Germaine M. Buck Louis, Ph.D., M.S.
Environmental Influences on Human Reproduction and Development
Director: Germaine M. Buck Louis, Ph.D., M.S.
In 2012, The Division comprised approximately 31 scientific and support positions and a comparable number of fellows. A more complete description of Branch investigators is provided in their individual reports.
Human reproduction and development is dependent upon the successful completion of a series of timed and highly interrelated biologic processes involving both partners of the couple. While important research advances have markedly increased our understanding of the biologic basis of reproduction and development, critical data gaps exist regarding the identification of the determinants that impact men and women's reproductive health. Examples of such data gaps include our inability to explain the marked variation in time couples require for becoming pregnant, our limited understanding of the natural history of pregnancy loss, our inability to identify factors that diminish or enhance male and female fecundity and fertility, and the limited power of semen analysis in predicting fertility, conception delays or pregnancy outcomes. These and other data gaps are in the context of novel and emerging research paradigms that suggest human fecundity and fertility may have an early origin (preconception through pregnancy) with further modification during childhood and adolescence depending upon lifestyle, behavior and other environmental exposures during these sensitive windows. Moreover, evolving data suggests that human fecundity, defined as the biologic capacity of men and women for reproduction irrespective of pregnancy intentions, may be predictive of health status during pregnancy and later onset adult diseases.
In response to these data gaps, our Division-wide research teams design and complete trans-disciplinary epidemiologic investigations with the overarching goal of identifying potential reproductive and/or developmental toxicants arising from contemporary living, as well as factors that enhance reproductive health. The goal of this avenue of research is to identify environmental (defined as non-genetic) factors that positively and adversely impact reproduction and development, and to identify population level interventions. The ultimate goal of our research is to prevent the occurrence of adverse reproductive or developmental outcomes in populations.
Recently, three creative epidemiologic studies have been successfully conducted. Each of these studies is unique and has generated some of the first empirical data regarding the environmental determinants of reproduction. Two of these studies – the LIFE Study and the ENDO Study – were original research initiatives designed by Division investigators, while the Oxford Conception Study was a collaborative investigation under the leadership of Dr. Cecila Pyper, Oxford University.
The overarching goal of the LIFE Study is to determine whether ubiquitous persistent environmental chemicals in the context of lifestyle affect male and female fecundity and fertility, which are defined as the biologic capacity for reproduction and live births, respectively (LIFE Study). A spectrum of reproductive endpoints have been captured in the LIFE Study, allowing for eventual study of their interrelatedness in keeping with the highly timed and conditional nature of human reproduction and development (i.e., hormonal profiles, menstruation and ovulation, semen quality, time-to-pregnancy, pregnancy loss, gestation, and infant birth size). The LIFE Study developed a cohort comprising 501 couples who completed daily journals while trying to become pregnant and during pregnancy. Blood and urine samples were taken to quantify 3 heavy metals (cadmium, lead, mercury); 9 organochlorine pesticides (OCPs); 7 perfluorochemicals (PFCs), 1 polybrominated biphenyls, 10 polybrominated diphenyl ethers (PBDEs), 36 polychlorinated biphenyls (PCBs), and 7 perfluorchemicals (PFCs). Men provided semen samples during the women's first two menstrual cycles, while women provided two saliva samples for the measurement of stress biomarkers - cortisol and alpha amylase. Women were instructed in the use of the Clearblue® Easy Fertility Monitor to help time intercourse relative to ovulation along with the use of Clearblue® (digital) home pregnancy test kits for the detection of pregnancy.
Following publication of the study design and methods paper in 2011, two substantive papers were published in 2012. In our first paper, blood cadmium (mg/L), lead (mg/dL) and mercury (mg/L) concentrations in each partner were analyzed in relation to couple fecundity as measured by time-to-pregnancy (Buck Louis et al., 2012). Female cadmium concentrations were associated with fecundability odds ratios (FORs) below one indicative of a longer time to pregnancy (0.78; 95% CI 0.63–0.97), as was male lead concentration (0.85; 95% CI 0.73–0.98). When jointly modeling couples' exposures, only male blood lead concentration significantly reduced the FOR (0.82; 95% CI 0.68, 0.97), though the FOR remained <1 for female cadmium (0.80; 95% CI 0.64, 1.00). These are the first finding based upon prospective cohort designs that suggest the potential reproductive toxicity of cadmium and lead at environmentally relevant concentrations.
A second paper reported a reduction in fecundability per 1-standard deviation increase in chemical concentration for a number of persistent chemicals (Buck Louis et al. 2012). Reductions in fecundability ranged between 18%-21% for female PCB congeners #118, 167, 209 and perfluorooctane sulfonamide, along with a reduction ranging between 17%-29% for male p,p'-DDE, PCB congeners #138, 156, 157, 167, 170, and 172. The strongest associations were observed for female PCB #167 (FOR 0.79; 95% CI 0.64, 0.97) and male PCB #138 (FOR=0.71; 95% CI 0.52, 0.98). Of note is that the magnitude of effect for select chemicals and couple fecundity is within the range reported for age and cigarette smoking.
