Xenobiotic Detoxification Genes Research Articles

Polymorphism of xenobiotic biotransformation enzyme genes and their role in early pregnancy loss

Considering the progressive decrease in the number of women of fertile age, as well as children and adolescents, the primary medical and social task at the present stage is to preserve the reproductive health and life of women, preserving every desired pregnancy. The concept of demographic policy of the Russian Federation for the period until 2025 defines the global national goals, i.e. to increase the total fertility rate by 1.5 times, to reduce maternal and infant mortality by at least 2 times, and to improve the reproductive health of women, children and adolescents. Today every fifth desirable pregnancy ends in early loss, and the rate of miscarriage does not tend to decrease and, in fact, increases every year. Carriage of susceptibility or candidate genes can alter the course of biochemical processes in women and cause early pregnancy losses. According to the literature, the cytochrome P-450 gene (CYP1A1, CYP1B1), xenobiotic detoxification genes (GSTT1, GSTM1, GSTP1) and many others are recognized as candidate genes (genetic markers) associated with reproductive losses. Adverse pregnancy outcome is usually multifactorial; in turn, the combination of polymorphic variants of different candidate genes can increase the risk of early losses. A detailed study of the role of candidate genes with clarity and confirmation of the interest of candidate genes in the development of pregnancy loss is undeniable. In this regard, the interest of many researchers in studying the polymorphism of genes of the xenobiotic biotransformation enzyme system as one of the causal factors of pregnancy failure is understandable. The study of this group of genes is of particular relevance in regions with developed industry and high anthropogenic load. The article is devoted to the analysis of the existing data of foreign and domestic literature sources concerning the relationship between polymorphism of xenobiotic biotransformation system genes and reproductive losses.

Case-Control Study of the Association between Single Nucleotide Polymorphisms of Genes Involved in Xenobiotic Detoxification and Antioxidant Protection with the Long-Term Influence of Organochlorine Pesticides on the Population of the Almaty Region.

The association of genetic polymorphisms with the individual sensitivity of humans to the action of pesticide pollution is being actively studied in the world. The aim of this study was a molecular epidemiological analysis of candidate polymorphisms of genes involved in pesticide metabolism, detoxification, and antioxidant protection. Some of the selected polymorphisms also relate to susceptibility to cancer and cardiovascular, respiratory, and immune system diseases in individuals exposed to pesticides for a long time. For a case-control study of a unique cohort of people exposed to organochlorine pesticides for 10 years or more were chosen, a control cohort was selected that matched with the experimental group by the main population characteristics. PCR-PRLF and genome-wide microarray genotyping (GWAS) methods were used. We identified 17 polymorphisms of xenobiotic detoxification genes and 27 polymorphisms of antioxidant defense genes, which had a significantly high statistical association with the negative impact of chronic pesticide intoxication on human health. We also found 17 polymorphisms of xenobiotic detoxification genes and 12 polymorphisms of antioxidant defense genes that have a protective effect. Data obtained added to the list of potential polymorphisms that define a group at high risk or resistant to the negative effects of pesticides.

Cytochrome P450 Genes Expressed in Phasmatodea Midguts.

Simple SummaryCytochrome P450s are a group of detoxification enzymes found in all animals. They are highly diverse, with multiple copies of different families of these genes in individual organisms, especially those that need to digest chemically-defended foods, such as toxic plants. The stick insects are a group of leaf-feeding herbivores whose diets can include toxic species, such as Eucalyptus, so this study sought to identify what groups of cytochrome P450s are expressed in the digestive tracts of six species of stick insects and how they evolved. The results show a complement of detoxification genes comparable to or slightly more limited than those of other insects, except for multiple enzymes per species in the subfamily CYP15A1, while most insects will only have one enzyme in this group. The functions of these expanded enzyme groups should be investigated further.Cytochrome P450s (CYPs) are xenobiotic detoxification genes found in most eukaryotes, and linked in insects to the tolerance of plant secondary chemicals and insecticide resistance. The number and diversity of CYP clans, families, and subfamilies that an organism produces could correlate with its dietary breadth or specialization. This study examined the CYP diversity expressed in the midguts of six species of folivorous stick insects (Phasmatodea), to identify their CYP complement and see if any CYPs correlate with diet toxicity or specialization, and see what factors influenced their evolution in this insect order. CYP genes were mined from six published Phasmatodea transcriptomes and analyzed phylogenetically. The Phasmatodea CYP complement resembles that of other insects, though with relatively low numbers, and with significant expansions in the CYP clades 6J1, 6A13/14, 4C1, and 15A1. The CYP6 group is known to be the dominant CYP family in insects, but most insects have no more than one CYP15 gene, so the function of the multiple CYP15A1 genes in Phasmatodea is unknown, with neofunctionalization following gene duplication hypothesized. No correlation was found between CYPs and diet specialization or toxicity, with some CYP clades expanding within the Phasmatodea and others likely inherited from a common ancestor.

