Exposure to phthalates in couples undergoing in vitro fertilization treatment and its association with oxidative stress and DNA damage

This prospective study of 599 couples seeking fertility treatment and who were recruited between 2015 and 2017 was conducted to (a) explore the associations between phthalate exposure and in vitro fertilization (IVF) outcomes; and (b) examine the implication of oxidative stress as a mediator of these. We measured eight phthalate metabolites in two spot urine samples; oxidative stress biomarkers such as malondialdehyde, 8-hydroxy-2-deoxyguanosine, hydrogen peroxide, catalase (CAT), and total antioxidant capacity in follicular fluid and seminal plasma. We also examined DNA damage in sperm and granulosa cells. Couples were exposed to a broad range of phthalate compounds and seven metabolites were detected in over 94% of the urine samples, whereas monobenzyl phthalate was found in only 24% of women and 26% of men. Our results showed high levels of seven urinary phthalate metabolites (except monobenzyl phthalate) and a notable increase in many oxidative stress markers in both follicular fluid and seminal plasma. However, their associations with exposure were rather limited. Multivariate binomial regression modeling showed higher levels of follicular CAT levels reduced the probability of fertilization rate (<= 50%) [Adjusted relative risk (RR(ad)j) = 0.52, p = 0.005] and unsuccessful live birth (RRadj = 0.592, p = 0.023). We observed a 46% decrease in the probability of clinical pregnancy in association with an elevated percentage of DNA in the tail (RRadj = 0.536, p = 0.04). There was a 32% and 22% increase in the probability of clinical pregnancy and unsuccessful live birth associated with higher levels of mono-(2-ethylhexyl) phthalate (RRadj = 1.32, p = 0.049) and monoethyl phthalate (RRadj = 1.22, p = 0.032) in women, respectively. In contrast, the probability of clinical pregnancy reduced by 20% with higher levels of mono-(2-ethyl-5-carboxypentyl) phthalate (RRadj = 0.797, p = 0.037) and 19.6% with mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) (RRadj = 0.804, p = 0.041) in men. Other oxidative stress biomarkers or urinary phthalate metabolites showed suggestive relationships with certain IVF outcomes. Lastly, our results demonstrated that elevated levels of CAT in follicular fluid might have a positive impact on fertilization rate >= 50% and successful live birth. CAT seems to play a potential role in mediating the relationship between the risk of poor fertilization rate and MEOHP and mono-isobutyl phthalate. Additional data are required to understand the clinical implications of oxidative stress and its contribution to the reproductive toxicity of phthalate exposure.