Antagonistic Effect of Early Stage Zinc on Arsenic Toxicity Induced Preterm Birth During Pregnancy: Evidence from a Rural Bangladesh Birth Cohort
Preterm birth (PTB), defined as live birth before 37 completed weeks of gestation, is a significant public health concern due to its association with a high degree of immaturity in various organs. This immaturity places preterm infants at greater risk of both short-term and long-term comorbidities. In Bangladesh, the prevalence of PTB is already among the highest globally, estimated at 19.1%. This rate is even higher in rural areas, posing a substantial economic and emotional burden on families and the country as a whole. A critical factor contributing to this issue is the widespread exposure to arsenic (As) in Bangladesh, where approximately 22 million residents are exposed to arsenic concentrations exceeding 50 parts per billion (ppb), far above the World Health Organization’s safety limit of 10 ppb. Arsenic exposure has been well-documented to adversely impact birth outcomes, including PTB. Concurrently, low maternal zinc (Zn) levels are also associated with adverse pregnancy outcomes, including PTB. Although Zn deficiency and As exposure share common pathological symptoms, the mechanisms of interaction between these elements and their impact on physiology remain unclear. Animal studies have suggested that Zn supplementation can detoxify As toxicity. However, there is a lack of evidence from human studies regarding the protective effects of Zn against As-induced PTB.
This study aimed to explore the critical prenatal exposure times during which As and Zn are associated with PTB risk and to investigate how maternal serum Zn reduces the effect of As on PTB. The study included 780 pregnant women with available first-trimester serum samples, of which 610 participants also had second-trimester serum samples. These mother-offspring pairs were recruited from a prospective birth cohort in rural Bangladesh between 2008 and 2011. Serum Zn and As levels were analyzed using an iCAP Qc Inductively Coupled Plasma Mass Spectrometry (iCAP Qc ICP-MS) at Nanjing Medical University. The limits of detection (LODs) were calculated as three times the average of ten consecutive measurements of the blank diluent. Quality control samples, obtained from Seronorm Trace Elements Serum L-2, were analyzed in parallel with the study samples. Metal concentrations below the LOD were imputed as LOD/2. The relative standard deviations for As and Zn were 14.16% and 17.20%, respectively.
The analyses were conducted using R software Version 3.5.1. Baseline characteristics of PTB cases and controls were compared using t-tests or Mann-Whitney U tests for continuous variables, depending on data distribution, and Chi-square tests for categorical variables. Logistic regression models were separately performed for log-transformed Zn and As levels at each trimester to identify crucial metal exposures for PTB risk. Restricted cubic spline analysis was also performed to explore potential non-linear relationships. Additionally, Cox regression was used as a sensitivity analysis to compare the cumulative PTB rate under high and low levels of metal concentration. Zn levels were dichotomized by median (low-Zn group vs. high-Zn group), and As levels were categorized by tertiles. To evaluate the interaction between Zn and As, strata of the two elements were fully joined and compared to a reference stratum. Non-linear interaction analysis was performed using restricted cubic splines to explore potential non-linear interaction effects.
Among the 780 singleton live births, 175 (22.4%) were born preterm. Women delivering preterm were more likely to have been married before the age of 18, exposed to second-hand smoking, and have lower maternal weight, lower education levels, lower partner education levels, and lower income. Logistic regression models revealed that serum Zn levels in the first trimester (odds ratio [OR]: 0.28; 95% confidence interval [CI]: 0.13–0.58) and As levels in both the first (OR: 1.49; 95% CI: 1.20–1.84) and second trimesters (OR: 1.35; 95% CI: 1.05–1.74) were significantly associated with PTB. However, Zn levels in the second trimester did not show a significant association with PTB. Non-linear dose-response analysis confirmed these associations.
Stratified analysis demonstrated a statistically significant interaction between serum Zn in the first trimester and As in both the first (OR: 0.35; 95% CI: 0.12–0.97) and second trimesters (OR: 0.31; 95% CI: 0.11–0.90) in relation to PTB. The non-linear toxic effect of As in either the first or second trimester on PTB risk was fitted under a series of Zn quantiles, revealing that As toxicity is attenuated by high levels of serum Zn in the first trimester.
This study highlights the protective effect of serum Zn in the first trimester against PTB resulting from As toxicity. This finding aligns with a recent in vitro study showing that As exposure significantly reduces the amount of Zn in developing embryos. Arsenic competes with Zn to bind to a series of Zn finger proteins, which are recognized as DNA damage repair elements. Functional disruptions to Zn finger proteins or DNA damage repair are associated with PTB risk. Additionally, animal studies suggest that As exposure during pregnancy may lead to oxidative stress, and Zn supplementation can reverse oxidative stress indicators, potentially reducing As toxicity. Prior functional knowledge supports the findings that Zn acts as an antagonist for As toxicity on adverse birth outcomes.
In summary, this study identified that high maternal serum As levels during pregnancy are associated with increased PTB risk, which can be attenuated by increased maternal serum Zn levels during the first trimester. This finding opens up new prospects for Zn as a nutritional intervention during pregnancy to counteract As toxicity and its health implications.
doi.org/10.1097/CM9.0000000000001241
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