Remofuscin induces xenobiotic detoxification via a lysosome-to-nucleus signaling pathway to extend the Caenorhabditis elegans lifespan

Lipofuscin is a representative biomarker of aging that is generated naturally over time. Remofuscin (soraprazan) improves age-related eye diseases by removing lipofuscin from retinal pigment epithelium (RPE) cells. In this study, the effect of remofuscin on longevity in Caenorhabditis elegans and the underlying mechanism were investigated. The results showed that remofuscin significantly (p < 0.05) extended the lifespan of C. elegans (N2) compared with the negative control. Aging biomarkers were improved in remofuscin-treated worms. The expression levels of genes related to lysosomes (lipl-1 and lbp-8), a nuclear hormone receptor (nhr-234), fatty acid beta-oxidation (ech-9), and xenobiotic detoxification (cyp-34A1, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35C1, gst-28, and gst-5) were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. elegans with loss-of-function mutations (lipl-1, lbp-8, nhr-234, nhr-49, nhr-8, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A5, and gst-5), suggesting that these genes are associated with lifespan extension in remofuscin-treated C. elegans. In conclusion, remofuscin activates the lysosome-to-nucleus pathway in C. elegans, thereby increasing the expression levels of xenobiotic detoxification genes resulted in extending their lifespan.

Results of Studying Genotoxic Effects of Dioxins Depending on Polymorphisms of Xenobiotic Detoxification Genes and the Length of Service of Firefighters

Introduction: The work of firefighters is associated with a high risk to health and life. During firefighting, firemen are exposed to a combination of various factors, among which chemical agents rank first. Of all the toxic products of combustion, the most dangerous are genotoxic substances having a high cumulative effect and a very long clearance time, including dioxins and dioxin-like polychlorinated biphenyls generated during low-temperature combustion of organic chlorine compounds. Objective: To study karyopathological manifestations of the genotoxic effects of dioxins in firefighters, de¬pending on the length of service and various polymorphic variants of the xenobiotic detoxification genes. Materials and methods: The cytogenetic status of firefighters was assessed using an extended micronucleus test of buccal epithelium. The study was conducted in 2019–2022 involving 252 firefighters, 86 rescuers and other professionals. The risk of cytogenetic abnormalities in epitheliocytes was assessed using calculation methods and expressed as an index of accumulation of cytogenetic disorders. For each subject, two smears of buccal epithelium were prepared followed by the analysis of two thousand intact cells. Results: We noted an increase in the frequency of karyotype aberrations in buccal epithelial cells of firefighters compared to controls correlating with the length of service and dioxin concentrations in blood lipids. The analysis of the relationship between various polymorphic variants of xenobiotic detoxification genes, dioxins in blood lipids of firefighters, and the index of accumulation of cytogenetic damage showed that individuals with a combination of six genotypes (EPHX1 Tyr/Tyr, CYP1A1 A/A, GSTT1 I/I, GSTM1 I/I, GSTP1 A /A, and GSTP1 C/C) possessed xenobiotic detoxification enzymes with high activity and better resistance to karyotypic changes induced by genotoxicants. Conclusion: The levels of cytogenetic disorders established in the present study give evidence of adverse health effects of occupational exposure to toxic combustion products in firefighters of the State Fire Service of the Russian Ministry of Emergency Situations.

NHR-8 and P-glycoproteins uncouple xenobiotic resistance from longevity in chemosensory C. elegans mutants.

