Prenatal exposure to neurotoxic metals is associated with increased placental glucocorticoid receptor DNA methylation

Abstract

Epigenetic alterations related to prenatal neurotoxic metals exposure may be key in understanding the origins of cognitive and neurobehavioral problems in children. Placental glucocorticoid receptor (NR3C1) methylation has been linked to neurobehavioral risk in early life, but has not been examined in response to neurotoxic metals exposure despite parallel lines of research showing metals exposure and NR3C1 methylation each contribute to a similar set of neurobehavioral phenotypes. Thus, we conducted a study of prenatal neurotoxic metals exposure and placental NR3C1 methylation in a cohort of healthy term singleton pregnancies from Rhode Island, USA (n D 222). Concentrations of arsenic (As; median 0.02 ug/g), cadmium (Cd; median 0.03 mg/g), lead (Pb; median 0.40 mg/g), manganese (Mn; median 0.56 mg/g), mercury (Hg; median 0.02 mg/g), and zinc (Zn; 145.18 mg/g) measured in infant toenails were categorized as tertiles. Multivariable linear regression models tested the independent associations for each metal with NR3C1 methylation, as well as the cumulative risk of exposure to multiple metals simultaneously. Compared to the lowest exposure tertiles, higher levels of As, Cd, Pb, Mn, and Hg were each associated with increased placental NR3C1 methylation (all P<0.02). Coefficients for these associations corresponded with a 0.71-1.41 percent increase in NR3C1 methylation per tertile increase in metals concentrations. For Zn, the lowest exposure tertile compared with the highest tertile was associated with 1.26 percent increase in NR3C1 methylation (PD0.01). Higher cumulative metal risk scores were marginally associated with greater NR3C1 methylation. Taken together, these results indicate that prenatal exposure to neurotoxic metals may affect the offspring's NR3C1 activity, which may help explain cognitive and neurodevelopmental risk later in life.

Placental adaptations to micronutrient dysregulation in the programming of chronic disease

“…The gene which encodes for GR, NR3C1 contains nine exon 1 variants and methylation of the promoter region of these variants likely regulates which isoforms are expressed. Recent research has demonstrated that maternal exposure to a range of trace elements can regulate methylation of NR3C1 which is often linked to neurodevelopmental disorders in children . This study demonstrated that the methylation status of placental NR3C1 is increased by trace elements such as cadmium and manganese while low levels of zinc were also associated with increased methylation .…”

“…Recent research has demonstrated that maternal exposure to a range of trace elements can regulate methylation of NR3C1 which is often linked to neurodevelopmental disorders in children . This study demonstrated that the methylation status of placental NR3C1 is increased by trace elements such as cadmium and manganese while low levels of zinc were also associated with increased methylation . The placenta limits foetal exposure to glucocorticoids through the actions of the enzyme, 11‐beta‐hydroxysteroid dehydrogenase 2 (HSD‐11β2).…”

“…88 Low Zn associated with increase placental NR3C1 methylation. 76 Magnesium (Mg) 350 mg Increased risk of preterm birth, ↓ birth weight and preeclampsia 31 in humans. Animal models demonstrate foetal loss, placental abnormalities 89 as well as anxiety and renal dysfunction in offspring 15,16 Rare inducement of toxicity, positive effects on bone mineral density, neuroprotection.…”

Lead exposure and child maltreatment as models for how to conceptualize early‐in‐life risk factors for violence

“…In a second study to look at the epigenetic effects of lead exposure, prenatal lead exposure was associated with increased placental glucocorticoid receptor ( NR3C1 ) methylation in healthy, singleton newborns (Appleton, Jackson, Karagas, & Marsit, ). These findings are intriguing, given that this group found that increased methylation of a factor score defined by CpG sites on NR3C1 increased the odds that a newborn would be difficult to soothe, highly aroused, and poorly self‐regulated (Paquette et al., ).…”

Environmentally Induced Epigenetic Plasticity in Development: Epigenetic Toxicity and Epigenetic Adaptation

“…Another recent study has demonstrated that among 16 measured chemicals, CB-105 was identified as the most “epigenetically active” pollutant for female newborns [117]. One of our prior studies has investigated a positive association of co-action between prenatal metals exposure assessed by a cumulative risk score (higher scores represent greater cumulative metals exposure risk) with placental NR3C1 methylation [24], which suggested multiple metals exposure jointly exert accumulated epigenetic impacts. Demethylation of AHRR in the cord blood of children with prenatal smoking exposure is broadly reported.…”