BackgroundThe study of hyperoxia vs. hypoxia on tumor cell survival is often studied under experimental conditions that do not control for the shift in pH.MethodsHere, we examine the molecular genetic effects of (~91% O2 (hyperoxia) vs. ~2.5% O2 (hypoxia)) at a uniform pH ~7.2 using microarrays, HPLC, imaging probes and Western blot.ResultsHyperoxic and Hypoxic culture conditions for 24 hrs had no adverse effect on viability in malignant N2a cells, provided pH was neutral with ample glucose supply. The hyperoxic transcriptome showed elevation of mRNA of 42 mitochondrial genes, DNA/base excision repair, G protein signaling, protein synthesis, transcription and ubiquitin‐mediated proteolysis. The hypoxic transcriptome corresponded to major elevations in epigenetic (lysine (K)‐specific demethylases, H4k/d/j, Hist4h4, Hist2h3c1, Rara and REST corepressor 2) with greater expression of protein/mRNA for solute carrier family 16, member 3 MCT‐4 (lactate transporter). Blocking MCT‐4 (phloretin) lead to an alkaline shift in both pHex/pHi, corresponding to cell toxicity.ConclusionsTumor cells are capable of acclimatizing to extreme variation in O2, but are highly intolerant to factors that invoke alkalinity to the inclusion of rising levels of O2 or impeding lactate release. (Supported by NIH G12RR 03020, 8G12MD007582–28 and 1P20 MD006738–01))