Longevity is often associated with stress resistance, but whether they are causally linked is incompletely understood. Here we investigate chemosensory-defective Caenorhabditis elegans mutants that are long-lived and stress resistant. We find that mutants in the intraflagellar transport protein gene osm-3 were significantly protected from tunicamycin-induced ER stress. While osm-3 lifespan extension is dependent on the key longevity factor DAF-16/FOXO, tunicamycin resistance was not. osm-3 mutants are protected from bacterial pathogens, which is pmk-1 p38 MAP kinase dependent, while TM resistance was pmk-1 independent. Expression of P-glycoprotein (PGP) xenobiotic detoxification genes was elevated in osm-3 mutants and their knockdown or inhibition with verapamil suppressed tunicamycin resistance. The nuclear hormone receptor nhr-8 was necessary to regulate a subset of PGPs. We thus identify a cell-nonautonomous regulation of xenobiotic detoxification and show that separate pathways are engaged to mediate longevity, pathogen resistance, and xenobiotic detoxification in osm-3 mutants.

Evidence for the Role of CYP51A and Xenobiotic Detoxification in Differential Sensitivity to Azole Fungicides in Boxwood Blight Pathogens

Boxwood blight, a fungal disease of ornamental plants (Buxus spp.), is caused by two sister species, Calonectria pseudonaviculata (Cps) and C. henricotiae (Che). Compared to Cps, Che is documented to display reduced sensitivity to fungicides, including the azole class of antifungals, which block synthesis of a key fungal membrane component, ergosterol. A previous study reported an ergosterol biosynthesis gene in Cps, CYP51A, to be a pseudogene, and RNA-Seq data confirm that a functional CYP51A is expressed only in Che. The lack of additional ergosterol biosynthesis genes showing significant differential expression suggests that the functional CYP51A in Che could contribute to reduced azole sensitivity when compared to Cps. RNA-Seq and bioinformatic analyses found that following azole treatment, 55 genes in Cps, belonging to diverse pathways, displayed a significant decrease in expression. Putative xenobiotic detoxification genes overexpressed in tetraconazole-treated Che encoded predicted monooxygenase and oxidoreductase enzymes. In summary, expression of a functional CYP51A gene and overexpression of predicted xenobiotic detoxification genes appear likely to contribute to differential fungicide sensitivity in these two sister taxa.

The transcriptome of anal papillae of Aedes aegypti reveals their importance in xenobiotic detoxification and adds significant knowledge on ion, water and ammonia transport mechanisms

The anal papillae of mosquito larvae are osmoregulatory organs in direct contact with the external aquatic environment that actively sequester ions and take up water in dilute freshwater. In the disease vector Aedes aegypti mechanisms of ion, water and ammonia transport have only been partially resolved. Furthermore, A. aegypti larvae are known to reside in high ammonia sewage and high salt brackish waters, and understanding of anal papillae function in these conditions is in its infancy. The objective of this study was to identify the complement of ion and water transport genes expressed by the anal papillae of freshwater larvae by sequencing their transcriptome, and comparing their expression in anal papillae of larvae abruptly transferred to brackish water for 24 h. Results identified a number of ion and water transport proteins, ammonia detoxifying enzymes, a full suite of xenobiotic detoxifying enzymes and transporters, and G-protein coupled receptors of specific hormones. We identified a marked increase in transcript and protein abundance of aquaporin AaAQP2 in the anal papillae with abrupt transfer to brackish water. We present an updated and more comprehensive model for ion and water transport with additional putative transporters for Na+ and Cl- uptake in the anal papillae. These are organs which are actively engaged in Na+, Cl- and water uptake and regulation when the aquatic larvae encounter fluctuating salinities over the course of their development. Furthermore the transcriptome of the anal papillae includes a full set of xenobiotic detoxification genes suggesting that these are important detoxification organs which is particularly important when larvae reside in polluted water.

Transcriptome Sequencing of the Striped Cucumber Beetle, Acalymma vittatum (F.), Reveals Numerous Sex-Specific Transcripts and Xenobiotic Detoxification Genes.

