Michael Fenech - Academia.edu (original) (raw)

Papers by Michael Fenech

Food Chemistry, 2013

Three commercially grown native herbs unique to Australia, Tasmannia pepper leaf (Tasmannia lance... more Three commercially grown native herbs unique to Australia, Tasmannia pepper leaf (Tasmannia lanceolata R. Br., Winteracea; TPL), anise myrtle (Syzygium anisatum Vickery, Craven & Biffen, Myrtaceae; AM) and lemon myrtle (Backhousia citriodora F. Muell, Myrtaceae; LM) as well as a reference sample bay leaf (Laurus nobilis L., Lauraceae; BL) were examined for potential cytoprotective properties. All native herbs exhibited greater cellular antioxidant activity as measured by the cellular antioxidant activity (CAA) assay than bay leaf and reduced the hydrogen peroxide (H 2 O 2 ) induced death of hepatocellular carcinoma (HepG2) cells by 25-50%. All herb extracts reduced the proliferation of colon (HT-29; IC 50 = 0.75-1.39 mg/ml), stomach (AGS; IC 50 = 0.59-1.88 mg/ml), bladder (BL13; IC 50 = 0.56-1.12 mg/ml) and liver (HepG2; IC 50 = 0.38-1.36 mg/ml) cancer cells. No significant reduction of cell viability of non-transformed colon (CCD-18Co; IC 50 > 2.0 mg/ml) and mixed stomach and intestine (Hs 738.St/Int; IC 50 > 2.0 mg/ml) cells was observed. Flow cytometry analysis and the results of the cytokinesis block micronucleus cytome (CBMNCyt) assay conducted with respectively, promyelocytic leukaemia (HL-60) and colon adenocarcinoma (HT-29) cells suggest an increase in apoptosis following treatment with the herb extracts. The occurrence of apoptotic cells coincided with an increase in caspase-3 enzyme activity. The results of the CBMNCyt assay suggested no direct DNA damage in colon adenocarcinoma (HT-29) cells as a result of treatment with all extracts, applied at final concentrations of 0.5 and 1.0 mg/ml. Crown

Environmental and molecular mutagenesis, Jan 6, 2015

The relationship between particle size and cytogenotoxicity of ZnO particles was systematically s... more The relationship between particle size and cytogenotoxicity of ZnO particles was systematically studied in vitro using WIL2-NS human lymphoblastoid cells. Before toxicity measurements, the ZnO particles of three different sizes (26 nm, 78 nm, and 147 nm) were well characterized for their physical and chemical properties to ensure that variations in other properties including surface chemistry and particle shape, which also may influence particle toxicity, were minimal. Cell viability testing showed that increasing cytotoxicity was associated with decreasing particle size. Both the dissolution kinetics of ZnO particles in supplemented cell culture medium and the apparent numbers of ZnO particles internalized by cells were size dependent and showed strong correlation with cytotoxicity. Genotoxicity, as measured by micronucleus formation, was significantly enhanced in the presence of the medium-sized and large-sized particles. The observation that necrosis increased with smaller- sized...

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2005

Moderate intake of wine is associated with reduced risk of cardiovascular disease and possibly ca... more Moderate intake of wine is associated with reduced risk of cardiovascular disease and possibly cancer however it remains unclear whether the potential health benefits of wine intake are due to alcohol or the non-alcoholic fraction of wine. We therefore tested the hypothesis that the non-alcoholic fraction of wine protects against genome damage induced by oxidative stress in a crossover intervention

