ORCID Profile
0000-0002-3492-9403
Current Organisation
University of Adelaide
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Epigenetics (incl. Genome Methylation and Epigenomics) | Paediatrics and Reproductive Medicine | Reproduction | Environmental Sciences not elsewhere classified
Reproductive System and Disorders | Expanding Knowledge in the Biological Sciences |
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.TEM.2014.11.005
Abstract: Maternal over-nutrition during pregnancy is a risk factor for pregnancy complications and is increasingly associated with adverse childhood outcomes such as increased propensity for obesity and metabolic disease. However, there is emerging evidence that parental lifestyle factors prior to and at conception have a powerful impact on the health of the offspring for more than one generation. Maternal and paternal obesity prior to conception alters the molecular composition of both oocytes and sperm, which can partly escape epigenetic reprogramming at fertilization, altering the developmental trajectory of the resultant embryo, ultimately increasing the incidence of obesity and metabolic disorders in offspring. Understanding the molecular underpinning of these changes may help create interventions to reduce the risk of disease in future generations.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2021
Publisher: Medknow
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 14-04-2021
Publisher: Oxford University Press (OUP)
Date: 21-02-2012
Abstract: Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked. A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed. We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations. This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational lification of subfertility observed worldwide in humans.
Publisher: S. Karger AG
Date: 2014
DOI: 10.1159/000365026
Abstract: b i Background: /i /b The global rates of male overweight/obesity are rising, approaching 70% of the total adult population in Western nations. Overweight/obesity increases the risk of chronic diseases however, there is increasing awareness that male obesity negatively impacts fertility, subsequent pregnancy, and the offspring health burden. Developmental programming is well defined in mothers however, it is becoming increasingly evident that developmental programming can be paternally initiated and mediated through paternal obesity. b i Key Messages: /i /b Both human and rodent models have established that paternal obesity impairs sex hormones, basic sperm function, and molecular composition. This results in perturbed embryo development and health and an increased subsequent offspring disease burden in both sexes. The reversibility of obesity-induced parental programming has only recently received attention. Promising results in animal models utilizing diet and exercise interventions have shown improvements in sperm function and molecular composition, resulting in restorations of both embryo and fetal health and subsequent male offspring fertility. The direct mode for paternal inheritance is likely mediated via spermatozoa. We propose two main theories for the origin of male obesity-induced paternal programming: (1) accumulation of sperm DNA damage resulting in de novo mutations in the embryo and (2) changes in sperm epigenetic marks (microRNA, methylation, or acetylation) altering the access, transcription, and translation of paternally derived genes during early embryogenesis. b i Conclusions: /i /b Paternal overweight/obesity induces paternal programming of offspring phenotypes likely mediated through genetic and epigenetic changes in spermatozoa. These programmed changes to offspring health appear to be partially restored via diet/exercise interventions in obese fathers preconception, which have been shown to improve aspects of sperm DNA integrity. However, the majority of data surrounding paternal obesity and offspring phenotypes have come from rodent models therefore, we contend that it will be increasingly important to study population-based data to determine the likely mode of inheritance in humans.
Publisher: Elsevier BV
Date: 12-2021
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.ORCP.2019.11.003
Abstract: The influence of maternal body mass index (BMI) on pregnancy and child health outcomes is well characterised, however less is known about paternal BMI. This systematic review investigated the independent effects of increased paternal BMI on conception and pregnancy as well as neonatal and childhood outcomes. Our systematic search (Sept. 2018) of PubMed, Embase, Cinahl, Web of Science, ProQuest, and OpenThesis resulted in 11,045 hits from which 17 studies met the inclusion criteria (Participants: men Exposure: BMI or waist circumferences Outcomes: associations with time to pregnancy, incidence of infertility, pregnancy loss, pregnancy complications, birthweight and length, childhood weight and height, or incidence of any childhood disease). Studies had to adjust for maternal age and BMI. Meta-analysis was only possible for infertility which was significantly more prevalent in obese (OR=1.49 95%CI 1.30-1.70) and overweight (OR=1.18 95%CI 1.11-1.26) men. In idual studies showed increased likelihoods of small for gestational age and macrosomia in fathers who had increased BMI - possibly accounting for the general finding of no effect on mean birthweight in other studies. Most studies found increased BMI in fathers correlated with altered growth curves and increased BMI in childhood, while one study found a higher likelihood of autism spectrum disorder. Our findings support increased paternal BMI negatively affecting pregnancy and child health outcomes. Future studies must include or adjust for paternal contributions, as the longstanding assumption that only maternal factors are relevant is likely to have considerably confounded prior work.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Portico
Date: 21-01-2015
Abstract: The concept of non-genetic inheritance is gaining considerable attention in the assisted reproductive technology (ART) community due to the reported differences between children born from ART and those that are conceived naturally. It has been demonstrated that children conceived via ART have differences in fetal growth, birth weight, congenital abnormalities, cardiometabolic parameters, glucose homeostasis as well as changes to body composition compared to children conceived naturally. Although these changes may have a parental contribution and may be influenced by the pathology of infertility there is concern that the technologies themselves may play a role. In support of this, is emerging evidence that aspects of ART technology such as culture media formulation and insemination method can alter offspring phenotype. In addition it is also documented that exposure to environmental factors, such as toxins can impact on offspring gametogenesis such that these perturbations persist through generations. With the increasing use of ART and the development of new technologies it is vital that we understand whether ART can effect non-genetic inheritance so that we can optimise technology and prevent abnormal programming and its impact on all aspects of offspring health including fertility and a possible transmission to subsequent generations.