Acalymma vittatum (F.), the striped cucumber beetle, is an important pest of cucurbit crops in the contintental United States, damaging plants through both direct feeding and vectoring of a bacterial wilt pathogen. Besides providing basic biological knowledge, biosequence data for A. vittatum would be useful towards the development of molecular biopesticides to complement existing population control methods. However, no such datasets currently exist. In this study, three biological replicates apiece of male and female adult insects were sequenced and assembled into a set of 630,139 transcripts (of which 232,899 exhibited hits to one or more sequences in NCBI NR). Quantitative analyses identified 2898 genes differentially expressed across the male–female divide, and qualitative analyses characterized the insect’s resistome, comprising the glutathione S-transferase, carboxylesterase, and cytochrome P450 monooxygenase families of xenobiotic detoxification genes. In summary, these data provide useful insights into genes associated with sex differentiation and this beetle’s innate genetic capacity to develop resistance to synthetic pesticides; furthermore, these genes may serve as useful targets for potential use in molecular-based biocontrol technologies.

Evaluation of Blood Lipid Concentrations of Dioxins in Firefighters Depending on Polymorphic Variants of Xenobiotic Detoxification Genes

Summary. Background: The specifics of occupational activities of firefighters is determined by exposures to both fire hazards and a combination of occupational risk factors of various nature significantly exceeding their standard values. Adverse chemical exposures rank first due to unpredictable toxic effects of combustion products from burning synthetic polymers. Yet, the most dangerous are low-temperature fires emitting a wide range of air contaminants including highly lipophilic, bioaccumulative and persistent dioxins. The purpose of the research was to study the relationship between various polymorphic variants of xenobiotic detoxification genes and blood lipid concentrations of dioxins in firefighters. Materials and methods: We measured average dioxin concentrations in ambient air at different stages of firefighting and in blood lipids of firefighters with different length of service using the analytical method of gas chromatography–mass spectrometry (GC-MS). The cumulative effect of dioxins was estimated in relation to polymorphic variants of xenobiotic detoxification genes of the first and second phases of biotransformation by determining polymorphisms, the main research method being polymerase chain reaction (PCR). Results: High concentrations of dioxins measured in ambient air at all stages of firefighting and in blood lipids of firefighters with a significant correlation with work experience indicate that inhalation is one of the main routes of exposure to dioxins and that these chemicals are occupational risk factors for this professional group. The analysis of the relationship between various polymorphic variants of xenobiotic detoxification genes and blood lipid concentrations of dioxins in the firefighters showed a higher blood level of dioxins in carriers of minor alleles. Conclusions: Genotyping of firefighters and identification of carriers of minor alleles of xenobiotic detoxification genes may contribute to timely preventive and rehabilitation measures aimed at elimination of adverse health effects of occupational exposure to dioxins.

Influence of xenobiotic detoxication gene polymorphisms and experience on the level of accumulation of dioxins in Emercom of Russia employees

Relevance. Occupational activities of firefighters are considered extreme. Toxic combustion products are the most dangerous. Among these products, dioxins and dioxin-like compounds are particularly dangerous due to their ability to accumulate in the body.Intention is to analyze the content of toxic combustion products in atmospheric air during and after fires of various locations, as well as to evaluate dioxin concentrations in the blood plasma of employees of the Federal Firefighting Service of the Emercom of Russia, depending on the polymorphic variants of xenobiotic detoxification genes and professional experience.Methodology. To assess accumulation of dioxins in the body of firefighters with different polymorphic variants of xenobiotic detoxification genes, atmospheric air at different locations of fires was assessed for toxic combustion products. Accumulation of dioxins in the body of firefighters was analyzed depending on the polymorphisms of xenobiotic detoxification genes and work experience. 350 employees of the Federal Firefighting Service of the Emercom of Russia were examined, of them there were 234 firefighters and 116 supervisory staff involved in the investigations at the fire sites. The control group consisted of 82 rescue workers who were not directly involved in fire fighting. The examined individuals aged (32.2 ± 9.5) years.Results and Discussion. The data obtained indicate that high concentrations of dioxins in surface air at the fire site persist for more than 2 weeks, while the maximum permissible concentration is increased 4.5-10-fold. The highest concentration of dioxins is observed during fires in industrial enterprises and in residential buildings. According to the analysis of the dioxins in the blood of the Federal Firefighting Service employees and the control group, concentrations of individual chemical compounds among the employees of the Federal Firefighting Service were 2–7 times higher and 15 times higher in terms of the dioxin equivalent compared to the control group (p &lt;0.05). High concentrations of dioxins were also revealed in the blood of supervisory staff. Analysis of the dioxins in the blood of the staff of the Federal Firefighting Service, EMERCOM of Russia showed that increased length of service correlated with dioxin concentrations in the blood: variations in chemical compounds reached 2.3–6.8 times (p &lt;0.05) between those with 0–1 year vs 6 years or more experience and 1.3–1.7 times (p &lt;0.05) between those with 2–5 years vs 6 years and more experience. Concentrations of dioxins in the blood plasma of employees of the Federal Firefighting Service of the Emercom of Russia were assessed depending on the polymorphic variants of xenobiotic detoxification genes and professional experience. A group of individuals carrying the combination of the EPHX1 Tyr / Tyr, CYP1A1 A / A, GSTT1 I / I, GSTM1 I / I, GSTP1 A / A, GSTP1 C / C genotypes was revealed: their dioxin concentrations in the blood were as low as 25% of that among other groups despite length of service.Conclusion Genotyping of firefighters will help arrange timely measures to detoxify dioxins, especially in carriers of minor alleles of xenobiotic biotransformation genes, in order to reduce morbidity and increase professional longevity.