The aim of this study was to determine the association between dietary intake, determined using a... more The aim of this study was to determine the association between dietary intake, determined using a food frequency questionnaire, and genome damage in lymphocytes measured using the micronucleus (MN) assay. The study, performed on 190 healthy individuals (mean age 47.8 years, 46% males), also examined whether a supplementation with b-carotene, vitamins C and E along with zinc (ACEZn), in a randomized trial for 6 months, improves genome stability. Multivariate analysis of baseline data showed that (1) the highest tertile of intake of vitamin E, retinol, folic acid, nicotinic acid (preformed) and calcium is associated with significant reductions in MN frequency, i.e. À28, À31, À33, À46 and À49%, respectively (P 5 0.005) relative to the lowest tertile of intake and (2) the highest tertile of intake of riboflavin, pantothenic acid and biotin was associated with significant increases in MN frequency, i.e. þ36% (P ¼ 0.054), þ51% (P ¼ 0.021), and þ65% (P ¼ 0.001), respectively, relative to the lowest tertile of intake. Mid-tertile b-carotene intake was associated with an 18% reduction in MN frequency (P ¼ 0.038); however, the highest tertile of intake (46400 mg/day) resulted in an 18% increment in MN frequency. Supplementation with ACEZn significantly reduced the MN index by 13% (P ¼ 0.038). The study also showed interactive additive effects such as the protective effect of increased calcium intake (À46%) and the exacerbating effect of riboflavin (þ42%) on increased genome damage caused by low folate intake. The results from this study illustrate the strong impact of a wide variety of micronutrients and their interactions on genome health, depending on the level of intake. Abbreviations: CBMN, cytokinesis-block micronucleus; FFQ, food frequency questionnaire; MN, micronucleus; MTHFR, methylene tetrahydrofolate reductase; PARP, polyADPribose polymerase. Carcinogenesis vol.26 no.5 # Oxford University Press 2005; all rights reserved.

The British journal of nutrition, Jan 31, 2015

The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic... more The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled 'Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies'. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation-health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on ...

Molecular nutrition & food research, Jan 29, 2015

Maintenance of normal cellular phenotype depends largely on accurate DNA replication and repair. ... more Maintenance of normal cellular phenotype depends largely on accurate DNA replication and repair. DNA damage causes gene mutations and predisposes to cancer and other chronic diseases. Growing evidence indicates that nutritional factors are associated with DNA damage in adults; here, we investigate these associations in children. We conducted a cross-sectional study among 462 healthy children 3, 6 and 9 years of age. Whole blood was collected and micronutrient levels were measured. The cytokinesis-block micronucleus cytome assay was used to measure chromosomal DNA damage (micronuclei, nucleoplasmic bridges, and nuclear buds) in lymphocytes. Cell apoptosis, necrosis, and the nuclear division index (NDI) were also measured. Nine loci in genes involved in folate metabolism and DNA repair were genotyped. Data were analysed using linear regression with adjustment for potential confounders. Calcium was positively associated with micronuclei and necrosis, and α-tocopherol negatively associa...

Urologic Oncology-seminars and Original Investigations, 2011

ObjectiveSingle nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and... more ObjectiveSingle nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and cancer risk. To elucidate the role of SNPs in DNA repair genes in prostate cancer (PC) we conducted a case-control study comprising of 118 Caucasian men affected with late onset PC and 132 age-matched healthy controls from South Australia.

Mutation Research/Reviews in Mutation Research, 2015

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r e v i e w s m r... more j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r e v i e w s m r C o m m u n i t y a d d r e s s : w w w . e l s e v i e r . c o m / l o c a t e / m u t r e s http://dx.

Chromosomal Alterations, 2007

... and/or nutritional deficiencies and/or exogenous genotoxins, opening up an exciting future fo... more ... and/or nutritional deficiencies and/or exogenous genotoxins, opening up an exciting future for the ... by suboptimal cell division kinetics, which is a major variable in this assay (Fenech 2000a). Over the past 17 years the CBMN assay has evolved into a comprehensive method for ...

Methods in Molecular Biology, 2010

Chemoprevention of Cancer and DNA Damage by Dietary Factors, 2009

European Journal of Psychotraumatology, 2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2015