Publisher: Wiley
Date: 21-12-2023
DOI: 10.1111/ANDR.13356
Abstract: Oxidative stress in semen contributes up to 80% of all infertility diagnosis. Diagnostics to measure oxidative stress in semen was recently added to the 6th edition WHO methods manual, although diagnostic predictive values need to be interpreted with caution as there are still several research questions yet to be answered. To determine the natural fluctuations in semen redox indicators (MiOXSYS ® and OxiSperm ® II) within and between men and their association with markers of sperm oxidative stress. Total, 118 repeat semen s les from 31 generally healthy men aged 18–45 years, over 6 months. Standard semen analysis as per 5th WHO manual. Semen redox levels measured via MiOXSYS ® and OxiSperm ® II. Additional attributes of sperm quality HBA ® binding assay and sperm hyperactivation and oxidative stress DNA fragmentation (Halo ® Sperm) and lipid peroxidation (BODIPY™ 581/591 C11) were assessed. S les with high redox‐potential (MiOXSYS ® ≥1.47 sORP/10 6 sperm/ml) had lower sperm, motility, morphology and higher DNA fragmentation ( P 0.05). Upon further analysis, these associations were driven solely by the adjustment of sperm concentration (10 6 /ml) in normalised redox‐potential. No significant associations between NBT‐reactivity (OxiSperm ® II) and measures of the sperm function or oxidative stress were observed ( P 0.05). Fluctuations in semen redox levels varied greater between men than within men over the study period. Neither MiOXSYS ® nor OxiSperm ® II assays were predictive of sperm function or sperm oxidative stress. This was likely due at least in part to limited understanding of their biochemistry and clinical application. As a result, these assays seem to provide no additional clinical utility beyond that of a standard semen analysis, highlighting the imperative for the development of new robust point‐of‐care devices for accurately determining sperm oxidative stress. These findings suggest that MiOXSYS ® and OxiSperm ® II systems for the measurement of sperm oxidative stress may have limited diagnostic potential.
Publisher: Elsevier BV
Date: 06-2020
Publisher: American Physiological Society
Date: 15-09-2015
DOI: 10.1152/AJPENDO.00230.2015
Abstract: The prevalence of overweight and obesity in reproductive-age adults is increasing worldwide. While the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/obese on fecundity and offspring health has received minimal attention. Using a 2 × 2 study design in rodents we established the relative contributions of paternal and maternal obesity on fetal and embryo development and whether combined paternal and maternal obesity had an additive effect. Here, we show that parental obesity reduces fetal and placental weights without altering pregnancy establishment and is not dependent on an in utero exposure to a high-fat diet. Interestingly combined parental obesity seemed to accumulate both the negative influences of paternal and maternal obesity had alone on embryo and fetal health rather than an lification, manifested as reduced embryo developmental competency, reduced blastocyst cell numbers, impaired mitochondrial function, and alterations to active and repressive embryonic chromatin marks, resulting in aberrant placental gene expression and reduced fetal liver mtDNA copy numbers. Further understanding both the maternal cytoplasmic and paternal genetic interactions during this early developmental time frame will be vital for understanding how developmental programming is regulated and for the proposition of interventions to mitigate their effects.