Gene family expansion of pinewood nematode to detoxify its host defence chemicals.

Gene gain/loss in the context of gene family dynamics plays an important role in evolutionary processes as organisms, particularly invasive species, adapt to new environments or niches. One notable example of this is the duplication of digestive proteases in some parasitic insects and helminths to meet nutritional requirements during animal parasitism. However, whether gene family expansion participates in the adaptation of a plant parasite nematode to its host remains unknown. Here, we compared the newly sequenced genomes of the pinewood nematode, Bursaphelenchus xylophilus, with the genomes of free-living, animal-parasitic and plant-parasitic nematodes. The results showed gene expansions occurring in 51 gene families in B. xylophilus, especially in xenobiotic detoxification pathways, including flavin monooxygenase (FMO), cytochrome P450 (CYP450), short chain dehydrogenase (SDR), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST). Although a majority of these expansions probably resulted from gene duplications, nine ADH genes were potentially acquired by horizontal gene transfer (HGT) from fungi. From the transcriptomes of B. xylophilus treated with pine saplings and terpenes, candidate xenobiotic detoxification genes were identified. We propose that host defence chemicals led to gene family expansions of xenobiotic detoxification pathways in B. xylophilus facilitating its survival in pine resin ducts. This study contributes to a better understanding of how a parasitic nematode adapts to its host.

Dose Dependence of Hypermethylation of Gene Promoters in Blood Leukocytes in Humans Occupationally Exposed to External γ-Radiation

Abstract—A study of promoter hypermethylation of cell cycle (RASSF1A, p16/INK4A, p14/ARF, p53, АТМ), xenobiotic detoxification (GSTP1), antioxidant defense (SOD3), and estrogen receptor (ESR1) genes in blood leukocytes of 88 nuclear industry workers from the Mayak facility (53–86 years old at sampling) exposed to prolonged external γ-radiation was carried out. Accumulated doses to red bone marrow (RBM) ranged from 0.2 to 2.95 Gy. The time between the end of work with radiation and blood sampling was on average 15.95 ± 1.22 years. Fifty unirradiated residents of Ozyorsk matched by age to the exposed group were enrolled as a control group. Promoter hypermethylation was analyzed using methylation-sensitive polymerase chain reaction (PCR) assay. The trend towards dependence of promoter hypermethylation of p14/ARF and RASSFA genes on age rather than radiation exposure (logistic regression: p = 0.072) confirms previous results. The frequency of individuals with promoter methylation of at least one of the following six genes: p16/INK4A, GSTP1, р53, АТМ,SOD3,ESR1, in irradiated group was significantly higher than in the control group (62.5 versus 34%, respectively, p = 0.001, OR = 3.24, 95% CI 1.56–6.69). A significantly elevated frequency of individuals with hypermethylated СpG islands in GSTP1 and SOD3 promoters was revealed among exposed subjects compared to the control group (p = 0.014 and p = 0.021, respectively). A statistically significant association between the cumulative dose and the number of methylated promoters was revealed (r = 0.304, р = 3.2 × 10–4). Therefore, the dose-dependent hypermethylation of CpG islands in gene promoters that is revealed in blood leukocytes long term after external exposure to γ-radiation was found.