Successful maintenance of metabolic systems relating to accurate DNA replication and repair is cr... more Successful maintenance of metabolic systems relating to accurate DNA replication and repair is critical for optimal lifelong human health. Should this homeostatic balance become impaired, genomic instability events can arise, compromising the integrity of the genome, which may result in gene expression and human disease. Both genome instability and micronutrient imbalance have been identified and implicated in diseases associated with accelerated ageing which potentially leads to an increased risk for the future development of clinically defined neurodegenerative disorders. Cognitive decline leading to the clinical diagnosis of mild cognitive impairment (MCI) has been shown to predict an increased risk in later life of developing Alzheimer's disease (AD). Knowledge on the impact of dietary factors in relation to MCI and AD risk is improving but incomplete; in particular the role of nutrient combinations (i.e. nutriomes) has not been thoroughly investigated. Currently, there is a need for preventative strategies as well as the identification of robust and reproducible diagnostic biomarkers that will allow identification of those individuals with increased risk for neurodegenerative diseases. Growing evidence suggests cells originating from different somatic tissues derived from individuals that have been clinically diagnosed with neurodegenerative disorders exhibit elevated frequencies of DNA damage compared to tissues of cognitively normal individuals which could be due to malnutrition. The objective of this review is to discuss current evidence and identify knowledge gaps relating to genome instability biomarkers and blood micronutrient profiles from human studies of MCI and AD that may be specific to and contribute to the increased risk of these diseases. This is a vital step in order to create research strategies for the future development of diagnostics that are indicative of dementia risk and to inform preventative therapies.

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2002

We have validated the analysis of nucleoplasmic bridges (NPBs) and nuclear buds as biomarkers of ... more We have validated the analysis of nucleoplasmic bridges (NPBs) and nuclear buds as biomarkers of genomic instability within the cytokinesis-block micronucleus assay in long-term lymphocyte cultures. Lymphocytes from 20 subjects were cultured in medium containing 12-120 nM folic acid for 9 days. Binucleate cells were scored for micronuclei (MN), NPBs and nuclear budding on day nine after 24h incubation in the presence of the cytokinesis inhibitor cytochalasin-B. Folic acid concentration was correlated significantly (P<0.0001) and negatively (r=-0.63 to -0.74) with all these markers of chromosome damage. Chromosome damage was minimised at 60-120 nM folic acid, which is greater than the concentration of folate normally observed in plasma (<30 nM). Current evidence suggests that (a) NPBs originate from dicentric chromosomes in which the centromeres have been pulled to the opposite poles of the cell at anaphase and are therefore, indicative of chromosome rearrangement and (b) that the nuclear budding process is the mechanism by which cells remove amplified DNA and is therefore a marker of gene amplification. The strong correlation between micronucleus formation, nuclear budding and NPBs (r=0.75-0.77, P<0.001) is supportive of the hypothesis that folic acid deficiency causes genomic instability and gene amplification by the initiation of breakage-fusion-bridge (BFB) cycles. These results also suggest that the CBMN assay may be a useful model for the study of the BFB cycle which may be one of the key mechanisms for the hypermutability phenotype required for the rapid evolution of cancer cells.

Mutagenesis, Jan 20, 2015

The buccal micronucleus cytome (BMCyt) assay is a minimally invasive approach for measuring DNA d... more The buccal micronucleus cytome (BMCyt) assay is a minimally invasive approach for measuring DNA damage, cell proliferation, cell differentiation and cell death in exfoliated buccal cells. The main limitation for its use is the lack of knowledge about inter- and intra-laboratory variability in scoring micronuclei and other end points included in the cytome approach. In order to identify the main sources of variability across the BMCyt biomarkers, a scoring exercise was carried out between three experienced laboratories using the same set of slides and an identical set of detailed scoring criteria and associated images for the different end points. Single batches of slides were prepared from pooled samples of four groups of subjects characterised by different frequencies of cell types and micronuclei, namely Down syndrome patients, head and neck cancer patients undergoing radiotherapy and two age- and gender-matched control groups. A good agreement among the laboratories in the identi...

Chemical research in toxicology, Jan 27, 2015

We have revealed a connection between DNA-nanoparticle (NP) binding and in vitro DNA damage induc... more We have revealed a connection between DNA-nanoparticle (NP) binding and in vitro DNA damage induced by citrate- and branched polyethylenimine-coated silver nanoparticles (c-AgNPs and b-AgNPs) as well as graphene oxide (GO) nanosheets. All three types of nanostructures triggered an early onset of DNA melting, where the extent of the melting point shift depends upon both the type and concentration of the NPs. Specifically, at a DNA/NP weight ratio of 1.1/1, the melting temperature of lambda DNA dropped from 94 °C down to 76 °C, 60 °C, and room temperature for GO, c-AgNPs and b-AgNPs, respectively. Consistently, dynamic light scattering revealed that the largest changes in DNA hydrodynamic size were also associated with the binding of b-AgNPs. Upon introduction to cells, b-AgNPs also exhibited the highest cytotoxicity, at the half-maximal inhibitory (IC50) concentrations of 3.2, 2.9, and 5.2 mg/L for B and T-lymphocyte cell lines and primary lymphocytes, compared to the values of 13.4,...

