The causes 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. Etiologic factors may include exposure to a wide range of synthetic chemicals that have become ubiquitous and as such result in widespread general population exposure. The Centers for Disease Control and Prevention found that a majority of the U.S. population, including men and women of reproductive age, are exposed to the flame retardants known as polybrominated diphenyl ethers (PBDE). While PBDEs are the flame retardants that have received the most attention to date, their use is being phased out in the U.S. and other countries. Although PBDEs will continue to be a public health concern for decades to come due to their presence in existing consumer products and their high level of persistence, there is an urgent need to also consider other flame retardants that are increasingly being used as alternatives to PBDEs. Despite evidence from experimental studies that PBDEs and some of their alternatives are developmental and reproductive toxicants, there are limited human studies on the potential health risks of PBDEs and no human studies on their alternatives. We propose to leverage our ongoing prospective preconception cohort study (ES009718) by extending recruitment to sufficiently power the exploration of the effect of maternal and paternal exposure to FRs on pregnancy outcomes and to also explore the joint effects (maternal-paternal interactions) on pregnancy outcomes. The study is innovative because we have access to both pre- and peri-conception maternal and paternal measures of exposure and couple level clinical outcome data. We propose to use in vitro fertilization (IVF) as a model to study the impact of flame retardants 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. In the proposed study, we will measure not only PBDEs, but will apply new and novel biomarkers of exposure for their replacements, including components of Firemaster 550 and organophosphate flame retardants. The specific aims are to explore both the maternal and paternal effects of flame retardants, as well as their joint effects on clinical pregnancy outcomes. Clinical outcomes of interest include oocyte fertilization, implantation failure, pregnancy loss and live birth. As shown in our preliminary data, there is widespread exposure of our cohort to PBDEs and alternative flame retardants, measured using novel analytical methods developed by our research team. Furthermore, in our preliminary data, we report suggestive associations of flame retardants with reproductive outcomes that although intriguing were within small datasets and need to be expanded to the full cohort study through the proposed application. ExpandCollapse Abstract