Ovarian follicular fluid: an innovative approach to assess internal dose for reproductive epidemiology

Abstract

Ovarian follicular fluid serves as a biological window revealing metabolic processes in the microenvironment of a maturing oocyte, and so may offer a more accurate biomarker of biologically effective dose than more traditional compartments, such as blood and urine. Investigators have measured myriad environmental pollutants in ovarian follicular fluid (FF), including toxic trace elements. As a plasma ultrafiltrate, FF content reflects both blood concentrations and in situ physiology. Evidence suggests substantial follicle-to-follicle variability in the concentrations of some analytes, necessitating a “one follicle-one oocyte” approach for investigating associations between exposure and reproductive endpoints. We collected individual FF specimens from up to four follicles, two from each ovary, among 56 women undergoing in vitro fertilization (IVF) with fresh embryo transfer. We determined toxic trace element concentrations using inductively coupled plasma with tandem mass spectrometry (ICP-MS/MS) and linked individual oocytes and embryos to the corresponding FF specimen. We used linear mixed regression models to evaluate associations between natural log transformed FF As, Cd, Pb, and Hg as predictors of IVF outcomes, adjusted for other toxic trace elements, age, race, smoking, and seafood consumption. Median FF As (0.34 μg/L), Cd (27.3 ng/L), Pb (0.06 μg/L), and Hg (0.34 μg/L) concentrations were similar to or lower than those reported previously. Greater FF Cd was associated with a lower probability for a symmetric embryo per 1 ng/L (RR=0.36, 95%CI: 0.17-0.76). Greater FF Pb (1 μg/L) was associated with lower probabilities for a fertilized oocyte per 1 μg/L (RR=0.56, 95%CI=0.25-1.24), although the association was non-linear, and with live birth per 1 μg/L (RR=0.72, 95%CI: 0.53-0.99). Greater Hg was associated with a lower probability of implantation per 1 μg/L (RR=0.31, 95%CI: 0.09-1.06), although the association was non-linear. Our results suggest that FF toxic trace elements may affect IVF outcomes, including live birth, even at comparatively low doses.