PloS one, 2015

Chronic psychological stress and nutritional deficiencies are factors that impact negatively on h... more Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9...

The journal of nutrition, health & aging, 2014

Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structur... more Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structure and its DNA hexamer (TTAGGG)n repeat sequence is critical for protecting the ends of chromosomes from degradation and in maintaining overall chromosomal stability. Currently, there are limited data on the influence that nutrition has on telomere length. Recent studies have suggested that micronutrients may influence telomere length. Here we examined the relationship between telomere length in lymphocytes and plasma calcium, magnesium, selenium and zinc status in a healthy cohort of younger and older adults. We report a negative association between telomere length and both plasma calcium and magnesium levels, (r=-0.47, P=0.03 and r=-0.61, P=0.001 respectively), in older females; Intriguingly Ca/Mg ratio was positively associated with telomere length (r=0.55, P=0.007). These relationships were not observed in the younger adults, nor in the older males. In conclusion, our study provides p...

Cancer treatment and research, 2014

DNA damage at the base sequence and chromosome level is a fundamental cause of developmental and ... more DNA damage at the base sequence and chromosome level is a fundamental cause of developmental and degenerative diseases. Multiple micronutrients and their interactions with the inherited and/or acquired genome determine DNA damage and genomic instability rates. The challenge is to identify for each individual the combination of micronutrients and their doses (i.e. the nutriome) that optimises genome stability, including telomere integrity and functionality and DNA repair. Using nutrient array systems with high-content analysis diagnostics of DNA damage, cell death and cell growth, it is possible to define, on an individual basis, the optimal nutriome for DNA damage prevention and cancer growth control. This knowledge can also be used to improve culture systems for cells used in therapeutics such as stem cells to ensure that they are not genetically aberrant when returned to the body. Furthermore, this information could be used to design dietary patterns that deliver the micronutrient...

Methods in molecular biology (Clifton, N.J.), 2013

The micronucleus (MN) assay, applied in different surrogate tissues, is one of the best validated... more The micronucleus (MN) assay, applied in different surrogate tissues, is one of the best validated cytogenetic techniques for evaluating chromosomal damage in humans. The cytokinesis-block micronucleus cytome assay (CBMNcyt) in peripheral blood lymphocytes is the most frequent method in biomonitoring human populations to evaluate exposure to genotoxic agents, micronutrient deficiency, or excess and genetic instability. Furthermore recent scientific evidence suggests an association between an increased MN frequency in lymphocytes and risk of cancer and other age-related degenerative diseases. The micronucleus cytome assay applied in buccal exfoliated cells (BMNCyt) provides a complementary method for measuring DNA damage and cytotoxic effects in an easily accessible tissue not requiring in vitro culture. The protocol for CBMNcyt described here refers to the use of ex vivo whole blood involving 72 h of culture with the block of cytokinesis at 44 h. BMNCyt protocol reports the establish...

