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Abstract: Pesticides are commonly used worldwide and almost every human is potentially exposed to these chemicals. Exposure to pesticides such as permethrin and malathion has been associated with hematological malignancies in epidemiological studies. However, biological evidence showing if these chemicals induce genetic aberrations involved in the etiology of leukemia and lymphoma is missing. In our previous work, we have shown that a single high exposure (200 μ m, 24 hours) of permethrin and malathion induce damage in genes associated with hematological malignancies in peripheral blood mononuclear cells analyzed by interphase fluorescence in situ hybridization (FISH). In the present study, we assessed by FISH whether exposure to low concentrations (0.1 μ m, 72 hours) of permethrin and malathion induce aberrations in KMT2A and IGH genes, which are involved in the etiology of leukemia and lymphoma. Peripheral blood mononuclear cells were exposed to the chemicals, and damage in these genes was assessed on interphases and metaphases. We observed that both chemicals at low concentration induced structural aberrations in KMT2A and IGH genes. A higher level of damage was observed in KMT2A gene with malathion treatment and in IGH gene with permethrin exposure. We also observed numerical aberrations induced by these chemicals. The most frequent aberrations detected on interphase FISH were also observed on metaphases. Our results show that permethrin and malathion induce genetic damage in genes associated with hematological cancer, at concentrations biologically relevant. In addition, damage was observed on dividing cells, which suggests that these cells maintain their proliferation capacity in spite of the genetic damage they possess. [ABSTRACT FROM AUTHOR]

The long-term effects of environmental pollution have been of concern as several pollutants are carcinogenic, potentially inducing a variety of cancers, including childhood cancer, which is a leading cause of death around the world and, thus, is a public health issue. The present scoping review aimed to update and summarize the available literature to detect specific environmental pollutants and their association with certain types of childhood cancer. Studies published from 2013 to 2023 regarding environmental pollution and childhood cancer were retrieved from the PubMed database. A total of 174 studies were eligible for this review and were analyzed. Our search strategy brought up most of the articles that evaluated air pollution (29%) and pesticides (28%). Indoor exposure to chemicals (11%), alcohol and tobacco use during pregnancy (16%), electromagnetic fields (12%), and radon (4%) were the subjects of less research. We found a particularly high percentage of positive associations between prenatal and postnatal exposure to indoor (84%) and outdoor (79%) air pollution, as well as to pesticides (82%), and childhood cancer. Positive associations were found between leukemia and pesticides and air pollution (33% and 27%); CNS tumors and neuroblastoma and pesticides (53% and 43%); and Wilms tumor and other rare cancers were found in association with air pollution (50%). Indoor air pollution was mostly reported in studies assessing several types of cancer (26%). Further studies are needed to investigate the mechanisms underlying the potential associations between indoor/outdoor air pollution and pesticide exposure with childhood cancer risk as more preventable measures could be taken.

The evidence supporting the biological plausibility of the association of permethrin and malathion with hematological cancer is limited and contradictory; thus, further studies are needed. This study aimed to investigate whether in vitro exposure to 0.1 μM permethrin and malathion at 0, 24, 48 and 72 h after cell culture initiation induced changes in the gene expression and DNA methylation in mononuclear cells from bone marrow and peripheral blood (BMMCs, PBMCs). Both pesticides induced several gene expression modifications in both tissues. Through gene ontology analysis, we found that permethrin deregulates ion channels in PBMCs and BMMCs and that malathion alters genes coding proteins with nucleic acid binding capacity, which was also observed in PBMCs exposed to permethrin. Additionally, we found that both insecticides deregulate genes coding proteins with chemotaxis functions, ion channels, and cytokines. Several genes deregulated in this study are potentially associated with cancer onset and development, and some of them have been reported to be deregulated in hematological cancer. We found that permethrin does not induce DNA hypermethylation but can induce hypomethylation, and that malathion generated both types of events. Our results suggest that these pesticides have the potential to modify gene expression through changes in promoter DNA methylation and potentially through other mechanisms that should be investigated.

