The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression

Emily F Winterbottom,Dennis Liang Fei,Carmen J Marsit,David J Robbins,Devin C Koestler,Margaret R Karagas,Anthony J Capobianco,Eric Wika

doi:10.1186/s12940-017-0267-8

Abstract

BackgroundSex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure. Increasing evidence suggests that such sex differences also exist during fetal development. In a previous report using the resources of the New Hampshire Birth Cohort Study (NHBCS), we found that low-to-moderate in utero exposure to arsenic, a highly toxic and widespread pollutant, was associated with altered expression of several key developmental genes in the fetal portion of the placenta. These associations were sex-dependent, suggesting that in utero arsenic exposure differentially impacts male and female fetuses. In the present study, we investigated the molecular basis for these sex-specific responses to arsenic.MethodsUsing NanoString technology, we further analyzed the fetal placenta samples from the NHBCS for the expression of genes encoding arsenic transporters and metabolic enzymes. Multivariable linear regression analysis was used to examine their relationship with arsenic exposure and with key developmental genes, after stratification by fetal sex.ResultsWe found that maternal arsenic exposure was strongly associated with expression of the AQP9 gene, encoding an aquaglyceroporin transporter, in female but not male fetal placenta. Moreover, AQP9 expression associated with that of a subset of female-specific arsenic-responsive genes.ConclusionsOur results suggest that AQP9 is upregulated in response to arsenic exposure in female, but not male, fetal placenta. Based on these results and prior studies, increased AQP9 expression may lead to increased arsenic transport in the female fetal placenta, which in turn may alter the expression patterns of key developmental genes that we have previously shown to be associated with arsenic exposure. Thus, this study suggests that AQP9 may play a role in the sex-specific effects of in utero arsenic exposure.

Highlights

Sex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure
We examined the mRNA expression of a set of four genes with known roles in arsenic transport (AQP9 and SLC39A2) or arsenic metabolism (AS3MT and GSTM1) in male and female fetal placenta, to start to examine the possibility that differences in arsenic transport or metabolism might account for the sexually dimorphic effects of arsenic on the placental expression of these developmental genes
We observed a positive association of maternal urinary arsenic (U-As) levels with expression of the aquaglyceroporin transporter, AQP9, in female, but not male, fetal placenta, indicating that AQP9 may be upregulated in response to arsenic in a female sexspecific manner

Summary

Introduction

Sex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure. In a previous report using the resources of the New Hampshire Birth Cohort Study (NHBCS), we found that low-to-moderate in utero exposure to arsenic, a highly toxic and widespread pollutant, was associated with altered expression of several key developmental genes in the fetal portion of the placenta. Millions of people worldwide are exposed to arsenic at lower levels than those witnessed in the above populations, but which are close to or exceed the US Environmental Protection Agency Maximum Contaminant Level (EPA MCL) of 10 μg/L [8] The consequences of this common low-level exposure are poorly understood, but increasing evidence from our laboratories and others suggests that such exposure impacts fetal tissue biology and adversely affects infant health [17,18,19,20,21,22,23]

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Conclusion