PCB exposure and potential future cancer incidence in Slovak children: an assessment from molecular finger printing by Ingenuity Pathway Analysis (IPA®) derived from experimental and epidemiological investigations

The risk of cancer due to PCB exposure in humans is highly debated. In eastern Slovakia, high exposure of the population to organochlorines (especially PCBs) was associated with various disease and disorder pathways, viz., endocrine disruption, metabolic disorder & diabetes, and cancer, thereby disturbing several cellular processes, including protein synthesis, stress response, and apoptosis. We have evaluated a Slovak cohort (45-month children, at lower and higher levels of PCB exposure from the environment) for disease and disorder development to develop early disease cancer biomarkers that could shed new light on possible mechanisms for the genesis of cancers under such chemical exposures, and identify potential avenues for prevention.

Microarray studies of global gene expression were conducted from the 45-month-old children on the Affymetrix platform followed by Ingenuity Pathway Analysis (IPA®) to associate the affected genes with their mechanistic pathways. High-throughput qRT-PCR TaqMan low-density array (TLDA) was performed to further validate the selected genes on the whole blood cells of the most highly exposed children from the study cohort (n = 71).

TP53, MYC, BCL2, and LRP12 differential gene expressions suggested strong relationships between potential future tumor promotion and PCB exposure in Slovak children. The IPA analysis further detected the most important signaling pathways, including molecular mechanism of cancers, prostate cancer signaling, ovarian cancer signaling, P53 signaling, oncostatin M signaling, and their respective functions (viz., prostate cancer, breast cancer, progression of tumor, growth of tumor, and non-Hodgkin’s disease). The results suggest that PCB exposures, even at the early age of these children, may have lifelong consequences for the future development of chronic diseases.

     

Gene expression signatures in PCB-exposed Slovak children in relation to their environmental exposures and socio-physical characteristics

Environmental Science and Pollution Research - Our previous gene expression studies in a PCB-exposed cohort of young children in Slovakia revealed that early-life exposures to PCBs and other...     

Comparison of organochlorine compound concentrations in colostrum and mature milk

Human breast milk represents the best choice for the nutrition of infants. It is often used for monitoring human exposures to environmental chemicals. Uniquely suited to meet human biological needs, breast milk composition, especially fat content, changes significantly with time from delivery. With the aim to compare the concentration of organochlorine compounds (OCs) in colostrum versus mature milk, we obtained samples of fourth-fifth day postpartum milk (colostrum) and day-14 postpartum milk (mature milk) from 12 women enrolled in the project "Early Childhood Development and PCB Exposure in Slovakia". The concentrations of selected organochlorine pesticides and congeners of polychlorinated biphenyls (PCBs) were measured using gas chromatography with electron capture detection and reported on lipid adjusted basis. No significant differences were found between organochlorine levels in colostrum and those in mature milk samples. A very close correlation was found between the concentrations of organochlorine compounds in colostrum and mature milk (Spearman correlation coefficient r=0.94-0.98 for PCBs, and r=0.85-0.99 for organochlorine pesticides, p<0.001 for all compounds). The present study concludes that the use of colostrum samples provides a close estimate of the child's exposure to OCs in the early neonatal period and demonstrates that, despite the lower fat content, colostrum specimens are adequate to conduct OC analyses.     

Analysis of the toxicogenomic effects of exposure to persistent organic pollutants (POPs) in Slovakian girls: correlations between gene expression and disease risk

The chemical composition of persistent organic pollutants (POPs) in the environment is not uniform throughout the world, and these contaminants contain many structurally different lipophilic compounds. In a well-defined study cohort in the Slovak Republic, the POP chemicals present in the peripheral blood of exposed children were chemically analyzed. The chemical analysis data revealed that the relative concentration and profile of structurally different organic pollutants, including polychlorinated biphenyls (PCBs), 2,2′-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p′-DDE), 2,2′-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p′-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), may vary from individual to individual, even within the same exposure area. These chemicals can be broadly classified into two groups. The first group, the PCB congeners, primarily originated from industrial compounds and their byproducts. The second group of compounds originated from or was commonly used in the agricultural sector (e.g., DDT, HCB). The objective of this study was to examine the effects of the two POP exposure profiles on gene expression. For the study population, we selected pre-pubertal girls (mean age of 46.2 ± 1.4 months) with high POP concentrations in their blood (> 75% tile of total POP) and classified them in the high ‘PCB’ group when the total PCB concentration was significantly higher than the total concentration of other POP components and in the ‘Other Than PCB’ (OTP) group, when the total PCB concentration was significantly lower than the concentration of the other major POP constituents. A matched control group of girls (< 25% tile of total POP) was selected for comparison purpose (n = 5 per group). Our aims were to determine whether there were any common effects of high POP exposure at a toxicogenomic level and to investigate how exposure may affect physiological functions of the children in two different exposure scenarios. Global gene expression analysis using a microarray (Affymetrix Gene Chip Human genome U133 Plus 2.0 Array) platform was conducted on the total RNA of peripheral blood mononuclear cells from the girls. The results were analyzed by Partek GS, Louis, MI, which identified twelve genes (ATAD2B, BIVM, CD96, CXorf39, CYTH1 ETNK1, FAM13A, HIRA, INO80B, ODG1, RAD23B, and TSGA14) and two unidentified probe sets, as regulated differentially in both the PCB and OTP groups against the control group. The qRT-PCR method was used to validate the microarray results. The Ingenuity Pathway Analysis (IPA) software package identified the possible molecular impairments and disease risks associated with each gene set. Connective tissue disorders, genetic disorders, skeletal muscular disorders and neurological diseases were associated with the 12 common genes. The data therefore identified the potential molecular effects of POP exposure on a genomic level. This report underscores the importance of further study to validate the results in a random population and to evaluate the use of the identified genes as biomarkers for POP exposure.