Publisher: Public Library of Science (PLoS)
Date: 09-07-2014
Publisher: Wiley
Date: 23-02-2023
DOI: 10.1111/ANDR.13409
Abstract: Obesity prevalence worldwide is increasing significantly. Whilst maternal obesity has clear detrimental impacts on fertility, pregnancy and foetal outcomes, more recently there has been an increasing focus on the role of paternal obesity in human fertility. Recent meta‐analyses have indicated that obesity in men negatively affects basic sperm parameters such as sperm count, concentration and motility, increases the incidence of infertility and reduces the chances of conception. Sperm DNA damage, typically characterised by DNA strand breaks and oxidation of DNA nucleotides, is a specialised marker of sperm quality that has been independently associated with recurrent miscarriage, reduced assisted reproduction success and increased mutational loads in subsequent offspring. Whilst, there are still conflicting data in humans as to the association of obesity in men with sperm DNA damage, evidence from rodent models is clear, indicating that male obesity increases sperm DNA damage. Human data are often conflicting because of the large heterogeneity amongst studies, the use of body mass index as the indicator of obesity and the methods used for detection of sperm DNA damage. Furthermore, comorbidities of obesity (i.e., heat stress, adipokines, insulin resistance, changes in lipids, hypogonadism and obstructive sleep apnoea) are also independently associated with increased sperm DNA damage that is not always modified in men with obesity, and as such may provide a causative link to the discrepancies amongst human studies. In this review, we provide an update on the literature regarding the associations between obesity in men and fertility, basic sperm parameters and sperm DNA damage. We further discuss potential reasons for the discrepancies in the literature and outline possible direct and indirect mechanisms of increased sperm DNA damage resulting from obesity. Finally, we summarise intergenerational obesity through the paternal linage and how sperm DNA damage may contribute to the transmission.
Publisher: Bioscientifica
Date: 12-01-2023
DOI: 10.1530/REP-22-0302
Abstract: Maternal obesity can impair metabolism in the embryo and the resulting offspring. This study shows that metabolic disruptions through α-ketoglutarate may link altered metabolism with epigenetic changes in embryos. Maternal obesity can impair offspring metabolic health however, the precise mechanism underpinning programming is unknown. Ten-Eleven translocase (TET) enzymes demethylate DNA using the TCA cycle intermediary α-ketoglutarate and may be involved in programming offspring health. Whether TETs are disrupted by maternal obesity is unknown. Five to six week-old C57Bl/6 female mice were fed a control diet (CD 6% fat, n = 175) or a high-fat diet (HFD 21% fat, n = 158) for 6 weeks. After superovulation, oocytes were collected for metabolic assessment, or females were mated and zygotes were cultured for embryo development, fetal growth, and assessment of global DNA methylation (5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxycytosine (5caC)) in the two-cell embryo. Zygotes collected from superovulated CBAF1 females were cultured in media containing α-ketoglutarate (0, 1.4, 3.5, or 14.0 mM) or with 2-hydroxyglutarate (2HG) (0 or 20 mM), a competitive inhibitor of α-ketoglutarate, with methylation and blastocyst differentiation assessed. After HFD, oocytes showed increased pyruvate oxidation and intracellular ROS, with no changes in Tet3 expression, while two-cell embryo global 5hmC DNA methylation was reduced and 5fC increased. Embryos cultured with 1.4 mM α-ketoglutarate had decreased two-cell 5mC, while 14.0 mM α-ketoglutarate increased the 5hmC:5mC ratio. In contrast, supplementation with 20 mM 2HG increased 5mC and decreased 5fC:5mC and 5caC:5mC ratios. α-ketoglutarate up to 3.5 mM did not alter embryo development, while culturing in 14.0 mM α-ketoglutarate blocked development at the two-cell. Culture with 2HG delayed embryo development past the four-cell and decreased blastocyst total cell number. In conclusion, disruptions in metabolic intermediates in the preimplantation embryo may provide a link between maternal obesity and programming offspring for ill health.
