Early Windows of Susceptibility to Phenols and OPE Mixtures: Implications for Anovulation, Delayed Conception, and Pregnancy Loss

About This Grant

ABSTRACT Exposure to endocrine-disrupting chemicals (EDCs) such as phenols and Organophosphate Esters (OPEs) is inevitable given their pervasive usage in manufacturing, commercial and domestic products. Phenols and OPEs are detectable in over 80% of the U.S. population and the rise in these exposures, mirrors increasing fertility challenges (early pregnancy loss, delayed conception) in the U.S. Both conditions carry profound physical and mental health impacts. Alarmingly, a substantial proportion of these cases remain unexplained. Phenols and OPEs may significantly affect fertility by disrupting the hypothalamic-pituitary-gonadal (HPG) axis that regulates the endocrine processes in pregnancy. However, there is a lack of population-level evidence linking mixtures of phenols and mixtures of OPEs to impaired fertility, which is essential for informing environmental policies and health recommendations. Existing epidemiologic studies on EDCs often begin in the late first trimester, missing early pregnancy losses and key early windows of susceptibility, as well as the opportunity to assess fertility outcomes. Alternatively, the focus of many studies on populations undergoing fertility treatments has limited generalizability of their findings. Additionally, reliance on single-day urine samples to measure metabolites of phenols and OPEs, which exhibit high temporal variability, limits the accuracy of exposure assessments and their potential impact on reproductive health. This proposal addresses these gaps by leveraging an established preconception cohort that includes daily urine samples from critical windows of susceptibility, along with detailed data on early pregnancy losses and other markers of fertility. By applying novel hybrid pooled-unpooled design to measure EDCs in daily urine samples and utilizing a suitable regression calibration to account for the temporal variability of these often costly EDCs, this research will overcome measurement challenges seen in prior studies. Aim 1 will trace the causes of anovulation, reduced fecundability, and early pregnancy loss by linking preconception phenol mixture levels with outcomes. Aim 2a will provide insights into the effects of preconception OPE mixture exposure on anovulation, reduced fecundability, and early pregnancy loss; Aim 2b will extend these insights to multi-class EDC mixtures exposure. Aim 3 will expand on Aim 2a by assessing whether early pregnancy OPE exposure has stronger effects than preconception exposure on early pregnancy loss, helping to define key windows for intervention. The K99/R00 Pathway to Independence award will provide essential training to achieve these aims, including but not limited to environmental toxicology, reproductive endocrinology, and advanced mixture modeling. These training objectives will be met with the guidance of an exceptional mentorship and advisory team. In summary, this proposal lays the groundwork for a future independent research program dedicated to evaluating the relationships between environmental exposomes and reproductive outcomes using advanced methodologies with the ultimate goal of informing interventions to improve reproductive success.