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BackgroundSpecific toxic compounds, such as polycyclic aromatic hydrocarbons (PAHs) and their metabolites, may affect the inhalation injury (INHI) grade, patients' status, and prognosis for recovery. This pilot prospective study aimed to: i) evaluate the suitability of bronchoalveolar lavage (BAL) for determination of PAHs in the LRT and of urine for determination of hydroxylated metabolites (OH-PAHs) in patients with INHI, ii) describe the dynamic changes in the levels of these toxic compounds, and iii) correlate these findings with clinical variables of the patients with INHI.MethodsThe BAL and urine samples from 10 patients with INHI were obtained on Days 1, 3, 5, 7, and 14 of hospitalization, if possible, and PAHs (BAL) and OH-PAHs (urine) were analyzed using chromatographic methods (GC-MS and HPLC).ResultsConcentrations of analyzed PAHs were in most cases and time points below the limit of quantification in BAL samples. Nine OH-PAHs were detected in the urine samples; however, their concentrations sharply decreased within the first three days of the hospitalization. On Day 14, the total amount of OH-PAHs in urine was higher in surviving patients with High-grade INHI (≥3) than in those with Low-grade INHI (ConclusionsBAL samples are not suitable for the analysis of PAHs. However, the OH-PAHs levels in urine can be measured reliably and were correlated with several clinical variables. Moreover, High-grade INHI was associated with higher total concentrations of OH-PAHs in urine.

The knowledge of the effects of organophosphate flame retardants on children’s neurodevelopment is limited. The purpose of the present research is to evaluate the association between exposure to organophosphate flame retardants and children’s neurodevelopment in two European cohorts involved in the Human Biomonitoring Initiative Aligned Studies. The participants were school-aged children belonging to the Odense Child Cohort (Denmark) and the PCB cohort (Slovakia). In each cohort, the children’s neurodevelopment was assessed through the Full-Scale Intelligence Quotient score of the Wechsler Intelligence Scale for Children, using two different editions. The children’s urine samples, collected at one point in time, were analyzed for several metabolites of organophosphate flame retardants. The association between neurodevelopment and each organophosphate flame retardant metabolite was explored by applying separate multiple linear regressions based on the approach of MM-estimation in each cohort. In the Danish cohort, the mean ± standard deviation for the neurodevelopment score was 98 ± 12; the geometric mean (95% confidence interval (95% CI)) of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) standardized by creatinine (crt) was 0.52 µg/g crt (95% CI = 0.49; 0.60), while that of diphenyl phosphate (DPHP) standardized by crt was 1.44 µg/g crt (95% CI = 1.31; 1.58). The neurodevelopment score showed a small, negative, statistically imprecise trend with BDCIPP standardized by crt (β = −1.30; 95%CI = −2.72; 0.11; p-value = 0.07) and no clear association with DPHP standardized by crt (β = −0.98; 95%CI = −2.96; 0.99; p-value = 0.33). The neurodevelopment score showed a negative trend with BDCIPP (β = −1.42; 95% CI = −2.70; −0.06; p-value = 0.04) and no clear association with DPHP (β = −1.09; 95% CI = −2.87; 0.68; p-value = 0.23). In the Slovakian cohort, the mean ± standard deviation for the neurodevelopment score was 81 ± 15; the geometric mean of BDCIPP standardized by crt was 0.18 µg/g crt (95% CI = 0.16; 0.20), while that of DPHP standardized by crt was 2.24 µg/g crt (95% CI = 2.00; 3.52). The association of the neurodevelopment score with BDCIPP standardized by crt was −0.49 (95%CI = −1.85; 0.87; p-value = 0.48), and with DPHP standardized by crt it was −0.35 (95%CI = −1.90; 1.20; p-value = 0.66). No clear associations were observed between the neurodevelopment score and BDCIPP/DPHP concentrations that were not standardized by crt. No clear associations were observed with bis(1-chloro-2-propyl) phosphate (BCIPP) in either cohort, due to the low detection frequency of this compound. In conclusion, this study provides only limited evidence of an inverse association between neurodevelopment and exposure to BDCIPP and DPHP. The timing of exposure and effect modification of other organophosphate flame retardant metabolites and other substances should be the subject of further investigations that address this scientific hypothesis.

Abstract Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss‐of‐function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia‐based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co‐receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

Over the last decades, concern has arisen worldwide about the negative impacts of pesticides on the environment and human health. Exposure via dust ingestion is important for many chemicals but poorly characterized for pesticides, particularly in Africa. We investigated the spatial and temporal variations of 30 pesticides in dust and estimated the human exposure via dust ingestion, which was compared to inhalation and soil ingestion. Indoor dust samples were collected from thirty-eight households and two schools located in two agricultural regions in South Africa and were analyzed using high-performance liquid chromatography coupled to tandem mass spectrometry. We found 10 pesticides in dust, with chlorpyrifos, terbuthylazine, carbaryl, diazinon, carbendazim, and tebuconazole quantified in >50% of the samples. Over seven days, no significant temporal variations in the dust levels of individual pesticides were found. Significant spatial variations were observed for some pesticides, highlighting the importance of proximity to agricultural fields or of indoor pesticide use. For five out of the nineteen pesticides quantified in dust, air, or soil (i.e., carbendazim, chlorpyrifos, diazinon, diuron and propiconazole), human intake via dust ingestion was important (>10%) compared to inhalation or soil ingestion. Dust ingestion should therefore be considered in future human exposure assessment to pesticides.

