The etiology of male and female infertility and adverse pregnancy outcomes are not well understood, but likely arise as a complex interplay of environmental and lifestyle factors evident at the population level. It is well appreciated that environmental exposures are potential risk factors for infertility, with experimental animal studie linking several classes of chemicals to infertility and adverse pregnancy outcomes. These include phthalates, bisphenol A, and parabens, all of which have documented widespread general population exposure. To increase our understanding of potential human health risks of environmental chemicals, we need to consider exposure to complex mixtures of chemicals rather than focusing only on a single (or a few) chemicals at a time and in essence ignoring other simultaneous exposures. The NIEHS Strategic Plan (2012- 2017) identified mixtures research as highly relevant to many of the Goals, with Goal 4 focusing on 'combined exposures', specifically calling for research to determine human health risks from exposure to multiple chemicals. In the proposed study, motivated by our earlier findings of associations of individual chemicals with adverse reproductive and pregnancy outcomes, we will extend our aims to explore the impact of chemical mixtures on pregnancy outcomes. Furthermore, most epidemiologic studies focus on either male or female exposures with few studies assessing the joint contribution of both paternal and maternal exposure to a healthy pregnancy. Our proposed study is innovative because it will explore the joint impact of both paternal and maternal exposure to mixtures of environmental chemicals. In our preliminary data, we found associations of male and female exposure to phthalates, bisphenol A and parabens with adverse pregnancy outcomes. In the proposed study, we will extend recruitment to provide sufficient power to determine the joint effects of maternal-paternal exposure to chemical mixtures on the primary outcomes of implantation failure and live birth, and the secondary outcomes of chemical pregnancy (with no subsequent clinical pregnancy) and spontaneous abortion. Our study is cost-effective because we have chemical levels and clinical data available for over 300 couples;we will recruit 250 additional couples. We collect both pre- and peri-conception maternal and paternal measures of exposure to phthalates, BPA and parabens, and maternal measures throughout pregnancy. We propose to use in vitro fertilization (IVF) as a model to study the impact of mixtures of chemicals on early human development and pregnancy. IVF provides epidemiologists with novel and unique opportunities to study early development and pre-clinical pregnancy loss. These early endpoints are not observable in women conceiving naturally, but are of high importance as they represent the majority of failures of pregnancy among all women and are considered more sensitive to environmental chemicals than later pregnancy endpoints.

Public Health Relevance

There is evidence over the last several decades of a decline in human fertility that has coincided with the increase in widespread human exposure to synthetic chemicals. Several classes of widely used chemicals have been shown to adversely affect fertility in experimental animals. The proposed study is designed to determine the impact of mixtures of chemicals on both maternal and paternal contributions to a healthy pregnancy.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Dilworth, Caroline H
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Harvard University
Public Health & Prev Medicine
Schools of Public Health
United States
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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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