Placental Expression of Imprinted Genes, Overall and in Sex-Specific Patterns, Associated with Placental Cadmium Concentrations and Birth Size

摘要

Background: Prenatal cadmium (Cd) exposure has been recognized to restrict growth, and male and female fetuses may have differential susceptibility to the developmental toxicity of Cd. Imprinted genes, which exhibit monoallelic expression based on parent of origin, are highly expressed in placental tissues. The function of these genes is particularly critical to fetal growth and development, and some are expressed in sex-specific patterns. Objectives: We aimed to examine whether prenatal Cd associates with the expression of imprinted placental genes, overall or in fetal sex-specific patterns, across two independent epidemiologic studies. Methods: We tested for Cd–sex interactions in association with gene expression, then regressed the placental expression levels of 74 putative imprinted genes on placental log-Cd concentrations while adjusting for maternal age, sex, smoking history, and educational attainment. These models were performed within study- and sex-specific strata in the New Hampshire Birth Cohort Study (NHBCS; n = 326 ) and the Rhode Island Child Health Study (RICHS; n = 211 ). We then used fixed-effects models to estimate the sex-specific and overall associations across strata and then examine heterogeneity in the associations by fetal sex. Results: We observed that higher Cd concentrations were associated with higher expression of distal-less homeobox 5 ( DLX5 ) ( p = 0.000025 ), and lower expression of h19 imprinted maternally expressed transcript ( H19 ) ( p = 0.00027 ) and necdin, MAGE family member ( NDN ) ( p = 0.00064 ) across study and sex-specific strata, while three other genes [carboxypeptidase A4 ( CPA4 ), growth factor receptor bound protein 10 ( GRB10 ), and integrin-linked kinase ( ILK )] were significantly associated with Cd concentrations, but only among female placenta ( p interaction 0.05 ). Additionally, the expression of DLX5, H19 , and NDN , the most statistically significant Cd-associated genes, were also associated with standardized birth weight z -scores. Discussion: The differential regulation of a set of imprinted genes, particularly DLX5, H19 and NDN , in association with prenatal Cd exposure may be involved in overall developmental toxicity, and some imprinted genes may respond to Cd exposure in a manner that is specific to infant gender.