Maternal blood cadmium, lead and arsenic levels, nutrient combinations, and offspring birthweight

Trace metals including cadmium (Cd), lead (Pb) and arsenic (As) are common environmental contaminants. Main routes of human exposure are ingestion and inhalation of contaminated dust and food [1]. These metals readily enter the food supply [2, 3], bioaccumulate, and target multiple organs. Exposure to these trace metals is implicated in cardiometabolic diseases, including cardiovascular diseases [4, 5], diabetes [4, 6], renal disorders [7, 8] and some types of cancer [9‐13]. Some data suggest effects of these metals are sex- or race-specific [14, 15]. In both humans and experimental model systems, fetal exposure to these trace metals is associated with lower birthweight [16‐23] and shorter birth length [17, 19, 24‐30]. While non-specific, low birthweight is a consistent risk factor for obesity and cardiometabolic disease in adulthood [31‐33]. Strategies to reduce or eliminate toxic metal exposure could have widespread implications for fetal health and adult chronic disease.

Dietary manipulation together with environmental management [34], are recommended strategies to mitigate exposure and its downstream health effects in chronically exposed populations. For example, iron (Fe) deficiency in humans has been linked to elevated levels of Cd in both blood and urine, independent of smoking, poverty, age, race, obesity and parity [35]. Deficiencies in essential metals including Cu [36], Fe [37‐40], manganese (Mn) [41] and magnesium (Mg) [42‐44], and zinc (Zn) [45, 46] have been associated with increased risk of low birth weight and adiposity in some, but not all investigations [47, 48]. In animals, deficiencies in folate (a one-carbon cycle nutrient critical to the generation of S-adenosyl methionine, the universal methyl group donor) reduce As methylation and excretion [49]. This animal data is bolstered by epidemiologic data showing that one-carbon cycle supplementation is associated with re-methylation of interspersed repeat elements [50] and lower As levels in populations chronically exposed to As [51].

Collectively, these data suggest that dietary repletion with essential metals may alleviate trace metal exposure and/or effects. However, associations are inconsistent and, to date, most investigations have only evaluated individual nutrients without examining their combinations or accounting for the non-linear relationship between toxic metals and nutrients [52]. These analyses overcome somes of these limitations by: [1] evaluating the cross sectional relationship between Cd, Pb and As, and eight nutrients (e.g. Fe, selenium [Se], calcium [Ca], Mg, Mn, copper [Cu], Zn and folate), both independently and in combination; and [2] using quantile regression models to account for non-linear effects. We additionally examined whether maternal blood concentrations of either toxic metals or nutrient combinations are associated with offspring weight at birth.

The distributions of individual toxic metals in strata of potential covariates are shown in Table 1. While there was some variation in the range of As by covariate, the median value remained comparable across covariates.

We evaluated associations between Cd, Pb and As, and eight nutrients in pregnant women, and determined if exposure to these metals were associated with lower birthweight. We found that higher levels of a combination comprising Fe, Ca, Se and folate was robustly related to lower Pb and Cd, regardless of concentration of these toxic metals, whereas the negative relationships with single nutrients were within very narrow ranges of exposure. Surprisingly, higher levels of Cu, Zn, Mg and Mn were associated with higher levels of Pb and Cd. With the exception of recent data supporting positive associations between Mn and Cd [61], these findings are despite accumulated animal data and human single nutrient data to the contrary. Finally, exposure to Cd and As were negatively associated with birthweight as would be expected; but these associations were modified by select nutrient combinations. These findings are consistent with previous studies demonstrating that dietary repletion with Fe, Ca, Se and folate can mitigate exposure to Cd and Pb. However, our findings suggesting that Cu, Zn, Mg and Mn are positively associated with Cd and Pb levels contrast with previous studies that form the basis for existing intervention guidelines as they suggest these minerals may exacerbate exposure.

Our data showing negative, but weak and inconsistent associations between Pb, As or Cd and single nutrients are consistent with these divalent cations Fe²⁺ or Ca²⁺ competitively displacing Cd²⁺ in transmetallation reactions. In animals, Fe reduces intestinal absorption of Cd [35]. These animal data are corroborated by human studies showing that Fe-deficiency is consistently associated with higher blood and urine Cd levels, independent of smoking, poverty, age, race, obesity and parity [35]. Our data however contrast with in vitro evidence that show >50% lower Cd levels with Zn and Mn treatment, and negative relationships between Zn, Cu and Mg with Cd [62]. These data provide early evidence that some essential metals, including Mn [63] may not mitigate exposure and effects of these metals. Specific mineral combinations that mitigate exposure may depend on the underlying nutritional status and may therefore vary by population exposed to Pb or Cd.

