toxicogenomics, in which changes in the transcriptome profile heavily depend on the dose and exposure time of the biologically active chemical compounds, the risk of the false positives increases unless specifically addressed. I will discuss the powerful aspects of the DNA microarray-based transcriptome profiling in pharmaco- and toxicogenomics research and suggest possible applications to the monitoring and assessing human reproductive health. I will also discuss typical pitfalls of this technology.

MS36. FUTURE FAMILIES: BACKGROUND CONTAMINATION AND HUMAN REPRODUCTIVE HEALTH. Swan, Shanna¹, ¹ University of Rochester, Rochester, NY
     The Study for Future Families is a multi-center pregnancy cohort study designed to examine geographic variation in reproductive parameters in fertile couples and their offspring. Study participants provided a variety of biological samples including pre- and postnatal urine and serum (from mothers); serum, urine and semen samples (fathers) and urines in early infancy (babies). To date we have measured monoester metabolites of current-use pesticides in urine from a sample of fathers and monoester metabolites of phthalates in urine samples from mothers (pre and post-natal) and infants. In the most agricultural of our study centers centers (Columbia, MO), metabolite levels were significantly associated with poor semen quality for the herbicides alachlor and atrazine, and for the insecticide diazinon (2-isopropoxy-4-methyl-pyrimidinol, or IMPY) (P-values = 0.0007, 0.012, and 0.0004, for alachlor, atrazine and IMPY, respectively). In addition, urinary concentrations of four phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono-isobutyl phthalate (MiBP)] in prenatal samples were inversely related to anogenital distance (AGD), a sensitive marker of anti-androgen activity [p-values ranged from 0.012 (MEP) to 0.055 (MBzP)]. Three of the monoesters associated with AGD are the same ones shown to shorten AGD in rodent pups exposed prenatally and the magnitude of the decreases in AGD in human and rodents are comparable. The alterative sources of exposure will be compared based on questionnaire data on product use and correlations between pesticide and phthalate metabolites in biological samples. We will discuss the public health impact of these findings in light of data from a national sample (NHANES) showing that the a substantial fraction of the population of the United States is exposed to these xenobiotics at levels we have shown to be significantly associated with adverse reproductive parameters.