Epigenome modulated xenobiotic detoxification pathways control DMBA-induced breast cancer in agouti Avy/a mice

ABSTRACTEnvironmental xenobiotics with genotoxic activity are carcinogenic. However, individual differences in the susceptibility to xenobiotic-induced breast cancer remain unclear. Since epigenetic modifications could control the expression of metabolic enzymes, our goal was to determine whether epigenome modulated metabolic networks determine susceptibility to xenobiotic-induced breast cancer. The effect of epigenetic background on predisposition to carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer development and progression was assessed using the Avy/a mouse model. In a randomized block design, 22 isogenic Avy/a (8 yellow, 7 slightly mottled, 7 pseudoagouti) and 8 wild type non-agouti (a/a black) age matched female mice were subjected to DMBA (30 mg/kg per mouse weight) once a week for 6 weeks to induce breast cancer. Compared to pseudoagouti littermates, a significant decrease in tumour latency with increased tumour burden was observed in slightly mottled and yellow littermates (p ≤ 0.05). However, tumour latency and tumour burden were similar in non-agouti a/a mice and Avy/a cohorts. Network analysis of differentially expressed liver genes identified altered metabolic gene networks among agouti phenotypes. Consequently, in HPLC analyses, DMBA metabolites were significantly increased in Avy/a pseudoagouti mice (p ≤ 0.05). Relative to Avy/a slightly mottled, Avy/a yellow and non-agouti a/a black mice, DMBA metabolites increased nine-, eight-, and four-fold, respectively, in Avy/a pseudoagouti mice. In agreement with this, seven phase 2 xenobiotic detoxification genes were significantly upregulated in Avy/a pseudoagouti mice (p ≤ 0.05). The Results from this study suggest that epigenome modulation of xenobiotic detoxification pathways may control xenobiotic-induced breast cancer susceptibility in Avy/a mice.

A Xenobiotic Detoxification Pathway through Transcriptional Regulation in Filamentous Fungi.

ABSTRACTFungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA-seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of-function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages.

Comparison of gene expression profiles in the aquatic midge (Chironomus tentans) larvae exposed to two major agricultural pesticides

We developed a high-resolution expression microarray based on 2456 unique transcripts from a cDNA library of the aquatic midge (Chironomus tentans). By using the microarray, we detected that 146, 434 and 243 genes were differentially expressed after C. tentans larvae were exposed to chlorpyrifos (organophosphate insecticide) at 0.1 and 0.5 μg/L, and atrazine (triazine herbicide) at 1000 μg/L, respectively, for 48 h. The number of differentially expressed genes in the larvae exposed to chlorpyrifos at 0.5 μg/L was three times of that in the larvae exposed to chlorpyrifos at 0.1 μg/L. Among the differentially expressed genes in response to chlorpyrifos exposures, 76 genes showed significant Blast hits, and among them 42 were in common between the chlorpyrifos and atrazine exposures. In 19 differentially expressed xenobiotic detoxification genes, 16 were significantly up-regulated in the larvae exposed to chlorpyrifos and/or atrazine. Two cytochrome P450 genes (CtCYP6EV1 and CtCYP4DG2) were specifically up-regulated by chlorpyrifos, whereas three cytochrome P450 genes (CtCYP4DG1, CtCYP6EX3 and CtCYP6EV3) were specifically up-regulated by atrazine. Our results showed that chlorpyrifos exposures even at low concentrations can lead to significant changes in gene expression. The significant transcriptional responses are likely attributed to larval intoxication by the insecticide. These results not only support our previous studies in which candidate gene approaches were used, but also can potentially help develop specific molecular markers for monitoring pesticide exposures in non-target organisms in aquatic systems.

Role of Glutathione-S-Transferase Family Genes in Male Infertility.