Exposure to bisphenols is related to negative effects on male reproduction. The bisphenols exposure is associated with several modes of action including negative impact on the blood–testis barrier (BTB) in testes or direct effect on spermatozoa. Bisphenols have been detected in human seminal plasma, but the possible mechanism of seminal transfer of bisphenols is not clear. Some authors consider the transfer through the blood–testis barrier to be crucial. Therefore, in this work, we compared normozoospermic men and men after vasectomy who have interrupted vas deferens and their ejaculate does not contain testicular products. We measured the concentration of bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) in the urine and seminal plasma of these men using liquid chromatography tandem mass spectrometry (LC/MSMS). We found that the ratio of urinary and seminal plasma content of bisphenols did not differ in normozoospermic men or men after vasectomy. From the obtained data, it can be concluded that the pathways of transport of bisphenols into seminal plasma are not primarily through the testicular tissue, but this pathway is applied similarly to other routes of transmission by a corresponding ejaculate volume ratio. To a much greater extent than through testicular tissue, bisphenols enter the seminal plasma mainly as part of the secretions of the accessory glands.

Fish are exposed to numerous stressors in the environment including pollution, bacterial and viral agents, and toxic substances. Our study with common carps leveraged an integrated approach (i.e., histology, biochemical and hematological measurements, and analytical chemistry) to understand how cyanobacteria interfere with the impact of a model viral agent, Carp sprivivirus (SVCV), on fish. In addition to the specific effects of a single stressor (SVCV or cyanobacteria), the combination of both stressors worsens markers related to the immune system and liver health. Solely combined exposure resulted in the rise in the production of immunoglobulins, changes in glucose and cholesterol levels, and an elevated marker of impaired liver, alanine aminotransferase (ALT). Analytical determination of the cyanobacterial toxin microcystin-LR (MC-LR) and its structurally similar congener MC-RR and their conjugates showed that SVCV affects neither the levels of MC in the liver nor the detoxification capacity of the liver. MC-LR and MC-RR were depurated from liver mostly in the form of cysteine conjugates (MC-LR-Cys, MC-RR-Cys) in comparison to glutathione conjugates (LR-GSH, RR-GSH). Our study brought new evidence that cyanobacteria worsen the effect of viral agents. Such inclusion of multiple stressor concept helps us to understand how and to what extent the relevant environmental stressors co-influence the health of the fish population.

Abstract Cyclin-dependent kinases (CDKs) are key regulators of both cell cycle progression and transcription. Since dysregulation of CDKs is a frequently occurring event driving tumorigenesis, CDKs have been tested extensively as targets for cancer therapy. Cyclin-dependent kinase 12 (CDK12) is a transcription-associated kinase which participates in various cellular processes, including DNA damage response, development and cellular differentiation, as well as splicing and pre-mRNA processing. CDK12 mutations and amplification have been recently reported in different types of malignancies, including loss-of-function mutations in high-grade serous ovarian carcinomas, and that has led to assumption that CDK12 is a tumor suppressor. On the contrary, CDK12 overexpression in other tumors suggests the possibility that CDK12 has oncogenic properties, similarly to other transcription-associated kinases. In this review, we discuss current knowledge concerning the role of CDK12 in ovarian and breast tumorigenesis and the potential for chemical inhibitors of CDK12 in future cancer treatment.

Congenital heart defects, dysmorphic facial features and intellectual developmental disorders (CHDFIDD) syndrome in humans was recently associated with mutation in CDK13 gene. In order to assess the loss of function of Cdk13 during mouse development, we employed gene trap knock-out (KO) allele in Cdk13 gene. Embryonic lethality of Cdk13-deficient animals was observed by the embryonic day (E) 16.5, while live embryos were observed on E15.5. At this stage, improper development of multiple organs has been documented, partly resembling defects observed in patients with mutated CDK13. In particular, overall developmental delay, incomplete secondary palate formation with variability in severity among Cdk13-deficient animals or complete midline deficiency, kidney failure accompanied by congenital heart defects were detected. Based on further analyses, the lethality at this stage is a result of heart failure most likely due to multiple heart defects followed by insufficient blood circulation resulting in multiple organs dysfunctions. Thus, Cdk13 KO mice might be a very useful model for further studies focused on delineating signaling circuits and molecular mechanisms underlying CHDFIDD caused by mutation in CDK13 gene.

