Global gene expression analysis in cord blood reveals gender-specific differences in response to carcinogenic exposure in utero

Abstract

Background: It has been suggested that such foetal exposure might lead to predisposition to develop cancer during childhood or in later life possibly through modulation of the foetal transcriptome. Since gender effects in the incidence of childhood cancers have been described, we hypothesized differences at the transcriptomic level in cord blood between male and female newborns as a consequence of foetal carcinogenic exposure. The objective was to investigate whether transcriptomic responses to dietary genotoxic and non-genotoxic carcinogens demonstrate gender-specific mechanisms-of-action relevant for chemical carcinogenesis. Methods: Global gene expression was applied in umbilical cord blood samples, the CALUX^®-assay was used for measuring dioxin(-like), androgen(-like) and estrogen(-like) internal exposure, and acrylamide-haemoglobin adduct levels were determined by mass spectrometry adduct-FIRE-procedure^TM. To link gene expression to an established phenotypic biomarker of cancer risk, micronuclei frequencies were investigated. Results: While exposure levels did not differ between sexes at birth, important gender-specific differences were observed in gene expressions associated with these exposures linked with cell cycle, the immune system and more general cellular processes such as (post)-translation. Moreover, oppositely correlating leukemia/lymphoma genes between male and female newborns were identified in relation to the different biomarkers of exposure which might be relevant to male-specific predisposition to develop these cancers in childhood. Conclusions/Impact: This study reveals different transcriptomic responses to environmental carcinogens between the sexes. In particular, male-specific TNF-alpha-NF-kB signaling upon dioxin exposure and activation of the Wnt-pathway in boys upon acrylamide exposure might represent possible mechanistic explanations for gender specificity in the incidence of childhood leukemia.