The Weight of The Evidence: Eating Food Plants and Food RNA Is Not Detrimental to Health

Dear Editor In a recent editorial article published by Salehi (2014) in Journal of Food Quality and Hazards Control (1: 93), the author cited two studies of plant microRNAs (miRNAs) as supporting "adverse health consequences" of genetically modified foods (Zhang et al., 2012a; Zhang et al., 2012b). The first of these studies reported that a conserved, ubiqui-tous, and high-abundance plant microRNA could regulate expression of the mammalian gene LDLRAP1 (Zhang et al., 2012a). On the other hand, analysis of public RNA expres-sion datasets (Zhang et al., 2012b) found little evidence for uptake of plant dietary miRNAs, or “xenomiRs” (Witwer, 2012) by ingesting animals. Strikingly, and of some poten-tial concern, it was suggested that the foods examined in these two studies (plants without specific modifications) are safe, while a food category not examined in the studies (ge-netically modified plants) represents a health risk. It might be useful to examine the two cited studies more closely, as well as to consider the more recent literature on the topic of xenomiRs. The first issue to resolve is that Zhang et al. (2012b) have not claimed that "double-stranded RNAs (dsRNAs) generat-ed in genetically modified plants...can create biosafety risks" indicated by mentioned article. Instead, they reported that MIR168a, a ubiquitous and abundant mature endogenous plant miRNA (not dsRNA), can affect the expression of a mammalian gene in the liver (Zhang et al., 2012b). This result was questioned in light of new evidence from a sub-sequent study (Dickinson et al., 2013) that included im-portant additional experimental controls. Had the initial finding been validated, it would still have had no specific relevance to genetically modified food as opposed to plants in general. If adverse consequences could be inferred from the original study, the logical conclusion would be "to avoid the hazards of..." eating any and all plants, not just genet-ically modified foods. Genetic modification, in this scenario, would have provided useful tools to reduce the expression of the putatively harmful MIR168a and thus allow safer con-sumption of plant material. The point is moot, however, since no xenomiR-based harm has been established for mod-ified or unmodified plants. Secondly, a subsequent independent publication (Zhang et al., 2012b) did not state that dietary xenomiRs "enter the serum and plasma of humans and animals." Quite the oppo-site: examining around 80 public datasets, the authors found that meager, highly variable evidence of xenomiR detection was most consistent with contamination rather than actual uptake. Sources of environmental plant RNA abound, espe-cially in labs that study plant sequences. Contamination is easily detected with sensitive high-throughput techniques (Tosar et al., 2014) and gives a possible explanation for previous, apparently positive results. The history of safe plant consumption demonstrates that hypothetical xenomiR-based regulatory mechanisms are not a health risk. Indeed, essential human genes contain many binding sites for plant RNA products, without evidence of adverse consequences (Jensen et al., 2013). Since interac-tions of these genes with foreign xenomiRs or other RNA interference effectors would have resulted in negative selec-tion, we must assume that the interactions do not occur. One reason why xenomiRs do not affect genes in the ingesting animal—and contrary to the statement that "food-derived small RNAs and dsRNAs can enter the circulation"—is that they are not normally present in circulation and cannot reach copy numbers in mammalian cells that would be consistent with regulatory influence. An increasing number of investi-gators have found no significant uptake of plant xenomiRs into mammalian blood (Baier et al., 2014; Dickinson et al., 2013; Snow et al., 2013; Witwer et al., 2013), even when the most abundant miRNAs in the food sources are examined. None has reported uptake of dsRNA. The many barriers to uptake and function of dietary RNA have been reviewed elsewhere (Petrick et al., 2013; Witwer and Hirschi, 2014). Considering the mounting evidence against uptake and func-tion of even high-abundance, ubiquitous plant xenomiRs, there is currently no scientific reason to discourage ingestion of genetically modified plants on the basis of small RNA considerations.