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/RD10326
Abstract: Male obesity is associated with reduced sperm function and increased incidence of sperm DNA damage however, the underlying molecular mechanisms have not yet been identified. Mammalian SIRT6 protein is involved in caloric-dependant DNA damage repair in other tissue types, yet a possible role for SIRT6 in male obesity and subfertility has not been investigated previously. To assess SIRT6 levels and activity in the testes, male mice (n = 12 per diet) were fed either a control diet (CD 6% fat) or a high-fat diet (HFD 21% fat) for 16 weeks before the collection of testes and spermatozoa. SIRT6 protein was localised to the nucleus of transitional spermatids and the acrosome of mature spermatozoa, with levels significantly decreased in HFD-fed male mice (P 0.05). This decrease in SIRT6 protein was associated with transitional spermatids having increased levels of acetylated H3K9 in the nucleus (P 0.01) and increased DNA damage (P 0.001). We propose a role for SIRT6 in spermiogenesis and potentially protamination processes, which are known to be compromised by male obesity.
Publisher: MDPI AG
Date: 12-09-2019
DOI: 10.3390/NU11092196
Abstract: Male obesity, which often co-presents with micronutrient deficiencies, is associated with sub-fertility. Here we investigate whether short-term dietary supplementation of micronutrients (zinc, selenium, lycopene, vitamins E and C, folic acid, and green tea extract) to obese mice for 12 days (designed to span the epididymal transit) could improve sperm quality and fetal outcomes. Five-week-old C57BL6 males were fed a control diet (CD, n = 24) or high fat diet (HFD, n = 24) for 10 weeks before allocation to the 12-day intervention of maintaining their original diets (CD, n = 12, HFD n = 12) or with micronutrient supplementation (CD + S, n = 12, HFD + S, n = 12). Measures of sperm quality (motility, morphology, capacitation, binding), sperm oxidative stress (DCFDA, MSR, and 8OHdG), early embryo development (2-cell cleavage, 8OHdG), and fetal outcomes were assessed. HFD + S males had reduced sperm intracellular reactive oxygen species (ROS) concentrations and 8OHdG lesions, which resulted in reduced 8OHdG lesions in the male pronucleus, increased 2-cell cleavage rates, and partial restoration of fetal weight similar to controls. Sub-fertility associated with male obesity may be restored with very short-term micronutrient supplementation that targets the timing of the transit of sperm through the epididymis, which is the developmental window where sperm are the most susceptible to oxidative damage.
Publisher: Public Library of Science (PLoS)
Date: 19-08-2013
Publisher: Elsevier BV
Date: 03-2020
Publisher: Medknow
Date: 2015
Publisher: Elsevier BV
Date: 09-2021
DOI: 10.1016/J.RBMO.2021.05.020
Abstract: Is PIEZO-intracytoplasmic sperm injection (ICSI) coupled with a new novel operational fluid (perfluoro-n-octane) superior to standard ICSI? A cohort of patients (n = 69) undertaking microinjection were recruited between January and November 2019 and were then prospectively case-matched. Patients required six or more mature oocytes for inclusion in the study. PIEZO-ICSI uses high-speed microinjection drilling to penetrate the zona and oolemma and deposit the spermatozoa into the cytoplasm, compared with the traditional 'cutting' action of ICSI. The primary outcome was fertilization, with secondary outcomes including oocyte degeneration, abnormal fertilization, embryo cryopreservation and embryo utilization. PIEZO-ICSI resulted in significantly higher fertilization rates (80.5 ± 2.4% vs 65.8 ± 2.3%, P < 0.0001) and lower oocyte degeneration rates (4.4 ± 1.3% vs 8.6 ± 1.2%, P = 0.019) and abnormal fertilization rates (2.9 ± 1.1% vs 7.4 ± 1.1% P = 0.003) compared with standard ICSI. This improvement in fertilization was of most benefit in patients aged ≥38 years. This increase in fertilization increased the number of good quality embryos that were available for cryopreservation/transfer (3.8 ± 0.2 vs 3.1 ± 0.2 P = 0.038), such that patients on average had one extra usable embryo per cycle compared with standard ICSI. There were no differences to Day 5 embryo development or clinical pregnancy from fresh embryo transfer (57.1% PIEZO-ICSI vs 60.0% ICSI) between microinjection methods, although pregnancy outcomes were underpowered. PIEZO-ICSI significantly increased fertilization rates, thereby increasing the number of embryos available for cryopreservation compared with standard ICSI. Further prospective studies assessing cumulative pregnancy rates are warranted.
