Humans who eat fish are exposed to mixtures of healthful nutrients and harmful contaminants that are influenced by environmental and ecological factors. Marine fisheries are composed of a multitude of species with varying life histories, and harvested in oceans, coastal waters and estuaries where environmental and ecological conditions determine fish exposure to both nutrients and contaminants. Many of these nutrients and contaminants are thought to influence similar health outcomes (i.e., neurological, cardiovascular, immunological systems). Therefore, our understanding of the risks and benefits of consuming seafood require balanced assessments of contaminants and nutrients found in fish and shellfish. In this paper, we review some of the reported benefits of fish consumption with a focus on the potential hazards of mercury exposure, and compare the environmental variability of fish oils, selenium and mercury in fish. A major scientific gap identified is that fish tissue concentrations are rarely measured for both contaminants and nutrients across a range of species and geographic regions. Interpreting the implications of seafood for human health will require a better understanding of these multiple exposures, particularly as environmental conditions in the oceans change.

Study question

Are follicular fluid (FF), arsenic (As), mercury (Hg), cadmium (Cd) and lead (Pb) concentrations associated with IVF outcomes among women undergoing IVF?

Summary answer

There was a non-linear association between higher FF Hg concentration and a lower likelihood of biochemical pregnancy and live birth. Higher FF Pb concentration was also associated with a lower probability of live birth.

What is known already

Previous research suggests that toxic elements may affect fertility among couples conceiving with and without assistance. However, the results have been inconsistent, possibly related in part to exposure misclassification. Very few studies have used ovarian FF to measure toxic elements, as it requires an invasive collection procedure, yet it may offer a more accurate estimate of a biologically effective dose than blood or urine.

Study design size duration

This is a prospective study of 56 women undergoing IVF, from October 2015 to June 2017. FF was collected for analysis on the day of oocyte retrieval.

Participants/materials setting methods

As, Cd, Hg and Pb were determined in 197 FF specimens, using inductively coupled plasma tandem mass spectrometry. FF glutathione peroxidase, glutathione reductase, total glutathione-S-transferase, superoxide dismutase, arylesterase and paraoxonase (PON1p) activities were measured using kinetic enzyme assays.

Main results and the role of chance

Non-linear associations were detected, in which the probabilities of biochemical pregnancy (P = 0.05) and live birth (P = 0.05) were lower in association with FF Hg greater than ∼0.51 µg/l Hg, adjusted for age, race, cigarette smoking and recent seafood consumption. Higher FF Pb was also associated with a lower likelihood of live birth (relative risk (RR) = 0.68, 95% CI: 0.46, 1.00; P = 0.05). We also found a suggestive, although imprecise, antagonizing mediating effect of PON1p activity on the association between FF Pb and live birth (-28.3%; 95% CI: -358%, 270%).

Limitations reasons for caution

The results should be interpreted judiciously given the limited sample size and difficulty accounting for correlated data in generalized additive models and mediation analyses. Additionally, women undergoing IVF are highly selected with respect to age and socioeconomic status, and so the generalizability of the results may be limited.

Wider implications of the findings

Overall, the results suggest that FF Hg was associated with a lower likelihood of biochemical pregnancy and live birth, with a potential threshold effect, and that higher FF Pb was associated with a lower probability of live birth. These results may help to guide clinical recommendations for limiting the exposure of patients to Hg and Pb and ultimately improve IVF success rates.

Study funding/competing interests

This work was funded in part by the National Institute of Environmental Health Sciences (NIEHS), grant number 1R56ES023886-01, to the University at Albany (M.S.B.), and in part by the National Institute of Environmental Health Sciences (NIEHS), grant number 1U2CES026542-01, to the Wadsworth Center (P.J.P.). The authors declare no competing interests.

Trial registration number

N/A.

Both essential and non-essential elements have been associated with female reproductive function in epidemiologic investigations, including among IVF populations. To date, most investigators have used blood or urine to assess biomarkers of exposure, with few employing ovarian follicular fluid (FF). FF may offer a more direct "snapshot" of the oocyte microenvironment than blood or urine, however previous studies report follicle-to-follicle variability in FF constituents that may contribute to exposure misclassification. Our objectives were to investigate sources of trace element variability, to estimate FF biomarker reliability among women undergoing IVF (n = 34), and to determine the minimum number of follicles required to estimate subject-specific mean concentrations. We measured As, Hg, Cd, Pb, Cu, Mn, Se, and Zn in FF samples using inductively coupled plasma tandem mass spectrometry. Inter-subject (between-women) variability contributed most of the variability in FF element concentrations, with ovarian, follicular, and analytical as smaller sources of variability. The proportion of variability attributable to sources between-follicles differed by age, body mass index (BMI), race, and cigarette smoking for Cu, Se, and Zn, by BMI and cigarette smoking for As, by primary infertility diagnosis for Hg, Cu, Se, and Zn, and by ovarian stimulation protocol for Mn and Se. Four to five individual follicles were sufficient to estimate subject-specific mean Cu, Se, and Zn concentrations, while >14 were necessary for As, Hg, Cd, Pb, and Mn. Overall, our results suggest that FF is a suitable source of biomarkers of As and Hg exposure in ovarian follicles. Although limited in size, our study offers the most comprehensive exploration of biological variation in FF trace elements to date and may provide guidance for future studies of ovarian trace element exposures.