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 #
5R01ES009718-14
Application #
8272597
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
2012-05-01
Budget End
2013-04-30
Support Year
14
Fiscal Year
2012
Total Cost
$716,360
Indirect Cost
$269,673
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
Mínguez-Alarcón, Lidia; Gaskins, Audrey J; Chiu, Yu-Han et al. (2016) Dietary folate intake and modification of the association of urinary bisphenol A concentrations with in vitro fertilization outcomes among women from a fertility clinic. Reprod Toxicol 65:104-112
Lewis, Ryan C; Hauser, Russ; Wang, Lu et al. (2016) Personal power-frequency magnetic field exposure in women recruited at an infertility clinic: association with physical activity and temporal variability. Radiat Prot Dosimetry 168:478-88
Mínguez-Alarcón, Lidia; Souter, Irene; Chiu, Yu-Han et al. (2016) Urinary concentrations of cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester, a metabolite of the non-phthalate plasticizer di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), and markers of ovarian response among women attending a fertility cent Environ Res 151:595-600
Braun, Joseph M; Gennings, Chris; Hauser, Russ et al. (2016) What Can Epidemiological Studies Tell Us about the Impact of Chemical Mixtures on Human Health? Environ Health Perspect 124:A6-9
Chavarro, Jorge E; Mínguez-Alarcón, Lidia; Chiu, Yu-Han et al. (2016) Soy Intake Modifies the Relation Between Urinary Bisphenol A Concentrations and Pregnancy Outcomes Among Women Undergoing Assisted Reproduction. J Clin Endocrinol Metab 101:1082-90
Gaskins, Audrey J; Chiu, Yu-Han; Williams, Paige L et al. (2016) Maternal whole grain intake and outcomes of in vitro fertilization. Fertil Steril 105:1503-1510.e4
Hauser, Russ; Gaskins, Audrey J; Souter, Irene et al. (2016) Urinary Phthalate Metabolite Concentrations and Reproductive Outcomes among Women Undergoing in Vitro Fertilization: Results from the EARTH Study. Environ Health Perspect 124:831-9
Xia, Wei; Chiu, Yu-Han; Afeiche, Myriam C et al. (2016) Impact of men's dairy intake on assisted reproductive technology outcomes among couples attending a fertility clinic. Andrology 4:277-83
Mínguez-Alarcón, Lidia; Chiu, Yu-Han; Messerlian, Carmen et al. (2016) Urinary paraben concentrations and in vitro fertilization outcomes among women from a fertility clinic. Fertil Steril 105:714-21
Gaskins, Audrey J; Williams, Paige L; Keller, Myra G et al. (2016) Maternal physical and sedentary activities in relation to reproductive outcomes following IVF. Reprod Biomed Online 33:513-521

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