Presented at the January 2007 UCSF-CHE Summit on Environmental Challenges to Reproductive Health and Fertility

Mary Wade, MJ, in collaboration with Tracey Woodruff, PhD*

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*University of California, San Francisco
Department of Obstetrics, Gynecology and Reproductive Sciences
Program on Reproductive Health and the Environment

Recent research substantiates and expands previous findings that exposure to certain chemical and heavy metal contaminants at low, ?environmentally relevant? levels can disrupt the development and function of the human endocrine system. These ?endocrine disrupting chemicals? (EDCs) have been linked to reproductive disorders including infertility/ subfertility in men and women; altered puberty onset, endometriosis, fibroids, breast, vaginal and uterine cancer in women; and poor sperm quality, cryptorchism, hypospadias, and testicular cancer in men; the incidence of many of these disorders is increasing. Adverse pregnancy and birth outcomes, including pre-eclampsia, preterm birth, low birth weight, and stillbirth, have also been associated with exposures to EDC and other environmental contaminants.

To address growing concern among leading scientists, clinicians, and public health advocates about the role of EDCs, in January 2007 the University of California, San Francisco and the national Collaborative on Health and the Environment held a three day conference, the Summit on Environmental Challenges to Reproductive Health and Fertility. At the Summit, leading researchers presented the state of the science on EDC impacts across the female and male reproductive life spans and explored implications for future research, clinical care and health policy. This article highlights recent research presented at the Summit that may be of particular interest to The Endocrine Society members.

The capacity of environmental contaminants to act as endocrine disruptors was initially discovered in wildlife studies, described by Dr. Rachel Carlson in Silent Spring (1962). In the intervening decades, numerous studies of reproductive and developmental abnormalities and declining populations in a wide array of wildlife species have pointed to EDCs as causative factors. A pioneer in this field, Dr. Louis Guillette of the University of Florida, spoke at the Summit on the relevance of wildlife and laboratory animal studies to human health: ?Endocrine systems across multiple vertebrate species, including humans, are very similar. We?re dealing with the same hormones; they do basically the same things across species.? Genetic signaling mechanisms are also highly similar across vertebrate classes. Dr. Linda Birnbaum of the US EPA?s Experimental Toxicology Division concurred: ?Just as in pharmaceutical research, animal studies give us much of our knowledge. When a particular environmental toxicant causes multiple effects in multiple species, people are highly likely to be susceptible.?

Proposed mechanisms through which EDCs may act include perturbation of nuclear hormone signaling, inappropriate activation or inactivation of transcription factors, and alterations in hormone metabolism.

Periconception and prenatal development are periods of heightened vulnerability to EDC exposures, and the health consequences of such exposures can be life-long. This fact was first documented in relation to diethylstilbesterol (DES), a synthetic estrogen, to which millions of human fetuses were exposed between the 1940s and 1970s when DES was prescribed as a miscarriage preventive (ultimately recognized as ineffective for this purpose.) Prenatal DES exposure resulted in > 90% prevalence of reproductive abnormalities, including infertility/ subfertility, in both female and male offspring; the majority of these abnormalities were not apparent until the onset of puberty or later. Dr. Retha Newbold, National Institutes of Environmental Health Sciences, has studied DES for years and reported at the Summit that many of the abnormalities that characterize DES syndrome are similar to those described following prenatal exposure to other EDCs in animal and human studies.

Newbold?s studies continue with DES-granddaughters, who show increased incidence of menstrual irregularities and ovarian cancer, and DES-grandsons, who have increased rates of hypospadias. The prenatal exposure of DES daughters apparently affected their developing oocytes in ways that affected the reproductive health of their daughters and sons---a trans-generational effect.

Dr. Patricia Hunt, Washington State- Pullman, reported at the Summit on a trans-generational effect seen in her research on prenatal exposure to bisphenol-A (BPA), a chemical used in the manufacture of many types of plastic food and beverage containers, and ubiquitous at low levels in the everyday environment. After exposing pregnant mice to BPA for a week, Hunt found the process of meiosis was perturbed in the oocytes of the female fetuses. Forty percent of the oocytes were found to be chromosomally abnormal. When as adults, these females oocytes were fertilized, the result was an increased number of chromosomally abnormal embryos.

?Our studies suggest that BPA acts on the fetal ovary not by mimicking the actions of estrogen but by interfering with the function of one of the known estrogen receptors. These results raise the possibility that BPA and other substances that mimic or interfere with the action of estrogen may affect early egg development in humans. The levels of BPA the female mice were exposed to were equivalent to only slightly higher than what people commonly encounter.?

