The Relation of IVF Success as Assessed by Oocyte Retrieval to Environmental Exposures to Endocrine Disrupting Chemicals Open Access

Opila, Tamara Lenore (2014)

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Introduction: Near ubiquitous exposure to phthalates and bisphenol A (BPA) in consumer products has recently become a growing concern for human health and reproduction. While most measurements of BPA and phthalate exposure have been previously studied in matrices such as urine or saliva, the novel matrix of follicular fluid (FF) was sampled to investigate the effects of measurable concentrations of these endocrine disruptors on target tissue (i.e. ovarian follicle). The aim of this study was to quantify levels of high-molecular weight phthalate (HMWP) and low-molecular weight (LMWP) metabolites in FF samples, compare metabolite concentrations in FF to levels previously published in urine and determine any relation between phthalate metabolite concentrations in FF and number of oocytes retrieved for IVF patients.

Methods: Samples were collected over several IVF cycles from a cohort of Israeli women and analyzed using HPLC/MS (n=86). Concentrations of HMWP and LMWP metabolites (ng/mL) were standardized using a molar sum procedure. Paired t-tests and intraclass correlation coefficients (ICC) were employed for determining repeat measure reliability and study subject interfollicular variation. Multiple linear regression was used to investigate the association between the number of oocytes retrieved and increasing quartiles of HMWP and LMWP.

Discussion: E2 levels were positively correlated with the number of oocytes retrieved (r=0.29, p<0.05). The greatest decline in estradiol (E2) was associated with the second quartile of LMWP, which closely approaches statistical significance (p=0.08). Conversely, the greatest appreciation in E2 levels was correlated with the unadjusted model of HMWP (p<.05). A non-linear response in oocytes retrieved was observed for both HMWP and LMWP. ICC for phthalate metabolites ranged from 0.47 to 0.89 and minimal interfollicular variation was observed among follicle pairs.

Conclusions: Repeat measure reliability and method development provided additional evidence supporting the validity of study design, however FF maximum concentration observed for all analytes were approximately 100x less than those observed in urine. Phthalates and BPA act additively as endocrine disruptors and result in a synergistic response, therefore additional analysis of all samples for detected BPA concentrations may elucidate why a linear-dose response was not observed among quartiles of increasing concentrations for phthalate monoesters.

Table of Contents



I. Introduction & Background 1

Health effects of endocrine modulation 2

Normal follicle development 3

BPA: Exposure routes and mechanisms 4

Phthalates: Exposure routes and mechanisms 4

Potential measurements and methods: Urine and follicular fluid as a matrix 5

Aims and Hypotheses 7

II. Methods 8

Study population and enrollment 8

Materials and chemicals 10

Chemical analysis 11

Method development 11

Liquid Chromatography-Mass Spec quantification 13

III. Results 15

Demographic data 15

Exploratory analysis of predictor variables 16

Correlation of LMW & HMW metabolites 17

Interfollicular variation 18

Repeat Measure Reliability 18

Linear regression analysis for metabolite quartiles 19

IV. Discussion 20

V. Conclusions and Future Direction 22

VI. References 23

VII. Tables and Figures 27

VIII. Appendix 39

Supplementary Sources 39

IRB Approval Form 40

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