Moms and Mercury: Fine-Tuning Fish Consumption During Pregnancy

Due to ongoing concerns that high mercury intake via fish can cause adverse neurologic effects in the developing fetus, the U.S. Food and Drug Administration now recommends that expectant mothers should limit their consumption of fish to two or fewer meals per week. But pregnant women shouldn’t throw the baby out with the bathwater. A new study by a group of Harvard researchers suggests that this advice, which could result in many pregnant women eliminating fish from their diets altogether, may be denying some babies substantial neurocognitive benefits gained from important nutrients found in fish, such as n-3 polyunsaturated fatty acids [EHP 113:1376–1380]. 
 
The scientists sought to determine whether fish consumption during pregnancy is harmful or beneficial to fetal brain development. To do this, they examined associations of maternal fish consumption during pregnancy, maternal hair mercury levels (a sensitive marker of organic mercury body burden) at delivery, and infant cognition at age 6 months. Study subjects were 135 mother–infant pairs who participated in Project Viva, a prospective pregnancy and child health cohort study in eastern Massachusetts. 
 
The mothers completed questionnaires about fish consumption during their second trimester. That period of time was used to best coordinate temporally with the mercury exposure reflected in maternal hair samples, which were taken at delivery. The questions concerned how much and what categories of fish (canned tuna, dark meat, light meat, shellfish) the women ate. 
 
Mothers consumed an average of 1.2 servings of combined fish categories per week. Their mean hair mercury level was 0.55 part per million (ppm), with 10% of the samples higher than 1.2 ppm, the current U.S. reference dose. Fish consumption was directly correlated with hair mercury levels. 
 
Infant cognition was assessed using a test called visual recognition memory (VRM). In the VRM test, which has been shown to correlate with later IQ, the child is first shown two identical photographs of an infant’s face, side by side, at a standardized distance. Then, one of the photos is replaced with a photo of another infant’s face. By tracking the percentage of time the baby looks at each photo, a novelty preference score is derived, reflecting the infant’s ability to encode a stimulus into memory, to recognize that stimulus, and to look preferentially at a novel stimulus. 
 
Mean VRM score among the children was 59.8, with a range of 10.9–92.5. After accounting for characteristics such as maternal age and education level, higher fish intake was found to be associated with higher infant cognition, especially after adjusting for mercury levels, which had a dose-dependent negative impact on the infants’ cognition. For each additional weekly serving of fish, the infants’ VRM score was 4.0 points higher. Conversely, the researchers found that an increase of 1 ppm in hair mercury was associated with a decrement in VRM score of 7.5 points. The babies with the highest cognition scores were from mothers who had eaten more than two weekly fish servings but had mercury levels of 1.2 ppm or less. 
 
Although the results may seem contradictory, the authors suggest that the most cognitive benefit is derived by mothers eating fish types with the combination of relatively little mercury and high amounts of beneficial nutrients. However, since the study assessed maternal fish consumption of four broad categories, there is no information presented on associations with specific types of fish. The researchers say that future studies could incorporate more detailed dietary information to help pregnant women make informed decisions about which fish meals are better or worse for their children’s cognition. 
 
Ultimately, the message behind these findings is that pregnant women should continue to eat fish, but should try to choose varieties known to be low in mercury and high in nutrients, such as canned light tuna and sardines. Finding the most appropriate balance between risk and benefit may be challenging in this situation, but given the strong associations found in the current study, making the right decisions about which fish to eat during pregnancy, and how often, may be even more important than previously suspected.

We wish to report some corrections to our study [1], none of which alters the interpretation of the data or the conclusions drawn. After publication, we noticed that one of the microarray hybridizations (on sample NB11) was performed on the same patient's material as another hybridization (sample NB4; see Table 1; a corrected version of Table 5 [1]). As this error leads to an incorrect subclassification of the patients into the 'favourable' and 'unfavourable' neuroblastoma subgroups, we would like to exclude this data point from the differential expression analysis of favorable versus unfavorable neuroblastoma given under the heading 'Differential expression analysis of favorable and unfavorable neuroblastoma' in the Results section of [1]. Careful reanalysis after exclusion of NB11 did not lead to important changes in the generated gene lists and conclusions; the changes are given in the corrected paragraph and Table 2 (a  corrected version of Table 4 [1]), and the Additional data files 1 and 2 (corrected versions of Additional data files 2 and 3 [1]) available online with this article.
We also noticed that sample NB1 is stage 1 instead of stage 4S and that sample NB2 was not localized to the adrenals (see Table 1).

Differential expression analysis of favorable and unfavorable neuroblastoma
So far, most published microarray studies on neuroblastomas mainly compared favorable with unfavorable neuroblastomas in order to identify prognostic markers or pathways that are involved in these clearly different neuroblastoma tumor types. In order to add value to such an analysis, we contrasted similar differentially expressed gene lists with the normal neuroblast expression profile (Additional data file 1). In a first step, we compared the differentially expressed genes between these two tumor types with published prognostic gene lists. We found that 23 of the 193 genes on our list were previously reported, including the well established markers MYCN, NTRK1, and CD44 (see NBGS analysis in Additional data file 2). This overlap demonstrates the validity of the selected neuroblastoma panel and their expression profile. Subsequently, we looked for the corresponding gene expression levels of the differentially expressed genes in the normal counterpart cells, aiming to select neuroblastoma candidate genes. Of the 100 genes that are more highly expressed in favorable tumors (compared to unfavorable) 41 also have a significant differential expression (either higher or lower) compared to neuroblasts, whereas 43 of the 93 genes that are more highly expressed in unfavorable tumors exhibit differential expression compared to the neuroblasts (Table 2).
From this analysis, a few putative positional tumor suppressor candidates emerge: CDC42 on 1p36, CACNA2D3 on 3p21 and DLK1 on 14q. The latter two genes are of particular interest because they are highly expressed in neuroblasts and favorable neuroblastomas and their expression is significantly lower in unfavorable neuroblastomas. Among the genes that are more highly expressed in unfavorable neuroblastomas than in favorable ones and neuroblasts, the proven oncogenic transcription factor MYCN emerges (and putative downstream genes KIFAP3, OPHN1, RGS7, ASCL1, ODC1, TWIST1 and TYMS, according to NBGS), as well as several other genes that have been identified or studied in the context of neuroblastoma such as ALK and PRAME, and positional candidates on 17q including BIRC5 and RNU2.

Additional data files
Additional data files 1 and 2 containing the corrected data available online with this article. Samples were subdivided into favorable or unfavorable type based on MYCN amplification, ploidy and age at diagnosis. *Neuroblastoma or nodular ganglioneuroblastoma. ND, not determined or unknown.

References
11p -Genes that are differentially expressed compared with neuroblasts among the differentially expressed genes in favorable neuroblastoma (NB) vs unfavorable NB, with an indication of the number of neuroblastoma microarray studies in which these genes were found through NBGS analysis. NBGS, Neuroblastoma Gene Server.