Transplacental chemical exposure and risk of infant leukemia with MLL genefusion

Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fus ions arise in utero and are similar to those found in leukemias secondary t o chemotherapy with inhibitors of topoisomerase II (topo II). This has led to the hypothesis that in utero exposures to chemicals may cause IAL via an effect on topo-II. We report a pilot case-control study of IAL across diff erent countries and ethnic groups. Cases (n = 136) were population-based in most centers. Controls (II = 266) were selected from inpatients and outpat ients at hospitals serving the same populations. MLL rearrangement status w as derived by Southern blot analysis, and maternal exposure data were obtai ned by interviews using a structured questionnaire. Apart from the use of cigarettes and alcohol, very few mothers reported exp osure to known topo-II inhibitors. Significant case-control differences wer e apparent for ingestion of several groups of drugs, including herbal medic ines and drugs classified as "DNA-damaging," and for exposure to pesticides with the last two being largely attributable, respectively, to one nonster oidal anti-inflammatory drug, dipyrone, and mosquitocidals (including Baygo n). Elevated odds ratios were observed for MLL+ve (but not MLL-ve) leukemia s (2.31 for DNA-damaging drugs, P = 0.03; 5.84 for dipyrone, P = 0.001; and 9.68 for mosquitocidals, P = 0.003). Although it is unclear at present whe ther these particular exposures operate via an effect on topo-II, the data suggest that specific chemical exposures of the fetus during pregnancy may cause MLL gene fusions. Given the widespread use of dipyrone, Baygon, and o ther carbamate-based insecticides in certain settings, confirmation of thes e apparent associations is urgently required.