Polymorphisms of xenobiotic detoxification genes GSTT1 and GSTM1 and activity of glutathione system enzymes were studied in men with infertility. The frequency of deletion variant of GSTT1 gene in men with infertility was by 2 times higher than in fertile men. Deletion variant of GSTM1 gene was 1.4-fold more frequent in infertile men than in fertile men. Complete deletion of two genes was found in 19% men with infertility and only in 6% fertile men. The balance of activity of glutathione system enzymes essential for the effective detoxification of exogenous xenobiotics and toxic endogenous metabolites was impaired in infertile carriers of deletion variants of genes. Our results suggest that adaptation mechanisms are disordered in infertile men.

Search for Common Molecular Genetic Markers of Nosocomial Pneumonia and Acute Respiratory Distress Syndrome

Genetic predisposition partially accounts for the clinical variability of the course of an infectious process. A total of 750 people, including 419 (81.1%) male patients aged 42.9±0.9 years, admitted to the clinics of the V. A. Negovsky Research Institute of General Reanimatology (Moscow, Russia), were genotyped to establish the influence of genetic factors on their susceptibility to critical conditions. Materials and methods. Tetra-primer allele-specific polymerase chain reaction was used to investigate single-nucleotide polymorphisms (SNP) in the xenobiotic detoxification and oxidative stress genes (CYP1A1 (three sites), AhR, ABCB1, SOD2, GCLC and CAT) and in the vascular homeostasis genes (ACE, AGT, AGTR1, NOS3, VEGFα and MTHFR). Results. A total of 268 nosocomial pneumonia (NP) cases were registered in a patient group. Individual SNP analysis has shown that among the patients with NP the risk of acute respiratory distress syndrome (ARDS) is associated with the carriage of the following genotypes: CYP1A1 rs2606345-Т/Т (p=0.0027, OR=2.38; 95% CI: 1.35—4.17) and AhRrs2066853-G/A-A/A (p=0.0012, OR=2.94; 95% CI: 1.54—5.60). The frequency of the C allele of the AGTR1 gene (re5186) was much higher among the survivors (in the NP group). The assessment of a multiplicative genetic model of genes that had demonstrated the highest single-locus effects because of a ARDS risk, as well as in-hospital mortality, could establish the complex genotype including a combination of risky alleles of the detoxi- fication and vascular homeostasis genes (CYP1A1 rs2606345-T — AhR rs2066853-A and ACE rs4340-D — AGT rs699-C — AGTR1 rs5186-C), which was associated with the increased risk of both NP and ARDS, as well as with the likelihood of a fatal outcome. Conclusion. An understanding of the risk factors of NP and ARDS will aid in predicting the outcome of the underlying disease and in developing possible preventive measures.

The genomes of two key bumblebee species with primitive eusocial organization.

BackgroundThe shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats.ResultsWe report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits.ConclusionsThese two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0623-3) contains supplementary material, which is available to authorized users.

A novel kinase regulates dietary restriction-mediated longevity in Caenorhabditis elegans.

Although dietary restriction (DR) is known to extend lifespan across species, from yeast to mammals, the signalling events downstream of food/nutrient perception are not well understood. In Caenorhabditis elegans, DR is typically attained either by using the eat-2 mutants that have reduced pharyngeal pumping leading to lower food intake or by feeding diluted bacterial food to the worms. In this study, we show that knocking down a mammalian MEKK3-like kinase gene, mekk-3 in C. elegans, initiates a process similar to DR without compromising food intake. This DR-like state results in upregulation of beta-oxidation genes through the nuclear hormone receptor NHR-49, a HNF-4 homolog, resulting in depletion of stored fat. This metabolic shift leads to low levels of reactive oxygen species (ROS), potent oxidizing agents that damage macromolecules. Increased beta-oxidation, in turn, induces the phase I and II xenobiotic detoxification genes, through PHA-4/FOXA, NHR-8 and aryl hydrocarbon receptor AHR-1, possibly to purge lipophilic endotoxins generated during fatty acid catabolism. The coupling of a metabolic shift with endotoxin detoxification results in extreme longevity following mekk-3 knock-down. Thus, MEKK-3 may function as an important nutrient sensor and signalling component within the organism that controls metabolism. Knocking down mekk-3 may signal an imminent nutrient crisis that results in initiation of a DR-like state, even when food is plentiful.