A Nano-sized Dose of Toxicology: Elucidating the Disconnect Between Nanomaterial Dosimetry and Biological Effects

Nanotechnologies continue to permeate a multitude of industries, with diverse applications ranging from pesticides to fuel additives. The unusual behavior of nanomaterials that drives their innovation also complicates the job of toxicologists tasked with assessing their potential environmental and public health impacts. This dissertation investigates the underlying reasons for uncertainty associated with the biological effects of nanomaterials. Chapter 2 and Chapter 3 focus on nanoparticles present in commercially available pesticide formulations and assess how particle size influences the environmental risk of a pesticide’s active ingredient. These studies reveal a size-specific effect on the toxicity of the nanoparticles despite normalized concentrations of active ingredient and highlight the potential for nanoparticles to mask the hydrophobic behavior of some chemicals. In Chapters 4 and 5, the focus shifts to soybeans and their microbiome as they respond to soils amended with cerium oxide nanoparticles. Utilizing metagenomic software to analyze large data sets and predict changes in ecological functionality, these companion chapters correlate plant growth with bacterial community structure and emphasize the atypical dose-response relationship of nanoparticles in terrestrial systems. Further, they address importance of acknowledging the difference between pristine and aged nanoparticle exposures. This body of work demonstrates the capacity for nanomaterials to confound toxicological assessment if the disconnect between nanomaterial dosimetry and biological response is not accounted for

The growth and hydrodynamic collapse of a protoplanet envelope

We have conducted three-dimensional self-gravitating radiation hydrodynamical models of gas accretion onto high mass cores (15-33 Earth masses) over hundreds of orbits. Of these models, one case accretes more than a third of a Jupiter mass of gas, before eventually undergoing a hydrodynamic collapse. This collapse causes the density near the core to increase by more than an order of magnitude, and the outer envelope to evolve into a circumplanetary disc. A small reduction in the mass within the Hill radius (R_H) accompanies this collapse as a shock propagates outwards. This collapse leads to a new hydrostatic equilibrium for the protoplanetary envelope, at which point 97 per cent of the mass contained within the Hill radius is within the inner 0.03 R_H which had previously contained less than 40 per cent. Following this collapse the protoplanet resumes accretion at its prior rate. The net flow of mass towards this dense protoplanet is predominantly from high latitudes, whilst at the outer edge of the circumplanetary disc there is net outflow of gas along the midplane. We also find a turnover of gas deep within the bound envelope that may be caused by the establishment of convection cells.Comment: 16 pages, 16 figures. Accepted for publication in MNRA

The Florey Adelaide Male Ageing Study (FAMAS): Design, procedures & participants

<p>Abstract</p> <p>Background</p> <p>The Florey Adelaide Male Ageing Study (FAMAS) examines the reproductive, physical and psychological health, and health service utilisation of the ageing male in Australia. We describe the rationale for the study, the methods used participant response rates, representativeness and attrition to date.</p> <p>Methods</p> <p>FAMAS is a longitudinal study involving approximately 1200 randomly selected men, aged 35–80 years and living in the north – west regions of Adelaide. Respondents were excluded at screening if they were considered incapable of participating because of immobility, language, or an inability to undertake the study procedures. Following a telephone call to randomly selected households, eligible participants were invited to attend a baseline clinic measuring a variety of biomedical and socio-demographic factors. Beginning in 2002, these clinics are scheduled to reoccur every five years. Follow-up questionnaires are completed annually. Participants are also invited to participate in sub-studies with selected collaborators.</p> <p>Results</p> <p>Of those eligible to participate, 45.1% ultimately attended a clinic. Non-responders were more likely to live alone, be current smokers, have a higheevalence of self-reported diabetes and stroke, and lower levels of hypercholesterolemia. Comparisons with the Census 2001 data showed that participants matched the population for most key demographics, although younger groups and never married men were under-represented and elderly participants were over-represented. To date, there has been an annual loss to follow-up of just over 1%.</p> <p>Conclusion</p> <p>FAMAS allows a detailed investigation into the effects of bio-psychosocial and behavioural factors on the health and ageing of a largely representative group of Australian men.</p

Systematic Evaluation of Factors Influencing ChIP-Seq Fidelity

We performed a systematic evaluation of how variations in sequencing depth and other parameters influence interpretation of Chromatin immunoprecipitation (ChIP) followed by sequencing (ChIP-seq) experiments. Using Drosophila S2 cells, we generated ChIP-seq datasets for a site-specific transcription factor (Suppressor of Hairy-wing) and a histone modification (H3K36me3). We detected a chromatin state bias, open chromatin regions yielded higher coverage, which led to false positives if not corrected and had a greater effect on detection specificity than any base-composition bias. Paired-end sequencing revealed that single-end data underestimated ChIP library complexity at high coverage. The removal of reads originating at the same base reduced false-positives while having little effect on detection sensitivity. Even at a depth of ~1 read/bp coverage of mappable genome, ~1% of the narrow peaks detected on a tiling array were missed by ChIP-seq. Evaluation of widely-used ChIP-seq analysis tools suggests that adjustments or algorithm improvements are required to handle datasets with deep coverage

Genome-Wide Tissue-Specific Occupancy of the Hox Protein Ultrabithorax and Hox Cofactor Homothorax in Drosophila

The Hox genes are responsible for generating morphological diversity along the anterior-posterior axis during animal development. The Drosophila Hox gene Ultrabithorax (Ubx), for example, is required for specifying the identity of the third thoracic (T3) segment of the adult, which includes the dorsal haltere, an appendage required for flight, and the ventral T3 leg. Ubx mutants show homeotic transformations of the T3 leg towards the identity of the T2 leg and the haltere towards the wing. All Hox genes, including Ubx, encode homeodomain containing transcription factors, raising the question of what target genes Ubx regulates to generate these adult structures. To address this question, we carried out whole genome ChIP-chip studies to identify all of the Ubx bound regions in the haltere and T3 leg imaginal discs, which are the precursors to these adult structures. In addition, we used ChIP-chip to identify the sites bound by the Hox cofactor, Homothorax (Hth). In contrast to previous ChIP-chip studies carried out in Drosophila embryos, these binding studies reveal that there is a remarkable amount of tissue- and transcription factor-specific binding. Analyses of the putative target genes bound and regulated by these factors suggest that Ubx regulates many downstream transcription factors and developmental pathways in the haltere and T3 leg. Finally, we discovered additional DNA sequence motifs that in some cases are specific for individual data sets, arguing that Ubx and/or Hth work together with many regionally expressed transcription factors to execute their functions. Together, these data provide the first whole-genome analysis of the binding sites and target genes regulated by Ubx to specify the morphologies of the adult T3 segment of the fly

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Geneenvironment interactions (G x E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G x E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G x E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G x E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant GxBMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103-14. ©2016 AACR

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development