Another mechanism by which BPA and other EDCs could affect female reproductive tract development is by altering a pattern of gene expression, reported Dr. Hugh Taylor, Yale University School of Medicine. (?Expression? refers to whether the gene is activated to perform its function.) The HOX genes are an ensemble of genes that specify positional values that control the anteroposterior patterning of body parts in the fetus, and also are involved in limb development. For example, is well known that DES affects the development of the uterus, at least in part, through altering the normal pattern of HOX gene expression. Taylor?s study exposed pregnant mice to BPA during a sensitive period for uterine development, to see whether a lasting alteration of uterine HOX-A10 expression would take place in the fetuses. Based on a dose-response result seen in the adult mice exposed in utero, Taylor concluded: ?In utero exposure to synthetic estrogens produces reproductive tract alterations by imprinting (silencing) essential developmental regulatory genes.? He said it appears that HOX genes are a common target of endocrine disruption.

Guillette explained DNA methylation, one mechanism by which environmental factors can alter gene expression patterns and consequent abnormalities of the reproductive and immune systems. When cytosine nucleotides in DNA are methylated to 5-methylcytosine, gene expression is affected; the number and pattern of methylated cytosines affect the expression of specific genes. ?Environmental contaminants can cause some genes to be methylated at times during development when methylation would not normally occur.? Low levels of methylation correspond with genes that could potentially be expressed; high methylation areas correspond with low gene activity. Distinct from genetic mutation because the genetic material itself remains unaltered, these changes in patterns of gene expression are termed ?epigenetic.? As the work of Newbold, Taylor and others indicate, some epigenetic alterations appear to be heritable; this mechanism shows how EDC exposures during critical developmental ?windows of vulnerability? may result in trans-generational health impacts.

Dr. Shanna Swan, University of Rochester School of Medicine and Dentistry, described her ground-breaking epidemiologic study that related levels of certain phthalates (plasticizers used in many common products and cosmetics) in pregnant women?s blood with the anogenital distance (AGD) of their male offspring. Swan embarked on this study to see whether human studies would correlate with numerous animal studies that document this ?phthalate syndrome.? In animals, decreased AGD/ phthalate syndrome is associated with fertility problems and other reproductive disorders in adulthood. Swan?s human study indeed found a significant shift toward decreased AGD in male offspring of mothers with the highest phthalate levels during pregnancy. ?Large epidemiological studies that prospectively assess later (in life) reproductive performance after pre and postnatal exposure to phthalates will be necessary to establish clear links between the two,? she said. Swan and other leading researchers emphasized the need for many additional human epidemiological studies based on the most compelling, concerning data from animal EDC studies.

Dr. Laura Fenster, California Department of Health Services Occupational Branch, reported on environmental and workplace contaminant exposures and preterm delivery, low birth weight and still birth. Preterm birth is an acute and growing problem in the US, Fenster said. Twelve percent of babies are born before 37 weeks gestation, up by 30% since 1980. Preterm birth is the main cause of death in the first month of life; it leads to long-term health problems that cost the US health system $26 billion in 2005. Half of all preterm births occur to mothers with no known risk factors. Fenster described ?strong; good; and less certain? associations between contaminant exposures and preterm birth. Strong: maternal smoking and second hand smoke; good: DDT, carbon monoxide, ethylene oxide, lead, DES, and particulate air pollution; limited: carbon disulfide, phenoxyacetic herbicides, and some phthalates, especially DEHP (di(2-ethylhexyl) phthalate.

Researchers acknowledged that much work remains to be done to elucidate the impacts of EDCs on human reproductive, developmental and other key systems (such as immune and neuroendocrine.) Two key recommendations formulated by researchers in a Summit strategic session were: a) that better biomarkers for human fertility and other indicators of reproductive disorders be identified, because until this occurs research is hampered by poor predictors of outcome; b) priority attention and funding should be directed to emerging areas of research, such as epigenetics, fetal programming and trans-generational effects, low-dose exposure effects, non-traditional dose-response curves, effects of simultaneous exposures to multiple chemicals (?mixtures,? thought to have synergistic effects beyond what an individual EDC would cause), cross-talk among endocrine systems and receptors, and the identification of new contaminants. Recommendations by policy experts from their strategic session included: revising chemical regulation and chemical licensing to develop sufficient scientific data for deciding on chemical harm, developing federal and state initiatives to limit or ban chemicals suspected of causing harm; incorporating current research and public health considerations into regulatory decision-making; and developing new initiatives to inform and engage the public on these important health issues.