Food Chemistry, 2013

Three commercially grown native herbs unique to Australia, Tasmannia pepper leaf (Tasmannia lance... more Three commercially grown native herbs unique to Australia, Tasmannia pepper leaf (Tasmannia lanceolata R. Br., Winteracea; TPL), anise myrtle (Syzygium anisatum Vickery, Craven & Biffen, Myrtaceae; AM) and lemon myrtle (Backhousia citriodora F. Muell, Myrtaceae; LM) as well as a reference sample bay leaf (Laurus nobilis L., Lauraceae; BL) were examined for potential cytoprotective properties. All native herbs exhibited greater cellular antioxidant activity as measured by the cellular antioxidant activity (CAA) assay than bay leaf and reduced the hydrogen peroxide (H 2 O 2 ) induced death of hepatocellular carcinoma (HepG2) cells by 25-50%. All herb extracts reduced the proliferation of colon (HT-29; IC 50 = 0.75-1.39 mg/ml), stomach (AGS; IC 50 = 0.59-1.88 mg/ml), bladder (BL13; IC 50 = 0.56-1.12 mg/ml) and liver (HepG2; IC 50 = 0.38-1.36 mg/ml) cancer cells. No significant reduction of cell viability of non-transformed colon (CCD-18Co; IC 50 > 2.0 mg/ml) and mixed stomach and intestine (Hs 738.St/Int; IC 50 > 2.0 mg/ml) cells was observed. Flow cytometry analysis and the results of the cytokinesis block micronucleus cytome (CBMNCyt) assay conducted with respectively, promyelocytic leukaemia (HL-60) and colon adenocarcinoma (HT-29) cells suggest an increase in apoptosis following treatment with the herb extracts. The occurrence of apoptotic cells coincided with an increase in caspase-3 enzyme activity. The results of the CBMNCyt assay suggested no direct DNA damage in colon adenocarcinoma (HT-29) cells as a result of treatment with all extracts, applied at final concentrations of 0.5 and 1.0 mg/ml. Crown

Environmental and molecular mutagenesis, Jan 6, 2015

The relationship between particle size and cytogenotoxicity of ZnO particles was systematically s... more The relationship between particle size and cytogenotoxicity of ZnO particles was systematically studied in vitro using WIL2-NS human lymphoblastoid cells. Before toxicity measurements, the ZnO particles of three different sizes (26 nm, 78 nm, and 147 nm) were well characterized for their physical and chemical properties to ensure that variations in other properties including surface chemistry and particle shape, which also may influence particle toxicity, were minimal. Cell viability testing showed that increasing cytotoxicity was associated with decreasing particle size. Both the dissolution kinetics of ZnO particles in supplemented cell culture medium and the apparent numbers of ZnO particles internalized by cells were size dependent and showed strong correlation with cytotoxicity. Genotoxicity, as measured by micronucleus formation, was significantly enhanced in the presence of the medium-sized and large-sized particles. The observation that necrosis increased with smaller- sized...

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2005

Moderate intake of wine is associated with reduced risk of cardiovascular disease and possibly ca... more Moderate intake of wine is associated with reduced risk of cardiovascular disease and possibly cancer however it remains unclear whether the potential health benefits of wine intake are due to alcohol or the non-alcoholic fraction of wine. We therefore tested the hypothesis that the non-alcoholic fraction of wine protects against genome damage induced by oxidative stress in a crossover intervention

The aim of this study was to determine the association between dietary intake, determined using a... more The aim of this study was to determine the association between dietary intake, determined using a food frequency questionnaire, and genome damage in lymphocytes measured using the micronucleus (MN) assay. The study, performed on 190 healthy individuals (mean age 47.8 years, 46% males), also examined whether a supplementation with b-carotene, vitamins C and E along with zinc (ACEZn), in a randomized trial for 6 months, improves genome stability. Multivariate analysis of baseline data showed that (1) the highest tertile of intake of vitamin E, retinol, folic acid, nicotinic acid (preformed) and calcium is associated with significant reductions in MN frequency, i.e. À28, À31, À33, À46 and À49%, respectively (P 5 0.005) relative to the lowest tertile of intake and (2) the highest tertile of intake of riboflavin, pantothenic acid and biotin was associated with significant increases in MN frequency, i.e. þ36% (P ¼ 0.054), þ51% (P ¼ 0.021), and þ65% (P ¼ 0.001), respectively, relative to the lowest tertile of intake. Mid-tertile b-carotene intake was associated with an 18% reduction in MN frequency (P ¼ 0.038); however, the highest tertile of intake (46400 mg/day) resulted in an 18% increment in MN frequency. Supplementation with ACEZn significantly reduced the MN index by 13% (P ¼ 0.038). The study also showed interactive additive effects such as the protective effect of increased calcium intake (À46%) and the exacerbating effect of riboflavin (þ42%) on increased genome damage caused by low folate intake. The results from this study illustrate the strong impact of a wide variety of micronutrients and their interactions on genome health, depending on the level of intake. Abbreviations: CBMN, cytokinesis-block micronucleus; FFQ, food frequency questionnaire; MN, micronucleus; MTHFR, methylene tetrahydrofolate reductase; PARP, polyADPribose polymerase. Carcinogenesis vol.26 no.5 # Oxford University Press 2005; all rights reserved.