Publisher: CSIRO Publishing
Date: 2018
DOI: 10.1071/AM16055
Abstract: Most of the Australian ‘old endemic’ rodents have greatly reduced distributions with several species now threatened with extinction. Application of assisted reproductive technology has the potential to assist in their conservation programs in at least a few species. Here we describe an attempt to cryopreserve spermatozoa from two of these species – those of the plains mouse (Pseudomys australis) and spinifex hopping mouse (Notomys alexis), which have dramatic differences in sperm morphology. Slow and rapid freezing and three different cryoprotectant media with either raffinose, glycerol and/or skim milk were used and the results compared with those of house mouse sperm, which were used as controls. Sperm morphology, motility, membrane integrity and DNA damage were determined. Prior to cryopreservation there was a higher percentage of morphologically normal, motile, P. australis sperm than in those from N. alexis. Following cryopreservation, regardless of treatment, the percentage of motile sperm was low but it was higher when raffinose with skim milk was used as a cryoprotectant than in raffinose with glycerol albeit that minimal differences in membrane integrity or DNA damage were evident. Raffinose with skim milk should thus be used as a cryoprotectant for storing sperm of these Australian rodents in the future.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Springer Science and Business Media LLC
Date: 07-01-2021
Publisher: American Physiological Society
Date: 05-2015
DOI: 10.1152/AJPENDO.00013.2015
Abstract: Obesity and type 2 diabetes are increasingly prevalent across all demographics. Paternal obesity in humans and rodents can program obesity and impair insulin sensitivity in female offspring. It remains to be determined whether these perturbed offspring phenotypes can be improved through targeted lifestyle interventions in the obese father. Using a mouse model, we demonstrate that diet or exercise interventions for 8 wk (2 rounds of spermatogenesis) in obese founder males restores insulin sensitivity and normalized adiposity in female offspring. Founder diet and/or exercise also normalizes abundance of X-linked sperm microRNAs that target genes regulating cell cycle and apoptosis, pathways central to oocyte and early embryogenesis. Additionally, obesity-associated comorbidities, including inflammation, glucose intolerance, stress, and hypercholesterolemia, were good predictors for sperm microRNA abundance and offspring phenotypes. Interventions aimed at improving paternal metabolic health during specific windows prior to conception can partially normalize aberrant epigenetic signals in sperm and improve the metabolic health of female offspring.
Publisher: Bioscientifica
Date: 08-2017
DOI: 10.1530/JOE-16-0382
Abstract: Animal and human studies demonstrate that acquired paternal traits can impair both a male’s fertility and the health of his offspring, including advanced age, smoking, stress, trauma, under-nutrition, infection, toxin exposure, and obesity. Many of these factors lead to similar changes to neurological, behavioural, and/or metabolic functioning in offspring. The molecular mechanisms that both respond to the paternal environment and act to transmit traits to offspring are beginning to emerge. This review focuses on three vices of men (alcohol consumption, overweight/obesity, and tobacco smoking) that damage fertility and pose risks to offspring health. These vices are not only the three most prevalent but are also leading risk factors for death and disability adjusted life years (DALYs) worldwide. Moreover, given that these vices are predominantly self-inflicted, interventions aimed at mitigating their consequences are readily identified.
Publisher: MDPI AG
Date: 28-01-2022
Abstract: Oxidative stress and elevated levels of seminal and sperm reactive oxygen species (ROS) may contribute to up to 80% of male infertility diagnosis, with sperm ROS concentrations at fertilization important in the development of a healthy fetus and child. The evaluation of ROS in semen seems promising as a potential diagnostic tool for male infertility and male preconception care with a number of clinically available tests on the market (MiOXSYS, luminol chemiluminescence and OxiSperm). While some of these tests show promise for clinical use, discrepancies in documented decision limits and lack of cohort studies/clinical trials assessing their benefits on fertilization rates, embryo development, pregnancy and live birth rates limit their current clinical utility. In this review, we provide an update on the current techniques used for analyzing semen ROS concentrations clinically, the potential to use of ROS research tools for improving clinical ROS detection in sperm and describe why we believe we are likely still a long way away before semen ROS concentrations might become a mainstream preconception diagnostic test in men.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2018
DOI: 10.11124/JBISRIR-2016-003289
Abstract: The objective of this review is to investigate the association between paternal body mass index (BMI) (particularly elevated paternal BMI) and complications of conception and pregnancy as well as neonatal and childhood health.