Despite the fact that the occurrence of polycyclic aromatic hydrocarbons (PAHs) in the atmospheric environment has been studied for decades the photochemistry, deposition and, consequently, the long-range transport potential (LRTP) are not well understood. The reason is gas-particle partitioning (GPP) in the aerosol, its sensitivity to temperature and particulate phase composition, and sampling artefacts', and reactivity's sensitivities towards particulate phase composition. Furthermore, most PAHs are subject to re-volatilisation upon deposition to surfaces (multihopping). Levels and sources of 2-6-ring unsubstituted PAHs were studied in remote environments of Europe, Africa and Antarctica. Global atmospheric transport and fate of 3-5-ring PAHs were simulated under various scenarios of photochemistry and GPP. GPP influences drastically the atmospheric lifetime, compartmental distributions and the LRTP of PAH. Mid latitude emissions seem to reach the Arctic but not the Antarctic.

A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination–mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.

Although cyanobacterial blooms and cyanotoxins represent a worldwide-occurring phenomenon, there are large differences among different countries in cyanotoxin-related human health risk assessment, management practices and policies. While national standards, guideline values and detailed regulatory frameworks for effective management of cyanotoxin risks have been implemented in many industrialized countries, the extent of cyanobacteria occurrence and cyanotoxin contamination in certain geographical regions is under-reported and not very well understood. Such regions include major parts of tropical West and Central Africa, a region constisting of more than 25 countries occupying an area of 12 million km2, with a total population of 500 milion people. Only few studies focusing on cyanotoxin occurrence in this region have been published so far, and reports dealing specifically with cyanotoxin contamination in drinking water are extremely scarce. In this study, we report seasonal data on cyanobacteria and microcystin (MC) contamination in drinking water reservoirs and adjacent treatment plants located in Ghana, West Africa. During January-June 2005, concentrations of MCs were monitored in four treatment plants supplying drinking water to major metropolitan areas in Ghana: the treatment plants Barekese and Owabi, which serve Kumasi Metropolitan Area, and the plants Kpong and Weija, providing water for Accra-Tema Metropolitan Area. HPLC analyses showed that 65% samples of raw water at the intake of the treatment plants contained intracellular MCs (maximal detected concentration was 8.73 µg L-1), whereas dissolved toxins were detected in 33% of the samples. Significant reduction of cyanobacterial cell counts and MC concentrations was achieved during the entire monitoring period by the applied conventional water treatment methods (alum flocculation, sedimentation, rapid sand filtration and chlorination), and MC concentration in the final treated water never exceeded 1 µg L-1 (WHO guideline limit for MCs in drinking water). However, cyanobacterial cells (93-3,055 cell mL-1) were frequently found in the final treated water and intracellular MCs were detected in 17% of the samples (maximal concentration 0.61 µg L-1), while dissolved MCs were present in 14% of the final treated water samples (maximal concentration 0.81 µg L-1). It indicates a borderline efficiency of the water treatment, thus MC concentrations in drinking water might exceed the WHO guideline limit if the treatment efficiency gets compromised. In addition, MC concentrations found in the raw water intake might represent significant human health risks for people living in areas with only a limited access to the treated or underground drinking water.

In spite of substantial research on health and the ecological risks associated with cyanobacterial toxins in the past decades, the understanding of the natural dynamics and variability of toxic cyanobacterial blooms is still limited. Herein, the results of long term monitoring 1998–1999/2001–2008 of three reservoirs (Vír, Brno and Nové Mlýny, Chech Republic), where toxic blooms develop annually, are reported. These three reservoirs provide a unique model because they are interconnected by the Svratka River, which allows possible transfer of phytoplankton as well as toxins from one reservoir to another. The frequency of the occurrence and dominance of the major cyanobacterial taxa Microcystis aeruginosa did not change during the investigated period but substantial variability was observed in the composition of other phytoplankton. Although absolute concentrations of the studied toxins (microcystins) differed among the reservoirs, there were apparent parallel trends. For example, during certain years, the microcystin concentrations were systematically elevated in all three studied reservoirs. Furthermore, the concentration profiles in the three sites were also correlated (parallel trends) within individual seasons based on monthly sampling. Microcystin-LR, a variant for which the World Health Organization has recommended a guideline value, formed only about 30–50 % of the total microcystins. This is of importance, especially in the Vír reservoir that serves as a drinking water supply. The maxima in the cell-bound microcystins (intracellular; expressed per dry weight biomass) generally preceded the maxima of total microcystins (expressed per volume of water sample). Overall, the maximum concentration in the biomass (all three reservoirs, period 1993–2005) was 6.1 mg g-1 dry weight and the median values were in the range 0.065–2.3 mg g-1 dry weight. These are generally high concentrations in comparison with both Czech Republic and worldwide reported data. The present data revealed substantial variability of both toxic cyanobacteria and their peptide toxins that should be reflected by detailed monitoring programs.