The gene fusions BCR-ABL1, TCF3-PBX1, and ETV6-RUNX1 are recurrent in B-cell acute lymphoblastic leukemia (B-ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor-like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant-negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B-ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant-negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR-ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3-PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6-RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3-PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8-CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR-ABL1 and TCF3-PBX1 patients. To obtain useful information for the assessment of treatment in B-ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant-negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways., (© 2021 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland & John Wiley & Sons, Ltd.)

A high impact of ARID5B SNPs on acute lymphoblastic leukemia (ALL) susceptibility has been described in Hispanic children; therefore, it is relevant to know if they influence the high incidence of childhood-ALL in Mexicans. Seven SNPs (rs10821936, rs10994982, rs7089424, rs2393732, rs2393782, rs2893881, rs4948488) of ARID5B were analyzed in 384 controls and 298 ALL children using genomic DNA and TaqMan probes. The SNPs were analyzed for deviation of Hardy-Weinberg equilibrium; Fisher's exact test was used to compare the genotypic and allelic frequencies between controls and patients. The association between SNPs and ALL susceptibility was calculated, and haplotype and ancestry analyses were conducted. All SNPs were associated with ALL, pre-B ALL, and hyperdiploid-ALL susceptibility (p < 0.05). No association with T-ALL and gene fusions was found (p > 0.05). The seven SNPs were associated with risk of pre-B ALL in younger children; however, rs2393732, rs2393782, rs2893881, and rs4948488 were not associated with susceptibility in older children and adolescents. The CAG haplotype (rs10821936, rs10994982, rs7089424) was strongly associated with ALL risk in our population (p < 0.00001). The frequency of all risk alleles in our ALL, pre-B, and hyperdiploid-ALL patients was higher than that in Hispanic children reported. This is the first report showing the association between rs2393732, rs2393782, and rs4948488 with pre-B hyperdiploid-ALL children. The G allele at rs2893881 confers major risk for pre-B hyperdiploid-ALL in Mexican (OR, 2.29) than in Hispanic children (OR, 1.71). The genetic background of our population could influence the susceptibility to ALL and explain its high incidence in Mexico.

Expression of the 6 and 8 dominant-negative Ikaros isoforms in pediatric patients with acute lymphoblastic leukemia has been associated with a high risk of relapse and death; due to these isoforms disrupting the differentiation and proliferation of lymphoid cells. The aim of this study was to know the frequency of Ik6 and Ik8 in 113 Mexican ALL-children treated within the National Popular Medical Insurance Program to determine whether there was an association with relapse-free survival, event-free survival and overall survival, and to assess its usefulness in the initial stratification of patients. The expression of these isoforms was analyzed using specific primer sets and nested RT-PCR. The detected transcripts were classified according to the isoforms's sizes reported. A non-expected band of 300 bp from one patient was analyzed by sequencing. Twenty-six patients expressed Ik6 and/or Ik8 and one of them expressed a variant of Ik8 denominated Ik8-deleted. Although the presence of them was not statistically associated with lower relapse free survival (p = 0.432), event free survival (p = 0.667) or overall survival (p = 0.531), inferior overall survival was observed in patients that expressed these isoforms and showed high or standard risk by age and white blood-cell count at diagnosis. Of the 26 patients Ik6+ and/or Ik8+, 14 did not present adverse events; from them 6 were exclusively Ik6+ and/or Ik8+, and 8 were positive for the other Ikaros isoforms (Ik1, Ik2, Ik5, Ik3A, Ik4, Ik4A, Ik7). In the patients studied, the expression of Ik6 and Ik8 did not constitute an independent prognostic factor for relapse or death related to disease; therefore, they could not be used in the initial risk stratification.

