Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling

Abstract

Exposure to inorganic arsenic (iAs) early in life is associated with adverse health effects in infants, children, and adults, and yet the biological mechanisms that underlie these effects are understudied. The objective of this research was to examine the proteomic shifts associated with prenatal iAs exposure using cord blood samples isolated from 50 newborns from Gómez Palacio, Mexico. Levels of iAs in maternal drinking water (DW-iAs) and the sum of iAs and iAs metabolites in maternal urine (U-tAs) were determined. Cord blood samples representing varying iAs exposure levels during the prenatal period (DW-iAs ranging from <1 to 236 μg As/l) were analyzed for altered expression of proteins associated with U-tAs using a high throughput, antibody-based method. A total of 111 proteins were identified that had a significant association between protein level in newborn cord blood and maternal U-tAs. Many of these proteins are regulated by tumor necrosis factor and are enriched in functionality related to immune/inflammatory response and cellular development/proliferation. Interindividual differences in proteomic response were observed in which 30 newborns were "activators," displaying a positive relationship between protein expression and maternal U-tAs. For 20 "repressor" newborns, a negative relationship between protein expression level and maternal U-tAs was observed. The activator/repressor status was significantly associated with maternal U-tAs and head circumference in newborn males. These results may provide a critical groundwork for understanding the diverse health effects associated with prenatal arsenic exposure and highlight interindividual responses to arsenic that likely influence differential susceptibility to adverse health outcomes.

Keywords: arsenic; arsenic metabolism; birth outcomes; in utero; metals; pregnancy.

FIG. 1.

Relative expression levels of U-tAs-associated cord blood proteins differ between newborns. Heat maps illustrate the relative protein expression levels of 111 U-tAs-associated cord blood proteins in activator newborns (A) and repressor newborns (B). Expression values for each protein are mean centered with high relative expression indicated in red and low relative expression indicated in blue. U-tAs: sum of inorganic arsenic (iAs) and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) in maternal urine (μg As/l urine).

FIG. 2.

Regulatory network of U-tAs-associated cord blood proteins. An upstream network predicted to regulate the expression of the majority (∼56%) of the 111 U-tAs-associated cord blood proteins was identified. Proteins are displayed as predicted to be activated (orange) or inhibited (blue) with increasing maternal U-tAs, a trend representative of the activator newborn response. HIF1A: hypoxia inducible factor 1, alpha subunit; IFNG: interferon gamma; IKBKB: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta; IL1B: interleukin 1 beta; IRF3: interferon regulatory factor 3; IRF8: interferon regulatory factor 8; NFKB complex: nuclear factor kappa light chain enhancer of activated B cells complex; NFKB1: nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NFKBIA: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; NFKBIB: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, beta; REL: v-rel reticuloendotheliosis viral oncogene homolog (avian); RELA: v-rel reticuloendotheliosis viral oncogene homolog A (avian); SMAD3: SMAD family member 3; STAT1: signal transducer and activator of transcription 1; TGFB1: transforming growth factor beta 1; TNF: tumor necrosis factor.

FIG. 3.

TNF-associated cord blood proteins. TNF is predicted to regulated the expression of the majority (n = 45) of the U-tAs-associated proteins. Proteins are displayed as predicted to be activated (orange), up-regulated (red), or down-regulated (green) with increasing maternal U-tAs, a trend representative of the activator newborn response. TNF: tumor necrosis factor. Complete names of the U-tAs-associated proteins are provided in Supplementary table 1.