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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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
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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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