Metabolic syndrome (MetS) is among the most important public health problems worldwide, and is recognized as a major risk factor for various illnesses, including type 2 diabetes mellitus, obesity, and cardiovascular diseases. Recently, oxidative stress has been suggested as part of MetS aetiology. The heme oxygenase 1 (HMOX1) and NADH:quinone oxidoreductase 1 (NQO1) genes are crucial mediators of cellular defence against oxidative stress. In the present study, we analysed the associations of HMOX1 (GT)n and NQO1 C609T polymorphisms with MetS and its components. Our study population comprised 735 Mexican Mestizos unrelated volunteers recruited from different tertiary health institutions from Mexico City. In order to know the HMOX1 (GT)n and NQO1 C609T allele frequencies in Amerindians, we included a population of 241 Amerindian native speakers. Their clinical and demographic data were recorded. The HMOX1 (GT)n polymorphism was genotyped using PCR and fluorescence technology. NQO1 C609T polymorphism genotyping was performed using TaqMan probes. Short allele (<25 GT repeats) of the HMOX1 polymorphism was associated with high systolic and diastolic blood pressure, and the T allele of the NQO1 C609T polymorphism was associated with increased triglyceride levels and decreased HDL-c levels, but only in individuals with MetS. This is the first study to analyse the association between MetS and genes involved in oxidative stress among Mexican Mestizos. Our data suggest that polymorphisms of HMOX1 and NQO1 genes are associated with a high risk of metabolic disorders, including high systolic and diastolic blood pressure, hypertriglyceridemia, and low HDL-c levels in Mexican Mestizo individuals.

Novel biomarkers for risk refinement and stratification in childhood acute lymphoblastic leukemia (ALL) are needed to optimize treatment results. We studied the expression of CASP8AP2 and H2AFZ associated with relapse and survival in bone marrow samples from newly diagnosed children with ALL. We found: (a) an increased risk for early relapse in those patients with low expression of CASP8AP2 (odds ratio [OR] 3.93, 95% confidence interval [CI] 1.40-11.02, p < 0.05) confirming its usefulness as a predictive risk marker, although H2AFZ did not present the same effect; (b) patients with low expressions of CASP8AP2 and H2AFZ had inferior survival rates (p < 0.001); (c) the predictive values regarding low expressions of H2AFZ and CASP8AP2 and high white blood cell count suggest that these features could help to identify more accurately patients at greater risk of relapse.

Trisomy 13, or Patau syndrome, is a chromosomal disorder that can occur in complete, partial, or mosaic forms. Mosaicism is observed in 6% of individuals with trisomy 13 and, in contrast to the complete form, has wide phenotypic variability, longer survival, and in some patients an unusual skin pigmentary pattern similar to phylloid hypomelanosis. We describe here a 12-year-old girl with trisomy 13 mosaicism (mos 47,XX,+13[9]/46,XX[16]) who had three major malformations, an unusual skin pigmentary pattern, and prolonged survival., (© 2014 Wiley Periodicals, Inc.)

We present the literature review of ring chromosome 7 and clinical, cytogenetic and fine molecular mapping of the first postnatal report of a male child with a non-supernumerary ring chromosome 7, r(7). The patient had dysmorphic features, developmental delay, dermatologic lesions with variable pigmentation, hypogenitalism, lumbar dextroscoliosis, cerebellar and ophthalmological abnormalities, and melanocytic congenital nevi. Cytogenetic analysis of peripheral blood and the nevus sample showed the presence of three different cell lines r(7), monosomy 7, and duplicated r(7) (idic r(7)), while findings on fibroblasts from both light and dark skin showed only mosaicism with r(7) and monosomy 7 cell lines in various proportions. FISH assay of the ring chromosome showed subtelomeric loss in both chromosome arms in all tissues studied. Analysis by genome-wide single-nucleotide polymorphism array showed a 0.8 Mb deletion in 7p22.3 (involving eight genes) and a 7.5 Mb deletion in 7q36 (involving 29 genes including some involved in genital and central nervous system development). The combination of results from our karyotypic and array analyses enabled us to establish an accurate genotype-phenotype relationship., (© 2014 Wiley Periodicals, Inc.)