Maternal cadmium, iron and zinc levels, DNA methylation and birth weight

Abstract

BackgroundCadmium (Cd) is a ubiquitous and environmentally persistent toxic metal that has been implicated in neurotoxicity, carcinogenesis and obesity and essential metals including zinc (Zn) and iron (Fe) may alter these outcomes. However mechanisms underlying these relationships remain limited.MethodsWe examined whether maternal Cd levels during early pregnancy were associated with offspring DNA methylation at regulatory sequences of genomically imprinted genes and weight at birth, and whether Fe and Zn altered these associations. Cd, Fe and Zn were measured in maternal blood of 319 women ≤12 weeks gestation. Offspring umbilical cord blood leukocyte DNA methylation at regulatory differentially methylated regions (DMRs) of 8 imprinted genes was measured using bisulfite pyrosequencing. Regression models were used to examine the relationships among Cd, Fe, Zn, and DMR methylation and birth weight.ResultsElevated maternal blood Cd levels were associated with lower birth weight (p = 0.03). Higher maternal blood Cd levels were also associated with lower offspring methylation at the PEG3 DMR in females (β = 0.55, se = 0.17, p = 0.05), and at the MEG3 DMR in males (β = 0.72, se = 0.3, p = 0.08), however the latter association was not statistically significant. Associations between Cd and PEG3 and PLAGL1 DNA methylation were stronger in infants born to women with low concentrations of Fe (p < 0.05).ConclusionsOur data suggest the association between pre-natal Cd and offspring DNA methylation at regulatory sequences of imprinted genes may be sex- and gene-specific. Essential metals such as Zn may mitigate DNA methylation response to Cd exposure. Larger studies are required.

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

“…Other studies on Cd-associated fetal epigenomic alterations have also observed sex-specific effects [47,48]. Of note, the relationship between maternal blood Cd and the methylation of imprinted genes was altered in a sexdependent manner in infants from the Newborn Epigenetic STudy (NEST) in North Carolina [47]. These relationships were also dependent on levels of circulating zinc and iron, indicating that Cd-associated epigenomic disruptions may be modified by maternal levels of essential metals.…”

“…Interestingly, in girls, the most significant probes were enriched for genes relating to bone mineralization and morphology, possibly shedding light on the sex-specific effects of Cd exposure, especially as it relates to the susceptibility of female populations to Cd-induced bone outcomes [46]. Other studies on Cd-associated fetal epigenomic alterations have also observed sex-specific effects [47,48]. Of note, the relationship between maternal blood Cd and the methylation of imprinted genes was altered in a sexdependent manner in infants from the Newborn Epigenetic STudy (NEST) in North Carolina [47].…”

“…As mentioned above, LaRocca et al found that maternal phthalate exposure was associated with methylation of the promoter regions of both IGF2 and H19, imprinted genes with roles in both pre-and postnatal development and cancer [138][139][140]. Likewise, results from iAs-and/or Cd-exposed infants reveals differential methylation of several imprinted genes, including KCNQ1, PEG3, and PLAG1 [8,47]. Interestingly, it has been shown that methylation at imprinted loci are stable across a wide range of human tissues in infants, suggesting that the observed changes in imprinted genes may be representative of changes occurring throughout the fetus [141].…”

Moderate Prenatal Cadmium Exposure and Adverse Birth Outcomes: a Role for Sex‐Specific Differences?

“…found an adverse association of maternal serum Cd with the baby being SGA in 3254 non‐smoking mother–infant pairs in China, with mothers with serum Cd ≥1.06 μg/L being 43% more likely to have an SGA infant than those with levels <1.06 μg/L in adjusted models. Other studies have found adverse associations of maternal B‐Cd with SGA and/or birthweight in models adjusted for smoking 14, 15, 16. Conversely, other studies have found no associations7, 9, 12, 30 or even beneficial associations31 with birthweight or SGA in models adjusted or stratified for smoking, even when mean or median maternal B‐Cd levels were high (>1 μg/L) 10, 32, 33.…”

“…Its effects on birth outcomes, however, particularly at moderate exposures, are not well understood and in this regard Cd has received far less research attention than its near neighbours in the periodic table, lead and mercury, The placenta is thought to be at least a partial barrier to Cd transfer to the fetus,5, 6 but determination of ratios of Cd in cord blood : maternal blood have left this in doubt (ratios ranging from 0.247 to 1.08,8 with others finding intermediate values9, 10). Studies with moderate maternal blood cadmium levels (B‐Cd; below a suggested reference value of 1 μg/L11) and adjustment for smoking have generally found no associations with birthweight, birth length, head circumference or preterm delivery,8, 12, 13 but other studies have found negative associations particularly with birthweight14, 15, 16 (Table S1). Even where exposure levels are higher and effects could potentially be more evident, again some studies have found no associations with birth outcomes,10, 17 while others have found adverse associations 18.…”