The effect of organic solvents and CYP1A1, CYP2E1, GSTM1 polymorphisms on the development of acute lymphoblastic leukemia in Quebec children
Bibliographic record
Abstract
Background: Childhood acute lymphoblastic leukemia (ALL) is a complex disease whose etiology remains largely unknown. Both genetic and environmental factors are believed to be involved in leukemogenesis. It has long been suspected that organic solvents are carcinogens. They are common in the workplace and are potentially important sources of exposure in mothers during various time periods: preconception, pregnancy and postnatal. These time windows are vital for the developing fetus and exposures to carcinogens through the placenta or breast milk could lead to DNA damage. In addition, variants in xenobiotic metabolizing genes that biotransform various chemicals entering the body, in particular CYP (cytochrome P450) and GST (glutathione S-transferase) genes, have equally been linked to the development of ALL. As such, it is quite possible that variants in CYP and GST genes affect the biotransformation of chemicals such as organic solvents in the fetus or infant, leading to increased DNA damage and potentially cancer. Methods: I analyzed the effects of maternal occupational exposure to organic solvents during pregnancy and breastfeeding on the risk of developing ALL in the offspring. The effects of organic solvents from household activities were also investigated in breastfeeding mothers during the postnatal period. In addition, I analyzed the joint effects of case genetic variants in certain likely functional xenobiotic metabolizing genes (CYP1A1, CYP2E1 and GSTM1) with organic solvent exposures. The data was taken from a large population based case-control with 790 cases and 790 controls recruited from Quebec, Canada. The data included state-of-art determination of occupational exposures, household exposures to various environmental exposures, and genotyped DNA samples from the study participants and their parents. The data was analyzed using logistic regression and Poisson log-linear models based on case-control, case-only and case parent-trio designs. Results: Significant main effects were found between case GSTM1 null and CYP1A1 *4 variants and ALL. Additionally, individuals with one copy of the CYP1A1 *2A variant and GSTM1 null had a significant odds ratio of developing ALL at 1.68 (95% CI: 1.03-2.75) as compared to an individual with neither. Offspring with the GSTM1 null variant whose mothers were occupationally exposed to aliphatic alcohols and aliphatic ketones, specific chemical families of organic solvents, during pregnancy had a lower risk of developing ALL than carriers of the wild type carriers. The case-parent trio analysis did detect a harmful interaction effect between offspring with the CYP1A1 *2B variant and maternal occupational exposure to any type of organic solvent during pregnancy. Similarly, the case-only analysis found important harmful interaction effects between the CYP1A1 *2A and *4 variants and maternal occupational exposures to any type of organic solvent during pregnancy and protective interaction effects between GSTM1 null variants and this same exposure. Among mothers who breastfed, exposure to organic solvents from household activities from one year before pregnancy to date of diagnosis did not generally increase the risk of ALL; however, there was evidence to suggest that the GSTM1 null and CYP1A1 *2A variants modified the effect of solvent exposure from furniture stripping, and likewise for the CYP2E1 *5 variant with certain activities involving exposure to electronics. The CYP1A1 *2A variant also appeared to significantly modify the effect of latex and/or acrylic paint exposures in a breastfeeding mother on the risk of ALL. Discussion: Although the study had limited power to uncover statistically significant interactions, the results suggest a role on the incidence of childhood ALL for gene variants involved in the metabolism of carcinogens in the presence of environmental prenatal or breastfeeding exposure to organic solvents.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".