Fetal programming and environmental exposures: implications for prenatal care and preterm birth.

Chair: L. David Wise (Merck) There are numerous consumer products on the market for which safety data are lacking. The FDA, academic institutions, and nongovernmental organizations are conducting studies to address the safety of these compounds for fetal development and postnatal health. Liang Ma (Washington University School of Medicine) described his research into the mechanism of action of diethylstilbestrol (DES), a synthetic estrogen that was widely used as an antimiscarriage drug between 1940 and 1970 but was later shown to induce reproductive tract malformations and other defects. 38 Ma's data show that DES represses key developmental genes such as Hoxa10, inhibits cell death, reduces cell proliferation in the uterine epithelium, induces accumulation of lipid droplets, and promotes upregulation of the glucose pathway. Ma predicts that the metabolic defects caused by DES exposure could also be present in other estrogen-responsive tissues, such as fatty tissue, and thus may contribute to obesity later in life. 39 Patricia Hunt (Washington State University) discussed reproductive tract abnormalities induced by BPA. Hunt's investigation of BPA was prompted by an observation that chromosomal abnormalities occur in mice that consume water from BPA bottles. 40 Treating mice with BPA at fetal and perinatal stages increased chromosomal recombination, increased multioocyte follicle formation in females, and affected spermatogenesis in males. Similar effects were detected in experiments in rhesus monkeys. 41 Future studies will analyze the effect of BPA on other organs, including the brain. L. David Wise described the guidelines issued by the International Conference on Harmonization ( http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html ) that outline a series of studies set by the United States, the European Union, and Japan for examining the effects of drugs on several stages of prenatal and postnatal development. These guidelines cover studies on fertility and early development (from fertilization until implantation), embryo-fetal development (from implantation until just before birth), and prenatal and postnatal development (from implantation until weaning). Additional guidelines address the need and design of juvenile toxicity (from birth until after sexual maturity) studies. Wise's talk detailed the design and types of data collected in the embryo-fetal studies in rodents and rabbits. 42 Although labor intensive, these studies provide the most suitable data for determining risk information for women of childbearing age.

Moderator: Patricia Hunt (Washington State University) Energy remained high during the meeting's final session, with panel members and the audience deliberating on the question, How can we better predict, assess, and lower the risk of, and/or prevent environmental and genetic factors that predispose to, adverse fetal outcomes and preterm birth? John Rogers (U.S. EPA) pointed out the challenges of developing defined in vitro and in vivo tests to better assess developmental exposures over critical windows of development. Rogers noted that it is also important to agree upon what defines adverse endpoints, such as gene expression, phenotypic changes, and functional developmental changes. He also noted that it is important to incorporate functional challenges to reveal effects, for example, providing a high-fat diet for studies of putative environmental obesogens. Fred vom Saal went on to add that we need to incorporate appropriate developmental assays that include long-latency outcomes. Thad Schug (National Institute of Environmental Health Sciences (NIEHS)) explained how a collaborative group of environmental health scientists and green chemists have developed a tiered endocrine disruption screening protocol (TiPED) ( Fig. 3 ) that is very different from current regulatory endocrine disruption screening programs. 43 The protocol is designed for chemists to use in early stages of chemical development and is completely voluntary. It involves a time- and cost-sensitive approach to toxicology testing, with assay complexity and cost increasing as one proceeds through testing tiers. The protocol starts with computer modeling and ends with mammalian testing. A positive test anywhere in the protocol means the chemical is problematic and needs further evaluation or redesign. The group has developed guiding principles for assays and guidelines for proper laboratory testing. The protocol will be online on December 6, 2012 and in print in January 2013 in the U.K. Royal Society of Chemistry's Green Chemistry journal; a real-time online version will soon be available. Schug noted that the NIEHS, the National Toxicology Program (NTP), and the FDA have formed the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) program to support a perinatal two-year good laboratory practices (GLP) chronic toxicity study on BPA. 44 In addition to the core elements of a GLP-compliant study, the study involves academic research partners and will incorporate a wide range of doses and disease-relevant endpoints that have not been used in any previous GLP-compliant BPA toxicity study. The consortium is making all experimental data available via the Chemical Effects in Biological Systems (CEBS) database system developed by the National Toxicology Program at NIEHS. CEBS is a public resource, comprising integrated depositions of data from academic, industry, and governmental laboratories, 45 and a tool designed to better coordinate multilevel studies and support meta-analysis. Toward the end of the session members of the panel and the audience engaged in an active discussion on the experimental challenges for determining the health implications of low-dose effects and nonmonotonic dose responses in relation to endocrine-active chemicals. 2 Debate centered on whether current observations in the literature are sufficient to reexamine the ways in which chemicals are tested for endocrine-disrupting properties and how risk to human health may be managed. To this end, the NEIHS cosponsored a workshop a that aimed to define research needs required to move closer to scientific agreement on low-dose effects and nonmonotonic dose responses for endocrine-active substances. Rogers noted that the EPA has created a workgroup to develop a response to a recent article on low-dose nonmonotonic dose responses, and an agency position on how such dose responses should be considered for risk-assessment purposes. In her closing remarks, Fisher said the research presented at the meeting will ultimately lead to developments that "will improve pregnancy outcomes and our ability to treat and prevent disorders that emerge later in life." "It's exciting to see how far we have come in our understanding of the complex interactions between genes and our environment occurring in utero," added Fisher.

Keynote address: Frederick S. vom Saal (University of Missouri-Columbia) Fetal programming is an enormously complex process that relies on numerous environmental inputs from uterine tissue, the placenta, the maternal blood supply, and other sources. Recent evidence has made clear that the process is not based entirely on genetics, but rather on a delicate series of interactions between genes and the environment. It is likely that epigenetic ("above the genome") changes are responsible for modifying gene expression in the developing fetus, and these modifications can have long-lasting health impacts. Determining which epigenetic regulators are most vital in embryonic development will improve pregnancy outcomes and our ability to treat and prevent disorders that emerge later in life. "Fetal Programming and Environmental Exposures: Implications for Prenatal Care and Preterm Birth" began with a keynote address by Frederick vom Saal, who explained that low-level exposure to endocrine disrupting chemicals (EDCs) perturbs hormone systems in utero and can have negative effects on fetal development. vom Saal presented data on the EDC bisphenol A (BPA), an estrogen-mimicking compound found in many plastics. He suggested that low-dose exposure to EDCs can alter the development process and enhance chances of acquiring adult diseases, such as breast cancer, diabetes, and even developmental disorders such as attention deficit disorder (ADHD). 1 vom Saal noted that conventional risk-assessment strategies used for most chemicals cannot be used to assess toxicity of endocrine-active compounds, which often display nonmonotonic dose responses ( Fig. 1 ). 2