The British journal of nutrition, Jan 31, 2015

The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic... more The importance of chronic low-grade inflammation in the pathology of numerous age-related chronic conditions is now clear. An unresolved inflammatory response is likely to be involved from the early stages of disease development. The present position paper is the most recent in a series produced by the International Life Sciences Institute's European Branch (ILSI Europe). It is co-authored by the speakers from a 2013 workshop led by the Obesity and Diabetes Task Force entitled 'Low-grade inflammation, a high-grade challenge: biomarkers and modulation by dietary strategies'. The latest research in the areas of acute and chronic inflammation and cardiometabolic, gut and cognitive health is presented along with the cellular and molecular mechanisms underlying inflammation-health/disease associations. The evidence relating diet composition and early-life nutrition to inflammatory status is reviewed. Human epidemiological and intervention data are thus far heavily reliant on ...

Molecular nutrition & food research, Jan 29, 2015

Maintenance of normal cellular phenotype depends largely on accurate DNA replication and repair. ... more Maintenance of normal cellular phenotype depends largely on accurate DNA replication and repair. DNA damage causes gene mutations and predisposes to cancer and other chronic diseases. Growing evidence indicates that nutritional factors are associated with DNA damage in adults; here, we investigate these associations in children. We conducted a cross-sectional study among 462 healthy children 3, 6 and 9 years of age. Whole blood was collected and micronutrient levels were measured. The cytokinesis-block micronucleus cytome assay was used to measure chromosomal DNA damage (micronuclei, nucleoplasmic bridges, and nuclear buds) in lymphocytes. Cell apoptosis, necrosis, and the nuclear division index (NDI) were also measured. Nine loci in genes involved in folate metabolism and DNA repair were genotyped. Data were analysed using linear regression with adjustment for potential confounders. Calcium was positively associated with micronuclei and necrosis, and α-tocopherol negatively associa...

Urologic Oncology-seminars and Original Investigations, 2011

ObjectiveSingle nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and... more ObjectiveSingle nucleotide polymorphisms (SNPs) in DNA repair genes may impact on DNA damage, and cancer risk. To elucidate the role of SNPs in DNA repair genes in prostate cancer (PC) we conducted a case-control study comprising of 118 Caucasian men affected with late onset PC and 132 age-matched healthy controls from South Australia.

Mutation Research/Reviews in Mutation Research, 2015

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r e v i e w s m r... more j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / r e v i e w s m r C o m m u n i t y a d d r e s s : w w w . e l s e v i e r . c o m / l o c a t e / m u t r e s http://dx.

Chromosomal Alterations, 2007

... and/or nutritional deficiencies and/or exogenous genotoxins, opening up an exciting future fo... more ... and/or nutritional deficiencies and/or exogenous genotoxins, opening up an exciting future for the ... by suboptimal cell division kinetics, which is a major variable in this assay (Fenech 2000a). Over the past 17 years the CBMN assay has evolved into a comprehensive method for ...

Methods in Molecular Biology, 2010

Chemoprevention of Cancer and DNA Damage by Dietary Factors, 2009

European Journal of Psychotraumatology, 2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2015