Endometriosis is a gynecologic disorder affecting menstruating women resulting in the implantation of endometrial glands and stroma outside the uterine cavity. The etiology of endometriosis is unknown, but increasing evidence suggests that environmental chemicals may play an important role. Moreover, recent findings suggest that women with endometriosis may be at increased risk of reproductive site cancers and autoimmune disorders than unaffected women, underscoring the interrelatedness between gynecologic disorders and later onset disease. The overarching goal of the ENDO Study is to assess the association between environmental chemicals and odds of an endometriosis diagnosis, and the consistency of the findings across diagnostic criteria, biologic media used for quantifying lipophilic chemicals and choice of comparison group (ENDO Study). We utilized a matched cohort design comprising two study cohorts – an operative and population cohort. The operative cohort underwent laparoscopy/laparotomy examination while the population underwent pelvic magnetic resonance imaging for the diagnosis of endometriosis. Blood and urine samples were collected for the quantification of bisphenol A (BPA), metals, organochlorine pesticides (OCPs), phthalates, polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), and perfluorchemicals (PFCs). A proteomic follow on study with the operative cohort (n=63) at the UCSF site also was completed in 2012 to explore fat, peritoneal and urine proteomes that may be informative for endometriosis status.
Several key research findings following the publication of the baseline ENDO Study paper in 2011 were published in 2012. With regard to persistent lipophilic chemicals, we found that the pesticide hexachlorocyclohexane (HCH) was significantly associated with an increased odds of an endometriosis diagnosis per 1-standard deviation increase in the log-transformed concentration in both cohorts, though different HCH isomers emerged (Buck Louis et al., 2012). Specifically, g-HCH in fat increased the odds (1.27; 95% CI 1.01, 1.59) in the operative cohort, while serum b-HCH was associated with an increased the odds in the population cohort (1.72; 95% CI 1.09, 2.72). Our findings were largely robust in the many sensitivity analyses performed to aid interpretation. These findings underscore the importance of cohort- and biologic medium- specific effects when interpreting results. An increased odds of an endometriosis diagnosis in the operative cohort was observed for one of five measured BP derivatives, viz., 2,4OH-BP (AOR=1.19; 95% CI 1.01, 1.41; Kunisue et al., 2012), and also for perfluorooctanoate (PFOA, AOR=1.89; 95% CI 1.17, 3.06) and perfluorononanonoate (PFNA, AOR=2.20; 95% CI 1.02, 4.75; Buck Louis et al., 2012).
Other findings from the ENDO Study beyond chemicals include evidence that self reported body size and shape is consistent with anthropometric measurements (Thoma et al., 2012), and that the diagnosis of endometriosis within and across surgeons was good (k=0.69; 95% CI 0.64, 0.74) and moderately good for disease severity (k=0.44; 95% CI 0.41, 0.47; Schliep et al., 2012). Research continues to focus on short lived chemicals (BPA and phthalates) and endometriosis, and will culminate in the analysis of chemical mixtures.
Stress has long been suspected to impact women's ability to conceive or carry a pregnancy to term. However, no prospective longitudinal cohort research has been done. In collaboration with colleagues at Oxford University, we developed a novel protocol to measure two biomarkers of stress in relation to time-to-pregnancy, pregnancy loss and secondary sex ratios. We enrolled 410 women who were participating in the Oxford Conception Study to collect basal saliva samples on day 6 of each menstrual cycle they were attempting pregnancy for the quantification of salivary alpha amylase and cortisol concentrations. These biomarkers were chosen as measures of the hypothalamic pituitary adrenal axis and sympathetic adrenomedullary system, respectively. In 2011, we reported a 12% reduction in fecundity each day during the estimated fertile window for women in the highest quartile of alpha amylase relative to women in the lowest, with no association for cortisol and time-to-pregnancy (Buck Louis et al., 2011). In our second paper, no association was observed between perceived psychosocial measures of stress and fecundability odds ratios or the day specific probabilities of pregnancy (Lynch et al., 2012). However, we did observe a reduced odds of a male birth for women in the 3rd (AOR=0.31; 95% CI 0.11, 0.93) and 4th (AOR=0.25; 95% CI 0.08, 0.74) quartiles of alpha amylase relative to women in the 1st quartile (Chason et al., 2012). This unique database was used to develop flexible Bayesian and joint models models for estimating human fecundity led by our statistical colleagues (Kim et al., 2012; McLain et al., 2012).
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