One-carbon cycle nutrients are critical in generating S-adenosyl methionine, key in the clearance of As [64]. In mice [65] and humans [66‐69], higher circulating one-carbon nutrients are associated with a lower body burden of inorganic As. Depletion of one-carbon cycle nutrients reduces As excretion and methylation [49, 70], whereas their repletion lowers blood As levels [51]. In 6-year old As-exposed children, one-carbon cycle supplementation was associated with re-methylation of interspersed repeat elements [50] and lower As levels [51]. Although fewer studies have been conducted on Pb or Cd, negative associations with folate or vitamin B12 have been reported [71]. Our data provides evidence for negative associations between folate in combination with Fe, Ca and Se, and Cd or Pb levels.

Consistent with previous studies, we also found that prenatal exposure to Cd or As is associated with lower birthweight [16‐20]. This adverse birth outcome increases the risk of rapid adiposity gain in young children; a consistent risk factor for cardiometabolic impairment in adulthood [72‐78]. In adult cross-sectional studies, elevated Cd, Pb and As have been associated with cardiometabolic risk markers [79‐85]. While metabolic syndrome is not clinically discernible in young children [86], individual cardiometabolic risk markers that include central adiposity, elevated systolic blood pressure and elevated levels of fasting insulin and/or glucose, triglycerides, cholesterol, accelerated adiposity, [87‐91, 76‐78, 92‐95] sometimes without overt obesity [96], predict metabolic syndrome, atherosclerosis, diabetes and hypertension in adulthood [97‐104]. While not confirmed by others [47], increased adiposity and higher insulin have been associated with deficiency of Cu [36], Fe [37‐40], Mn [41], Mg [42‐44] and Zn [45, 46]. Thus, the low birthweight that is associated with early exposure to these toxic metals supports the developmental origins of these cardiometabolic diseases, and may portend, and/or contribute to the increase in incidence of these diseases.

While these data suggest that some nutrients may mitigate toxic metal exposure and effects, mechanisms are poorly understood. In animal and in vitro models, ferritin reduces intestinal absorption of Cd [35] and Pb. Mn also shares transporters with Cd and Pb in vivo and in vitro. Cd induces oxidative stress via decreasing cellular antioxidant capacity, increases lipid peroxidation, and depletes glutathione and protein-bound sulfhydryl groups [105‐107]. Because the target organs for these metals such as the kidney and liver also play a critical role in the maintenance of blood glucose levels [108‐111], associations between these toxic metals and low birthweight that is often followed by accelerated adiposity gains and insulin resistance, are to be expected.

Our findings should be interpreted in the context of the study limitations. The relatively small sample size limited our ability to assess subgroup effects, and particularly higher order interactions (e.g. by combined maternal smoking, nutrient combinations and race/ethnicity), which may inform public health interventions. In addition, while we anticipate that some nutrient combinations may mitigate toxic metal exposure, cause-and-effect cannot be inferred in this cross-sectional study. Furthemore, we assessed maternal nutrient concentrations at a single time-point, yet these nutritional markers may vary throughout gestation, as the physiologic changes that occur during pregnancy may impact levels of toxic metals in maternal blood. For example, the increase in erythrocytes and plasma with advancing gestation may lower levels, presumably due to hemodilution, whereas essential elements may increase, in part due to increased supplementation. In support, a Canadian study reported that while Cd levels did not change, Pb levels decreased over the course of pregnancy, while Mn levels increased during the same period [63]. Thus, given our specimens were collected during a short gestational window (median 12 weeks, IQR 8–14 weeks), the full effect of toxic metal and nutrients on birthweight may only be partially realized. However, sensitivity analyses showed that restricting analysis to women with gestational age > 14 weeks at blood draw did not alter our findings. Despite these limitations, our study has several strengths including the multiethnic composition of the cohort and our ability to examine multiple nutrients to mitigate exposure and effects very early in gestation, when many metabolic set points are established.

In summary, we provide early data suggesting that a combination of Fe, Ca, Se and folate is negatively associated with Cd and As exposure, while Cu, Zn, Mg and Mn may exacerbate exposure to these toxic compounds. We also confirmed negative associations between birthweight and toxic compounds, Cd and As. Larger studies are required to identify other nutrients, which in combination, may mitigate exposure to these ubiquitous toxic metals in exposed populations.