Successful maintenance of metabolic systems relating to accurate DNA replication and repair is cr... more Successful maintenance of metabolic systems relating to accurate DNA replication and repair is critical for optimal lifelong human health. Should this homeostatic balance become impaired, genomic instability events can arise, compromising the integrity of the genome, which may result in gene expression and human disease. Both genome instability and micronutrient imbalance have been identified and implicated in diseases associated with accelerated ageing which potentially leads to an increased risk for the future development of clinically defined neurodegenerative disorders. Cognitive decline leading to the clinical diagnosis of mild cognitive impairment (MCI) has been shown to predict an increased risk in later life of developing Alzheimer's disease (AD). Knowledge on the impact of dietary factors in relation to MCI and AD risk is improving but incomplete; in particular the role of nutrient combinations (i.e. nutriomes) has not been thoroughly investigated. Currently, there is a need for preventative strategies as well as the identification of robust and reproducible diagnostic biomarkers that will allow identification of those individuals with increased risk for neurodegenerative diseases. Growing evidence suggests cells originating from different somatic tissues derived from individuals that have been clinically diagnosed with neurodegenerative disorders exhibit elevated frequencies of DNA damage compared to tissues of cognitively normal individuals which could be due to malnutrition. The objective of this review is to discuss current evidence and identify knowledge gaps relating to genome instability biomarkers and blood micronutrient profiles from human studies of MCI and AD that may be specific to and contribute to the increased risk of these diseases. This is a vital step in order to create research strategies for the future development of diagnostics that are indicative of dementia risk and to inform preventative therapies.

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2002

We have validated the analysis of nucleoplasmic bridges (NPBs) and nuclear buds as biomarkers of ... more We have validated the analysis of nucleoplasmic bridges (NPBs) and nuclear buds as biomarkers of genomic instability within the cytokinesis-block micronucleus assay in long-term lymphocyte cultures. Lymphocytes from 20 subjects were cultured in medium containing 12-120 nM folic acid for 9 days. Binucleate cells were scored for micronuclei (MN), NPBs and nuclear budding on day nine after 24h incubation in the presence of the cytokinesis inhibitor cytochalasin-B. Folic acid concentration was correlated significantly (P<0.0001) and negatively (r=-0.63 to -0.74) with all these markers of chromosome damage. Chromosome damage was minimised at 60-120 nM folic acid, which is greater than the concentration of folate normally observed in plasma (<30 nM). Current evidence suggests that (a) NPBs originate from dicentric chromosomes in which the centromeres have been pulled to the opposite poles of the cell at anaphase and are therefore, indicative of chromosome rearrangement and (b) that the nuclear budding process is the mechanism by which cells remove amplified DNA and is therefore a marker of gene amplification. The strong correlation between micronucleus formation, nuclear budding and NPBs (r=0.75-0.77, P<0.001) is supportive of the hypothesis that folic acid deficiency causes genomic instability and gene amplification by the initiation of breakage-fusion-bridge (BFB) cycles. These results also suggest that the CBMN assay may be a useful model for the study of the BFB cycle which may be one of the key mechanisms for the hypermutability phenotype required for the rapid evolution of cancer cells.

Mutagenesis, Jan 20, 2015

The buccal micronucleus cytome (BMCyt) assay is a minimally invasive approach for measuring DNA d... more The buccal micronucleus cytome (BMCyt) assay is a minimally invasive approach for measuring DNA damage, cell proliferation, cell differentiation and cell death in exfoliated buccal cells. The main limitation for its use is the lack of knowledge about inter- and intra-laboratory variability in scoring micronuclei and other end points included in the cytome approach. In order to identify the main sources of variability across the BMCyt biomarkers, a scoring exercise was carried out between three experienced laboratories using the same set of slides and an identical set of detailed scoring criteria and associated images for the different end points. Single batches of slides were prepared from pooled samples of four groups of subjects characterised by different frequencies of cell types and micronuclei, namely Down syndrome patients, head and neck cancer patients undergoing radiotherapy and two age- and gender-matched control groups. A good agreement among the laboratories in the identi...

Chemical research in toxicology, Jan 27, 2015

We have revealed a connection between DNA-nanoparticle (NP) binding and in vitro DNA damage induc... more We have revealed a connection between DNA-nanoparticle (NP) binding and in vitro DNA damage induced by citrate- and branched polyethylenimine-coated silver nanoparticles (c-AgNPs and b-AgNPs) as well as graphene oxide (GO) nanosheets. All three types of nanostructures triggered an early onset of DNA melting, where the extent of the melting point shift depends upon both the type and concentration of the NPs. Specifically, at a DNA/NP weight ratio of 1.1/1, the melting temperature of lambda DNA dropped from 94 °C down to 76 °C, 60 °C, and room temperature for GO, c-AgNPs and b-AgNPs, respectively. Consistently, dynamic light scattering revealed that the largest changes in DNA hydrodynamic size were also associated with the binding of b-AgNPs. Upon introduction to cells, b-AgNPs also exhibited the highest cytotoxicity, at the half-maximal inhibitory (IC50) concentrations of 3.2, 2.9, and 5.2 mg/L for B and T-lymphocyte cell lines and primary lymphocytes, compared to the values of 13.4,...

