Metal pollution contributes to reduced female fertility, with Zinc as a notable exception

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.Feb 7 2024

In a recent study published in the journal Ecotoxicology and Environmental Safety, researchers investigated the impacts of multiple metal exposure on female fertility. They used a nested case-control study comprising 180 participants and multiple regression models for their analyses. Their findings reveal that, out of the 22 metals analyzed, eight metals (especially Copper and Chromium) were found to have adverse effects on fertility. At the same time, Zinc was observed to exert a protective effect in the association. These findings form the basis for future research that may identify novel interventions in the battle against globally declining fertility rates.

Study: Associations between multiple metal exposure and fertility in women: A nested case-control study. Image Credit: Peakstock / Shutterstock

Global fertility alarm bells and the role of metals

The United Nations (UN) World Fertility and Family Planning (2020) document reports that in less than 30 years between 1990 and 2019, live births per female have declined by over 20% (3.2 to 2.5 live births). This presents an alarming and indisputable trend in the total fertility rate, which studies suggest will decline further in the coming years. When combined with medically-mediated increases in human life expectancy, fertility declines are anticipated to contribute to the rapid aging of the worldwide human population, triggering excessive financial pressure and labor shortages.

These adverse outcomes have prompted extensive research aimed at unraveling the causes and mechanisms underpinning this observation. Hitherto, education, social factors, environmental (pollutant) exposure, and the evolution of marriage have all been identified as potential reasons for declining fertility rates. Pollutant exposure, especially, has been implicated in adversely reducing the quantity of female ovarian germ cells via alternations to normal hormonal and reproductive functioning. Since the numbers of these cells are fixed at birth, this presents an ongoing and irreversible problem and posits that prevention is the most ideal response in preventing further declines.

Metals, especially heavy metals, are some of the most toxic environmental pollutants known to cause endocrine disruptions in women by exerting influence on the hypothalamic-pituitary-gonadal axis (HPG). The United States (US) Toxic Substances and Disease Registry (ATSDR) has labeled heavy metals as ‘priority chemicals,’ further bolstering research into their adverse effects. Unfortunately, conventional analytical techniques present severe limitations in identifying and computing the relative and synergistic impacts of multiple metals in tandem, which has restricted most work in the fertility field to single metal association studies.

The silver lining is that the increased attention garnered by metal groups (the sum total of metal ions in an individual) has helped advance cutting-edge inductively coupled plasma (ICP) spectroscopy techniques. When coupled with mass spectrometry (MS), ICP-MS is championed as a means to elucidate the concentrations of multiple elements in biological samples simultaneously, with sensitivity, efficiency, and measurable isotopes being its notable advantages over previous analyses. Applying these techniques to female fertility association studies would give policymakers and clinicians the information they need to classify the relative threats of different metal groups, allowing them to prioritize the ones with the most significant impacts.

About the study

In the present study, researchers used ICP-MS to evaluate the plasma concentrations and relative contributions of 22 metals to female fertility, identify the ones with the greatest impacts, and elucidate any synergistic interactions between different metal elements. The study cohort was derived from the Free Pre-pregnancy Health Examination Project carried out by the Maternal and Child Center of Gulou District, Nanjing, Jiangsu Province, China. Study inclusion criteria comprised age (20, the legal Chinese marriage age for women) and consent to pregnancy (provided by both spouses). Exclusion criteria included pregnancy at baseline (pre-pregnancy) checkup, diagnoses of infertility, genetic deformations, or sexually transmitted infections (STIs) in either spouse.

Four hundred and fifty-four individuals met the study inclusion criteria and were recruited into the research, with follow-ups every three months up to a duration of one year. Of these, 214 women became pregnant over the year-long duration. Participants were subsequently divided into a nest case-control study design comprising a pregnancy group (cases; n = 90) and a non-pregnancy group (controls; n = 90).

Data collection was obtained by conducting a baseline epidemiological survey of included participants. Collected data included age (including age difference between spouses), occupation, education, and pregnancy history. For the purposes of this study, fertility was defined solely as the ability to become pregnant, and successful delivery was not included as a requirement. Participant-provided plasma samples were used for metal concentration measurements of 22 common metal pollutants, obtained using a quadrupole inductively coupled plasma mass spectrometer (ICP-MS, BRUKER AURORA M90, Analytik Jena, Germany).

Metals screened in this study – “Lithium (Li), Natrium (Na), Magnesium (Mg), Aluminium (Al), Calcium (Ca), Titanium (Ti), Chromium (Cr), Manganese (Mn), Cobalt (Co), Nickel (Ni), Copper (Cu), Zinc (Zn), Gallium (Ga), Selenium (Se), Rubidium (Rb), Strontium (Sr), Zirconium (Zr), Molybdenum (Mo), Cesium (Cs), Barium (Ba), Thallium (Tl), and Lead (Pb)”

Statistical analyses included t-tests or the Kruskal-Wallis tests to assess continuous variable differences between groups. Similarly, the chi-squared test or Fisher’s exact probability test was used for classification variables. The least absolute shrinkage and selection operator (LASSO) penalty regression analysis was used to identify the metals contributing most significantly to observed fertility trends. The Bayesian kernel machine regression (BKMR) model was used to elucidate the combination effects of multiple metals on female health (fertility).

“We also used Weighted Quantile Sum (WQS) regression to estimate the effect of metal mixtures on fertility, The WQS estimates the impact of all exposure variables on outcomes by constructing a weighted index, testing the association of that index with the outcome, and assessing the relative importance of the impact of individual variables on the outcome through the weights assigned to each exposure variable by the model.”

Study findings and conclusions

Demographic data revealed a slight yet statistically significant difference between the mean ages of the case and control cohorts – 28.5 and 29.8 years, respectively. Education level was found to play a role in fertility, with a higher education level corresponding to improved fertility outcomes.

LASSO analyses revealed eight metals found to exert significant influence on female fertility, namely, Ca, Co, Cr, Cu, Rb, Zn, Sr, and Zr. Uncorrected logistic regression models revealed that Cr, Cu, Co, and Rb were negatively associated with fertility, while Zn was found to improve fertility outcomes. After correcting for demographic covariates and confounding factors, logistic regressions show that Cu and Co remain significant (negative association), as does Zn (positive association). While not substantial at recorded plasma concentrations, at higher doses, Cr and Rb were found to be closely associated with reduced female fertility.

When estimating the mixed/synergistic effects of metals in combination, Zn, Ca, and Zr showed a positive correlation with fertility, while Cr, Co, Rb, and Cu displayed a negative correlation.

In summary, this study reveals that Cu, Cr, Rb, and Co are associated with adverse fertility outcomes, and their environmental contamination may play a critical role in globally reducing fertility rates. In contrast, Zn was found to have a protective effect and improve fertility rates (in moderate concentrations). Cu, Cr, and Rb might show synergistic effects stronger than their individual contributions.

“Further research is required to identify specific interactions between metals.”