Although the widespread use of modern synthetic chemicals dates back many decades, we have a limited understanding of their potential impact on clinical diseases and public health. Two classes of modern chemicals, phthalates and bisphenol A (BPA), adversely affect development and reproductive function in experimental animals. Despite a majority of the U.S. general population being exposed to phthalates and BPA, there are very limited clinical and epidemiologic studies on their potential health risks, particularly in relation to fertility and pregnancy loss. In experimental studies, phthalates alter male reproductive tract development, decrease semen quality, and induce anovulatory infertility and pregnancy loss. BPA has been shown in experimental studies to lead to oocyte aneuploidy, pregnancy loss and adversely affect spermatogenesis. The proposed competing continuation is designed to determine the developmental and reproductive toxicity of phthalates and BPA in couples undergoing assisted reproductive technologies (ART), which can be used as a model for the assessment of the early stages of human development. The methods of gamete manipulation used in ART are now widely practiced and provide clinicians and epidemiologists with novel and unique opportunities to study infertility and early pregnancy loss. ART allows us to assess oocyte quality and fertilization rates, pre-implantation embryo development, and pre-clinical (early) pregnancy loss. These early developmental endpoints are not observable in women conceiving naturally, but are of high importance as they represent the majority of failures of pregnancy. Furthermore, experimental data show stage-specific differences in sensitivity to both phthalates and BPA, with early development endpoints being more sensitive to adverse affects than later pregnancy endpoints. The proposed study is a prospective preconception cohort study in which biological samples for phthalate and BPA exposure are collected at multiple time points, including preconception, periconception and throughout pregnancy. In addition, ovarian follicular fluid and amniotic fluid samples are collected to assess exposure in relevant target organs or in the fetal compartment, respectively.
The specific aims i nclude the determination of: 1) the relationship of urinary concentrations of BPA, mono-n-butyl (MnBP) and mono-(2-ethylhexyl) phthalate (MEHP), metabolites of di-n-butyl (DnBP) and di(2-ethylhexyl) phthalate (DEHP), respectively, with clinical measures of male fertility, including semen quality and sperm DNA damage;and 2) the relationship of pre- and periconception urinary concentrations of BPA, MnBP and MEHP with early developmental and pregnancy outcomes. Specific health endpoints of investigation include oocyte quality, fertilization rates, embryo quality, implantation failure and early pregnancy loss. Additional specific aims are to explore whether inter-individual phenotypic differences in DEHP metabolism modifies the association of urinary concentrations of MEHP with sperm DNA damage and adverse developmental and pregnancy endpoints.

Public Health Relevance

Although the widespread use of modern synthetic chemicals dates back many decades, we have a limited understanding of their potential impact on clinical diseases and public health. Two classes of modern chemicals, phthalates and bisphenol A, adversely affect reproductive function in experimental animals. Despite a majority of the U.S. general population being exposed to phthalates and BPA, there are very limited clinical and epidemiologic studies on their potential health risks, particularly in relation to fertility and pregnancy loss. The proposed study will investigate associations of phthalates and BPA with male and female fertility and pregnancy outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009718-13
Application #
8064667
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Dilworth, Caroline H
Project Start
1999-09-30
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
13
Fiscal Year
2011
Total Cost
$719,471
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Nassan, Feiby L; Chiu, Yu-Han; Vanegas, Jose C et al. (2018) Intake of protein-rich foods in relation to outcomes of infertility treatment with assisted reproductive technologies. Am J Clin Nutr 108:1104-1112
Mustieles, Vicente; Mínguez-Alarcón, Lidia; Christou, George et al. (2018) Placental weight in relation to maternal and paternal preconception and prenatal urinary phthalate metabolite concentrations among subfertile couples. Environ Res 169:272-279
Messerlian, Carmen; Williams, Paige L; Ford, Jennifer B et al. (2018) The Environment and Reproductive Health (EARTH) Study: A Prospective Preconception Cohort. Hum Reprod Open 2018:
Gaskins, Audrey J; Hart, Jaime E; Mínguez-Alarcón, Lidia et al. (2018) Residential proximity to major roadways and traffic in relation to outcomes of in vitro fertilization. Environ Int 115:239-246
Nassan, Feiby L; Williams, Paige L; Gaskins, Audrey J et al. (2018) Correlation and temporal variability of urinary biomarkers of chemicals among couples: Implications for reproductive epidemiological studies. Environ Int 123:181-188
Chiu, Y-H; Karmon, A E; Gaskins, A J et al. (2018) Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. Hum Reprod 33:156-165
James-Todd, Tamarra M; Chiu, Yu-Han; Messerlian, Carmen et al. (2018) Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic. Environ Health 17:55
Chiu, Yu-Han; Bellavia, Andrea; James-Todd, Tamarra et al. (2018) Evaluating effects of prenatal exposure to phthalate mixtures on birth weight: A comparison of three statistical approaches. Environ Int 113:231-239
Carignan, Courtney C; Mínguez-Alarcón, Lidia; Williams, Paige L et al. (2018) Paternal urinary concentrations of organophosphate flame retardant metabolites, fertility measures, and pregnancy outcomes among couples undergoing in vitro fertilization. Environ Int 111:232-238
Mínguez-Alarcón, Lidia; Afeiche, Myriam C; Williams, Paige L et al. (2018) Hair mercury (Hg) levels, fish consumption and semen parameters among men attending a fertility center. Int J Hyg Environ Health 221:174-182

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