PloS one, 2015

Chronic psychological stress and nutritional deficiencies are factors that impact negatively on h... more Chronic psychological stress and nutritional deficiencies are factors that impact negatively on human health and disease risk. Chronic stress has been associated with accelerated leukocyte telomere shortening in numerous cohorts, however, a mechanistic link has proven elusive. This study tested the hypotheses that chronic exposure to the stress hormone, cortisol, causes telomere shortening and chromosome instability (CIN) in vitro, and that these effects would be further exacerbated by folate (vitamin B9) deficiency. Primary human lymphocytes were maintained in vitro for 12 days in medium containing either 25 nM folic acid (FA(low)) or 100 nM FA (FA(high)), together with either 0, 400, 1000 or 3500 nM cortisol. The interactive effects of cortisol and FA were examined by comparing telomere length (TL), biomarkers of DNA damage, and cytostasis. At day 12 TL was 5-17% longer in lymphocytes cultured in FA(low) conditions (mean ± SD;10.2% ± 1.6), compared with those in FA(high) medium (9...

The journal of nutrition, health & aging, 2014

Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structur... more Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structure and its DNA hexamer (TTAGGG)n repeat sequence is critical for protecting the ends of chromosomes from degradation and in maintaining overall chromosomal stability. Currently, there are limited data on the influence that nutrition has on telomere length. Recent studies have suggested that micronutrients may influence telomere length. Here we examined the relationship between telomere length in lymphocytes and plasma calcium, magnesium, selenium and zinc status in a healthy cohort of younger and older adults. We report a negative association between telomere length and both plasma calcium and magnesium levels, (r=-0.47, P=0.03 and r=-0.61, P=0.001 respectively), in older females; Intriguingly Ca/Mg ratio was positively associated with telomere length (r=0.55, P=0.007). These relationships were not observed in the younger adults, nor in the older males. In conclusion, our study provides p...

Cancer treatment and research, 2014

DNA damage at the base sequence and chromosome level is a fundamental cause of developmental and ... more DNA damage at the base sequence and chromosome level is a fundamental cause of developmental and degenerative diseases. Multiple micronutrients and their interactions with the inherited and/or acquired genome determine DNA damage and genomic instability rates. The challenge is to identify for each individual the combination of micronutrients and their doses (i.e. the nutriome) that optimises genome stability, including telomere integrity and functionality and DNA repair. Using nutrient array systems with high-content analysis diagnostics of DNA damage, cell death and cell growth, it is possible to define, on an individual basis, the optimal nutriome for DNA damage prevention and cancer growth control. This knowledge can also be used to improve culture systems for cells used in therapeutics such as stem cells to ensure that they are not genetically aberrant when returned to the body. Furthermore, this information could be used to design dietary patterns that deliver the micronutrient...

Methods in molecular biology (Clifton, N.J.), 2013

The micronucleus (MN) assay, applied in different surrogate tissues, is one of the best validated... more The micronucleus (MN) assay, applied in different surrogate tissues, is one of the best validated cytogenetic techniques for evaluating chromosomal damage in humans. The cytokinesis-block micronucleus cytome assay (CBMNcyt) in peripheral blood lymphocytes is the most frequent method in biomonitoring human populations to evaluate exposure to genotoxic agents, micronutrient deficiency, or excess and genetic instability. Furthermore recent scientific evidence suggests an association between an increased MN frequency in lymphocytes and risk of cancer and other age-related degenerative diseases. The micronucleus cytome assay applied in buccal exfoliated cells (BMNCyt) provides a complementary method for measuring DNA damage and cytotoxic effects in an easily accessible tissue not requiring in vitro culture. The protocol for CBMNcyt described here refers to the use of ex vivo whole blood involving 72 h of culture with the block of cytokinesis at 44 h. BMNCyt protocol reports the establish...