Publisher: The Endocrine Society
Date: 25-06-2021
Abstract: Paternal experiences and exposures before conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects through modulating the female reproductive tract immune response after mating. To investigate whether paternal obesity affects seminal plasma immune-regulatory activity, C57Bl/6 male mice were fed an obesogenic high-fat diet (HFD) or control diet (CD) for 14 weeks. Although HFD consumption caused only minor changes to parameters of sperm quality, the volume of seminal vesicle fluid secretions was increased by 65%, and the concentrations and total content of immune-regulatory TGF-β isoforms were decreased by 75% to 80% and 43% to 55%, respectively. Mating with BALB/c females revealed differences in the strength and properties of the postmating immune response elicited. Transcriptional analysis showed & inflammatory genes were similarly regulated in the uterine endometrium by mating independently of paternal diet, and 13 were dysregulated by HFD-fed compared with CD-fed males. Seminal vesicle fluid factors reduced in HFD-fed males, including TGF-β1, IL-10, and TNF, were among the predicted upstream regulators of differentially regulated genes. Additionally, the T-cell response induced by mating with CD-fed males was blunted after mating with HFD-fed males, with 27% fewer CD4+ T cells, 26% fewer FOXP3+CD4+ regulatory T cells (Treg) cells, and 19% fewer CTLA4+ Treg cells, particularly within the NRP1+ thymic Treg cell population. These findings demonstrate that an obesogenic HFD alters the composition of seminal vesicle fluid and impairs seminal plasma capacity to elicit a favorable pro-tolerogenic immune response in females at conception.
Publisher: Oxford University Press (OUP)
Date: 05-2015
DOI: 10.1095/BIOLREPROD.114.123489
Abstract: The periconceptual environment represents a critical window for programming fetal growth trajectories and susceptibility to disease however, the underlying mechanism responsible for programming remains elusive. This study demonstrates a causal link between reduction of precompaction embryonic mitochondrial function and perturbed offspring growth trajectories and subsequent metabolic dysfunction. Incubation of embryos with carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), which uncouples mitochondrial oxidative phosphorylation, significantly reduced mitochondrial membrane potential and ATP production in 8-cell embryos and the number of inner cell mass cells within blastocysts however, blastocyst development was unchanged. This perturbed embryonic mitochondrial function was concomitant with reduced birth weight in female offspring following embryo transfer, which persisted until weaning. FCCP-treated females also exhibited increased adiposity at 4 wk, increased adiposity gain between 4 and 14 wk, glucose intolerance at 8 wk, and insulin resistance at 14 wk. Although FCCP-treated males also exhibited reduced glucose tolerance, but their insulin sensitivity and adiposity gain between 4 and 14 wk was unchanged. To our knowledge, this is one of the first studies to demonstrate that reducing mitochondrial function and, thus, decreasing ATP output in the precompacting embryo can influence offspring phenotype. This is of great significance as a large proportion of patients requiring assisted reproductive technologies are of advanced maternal age or have a high body mass index, both of which have been independently linked with perturbed early embryonic mitochondrial function.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.FERTNSTERT.2013.12.057
Abstract: To determine whether supplementation of embryo culture media with a substrate to stimulate mitochondrial activity improves embryo viability and pregnancy establishment in aged mice. Female mice were superovulated and mated. Zygotes were collected and cultured in either G1/G2 or G1/G2 with 1.0 mM dichloroacetic acid (DCA), a stimulator of pyruvate dehydrogenase complex. Embryos were cultured to the blastocyst stage and transferred into pseudopregnant female mice. University research facility. Swiss female mice 26- to 28-week-old. The addition of DCA to the embryo culture media. Embryo development, total, trophectoderm, inner cell mass (ICM) and epiblast cell number, mitochondrial membrane potential, reactive oxygen species, pyruvate oxidation, adenosine triphosphate (ATP) output, implantation rates, and fetal and placental size and weights. Supplementation of the embryo culture medium with DCA significantly increased blastocyst development rates in vitro, significantly improved total, trophectoderm, and ICM cell numbers and pluripotency of the ICM, significantly increased pyruvate oxidation and ATP output, and significantly increased fetal weights and size comparable to in vivo conditions. This study demonstrates that the addition of DCA to embryo culture media improves mitochondrial output in embryos produced from aged mice. Although DCA itself may be of limited therapeutic value in a clinical setting due to its low threshold of dosage and high toxicity, this proof of concept study does suggest that the addition of a physiological-based mitochondrial stimulator to embryo culture media for aged women may potentially improve IVF outcomes.
Publisher: Wiley
Date: 11-07-2013
DOI: 10.1096/FJ.12-224048
Abstract: Obesity is highly prevalent, and its incidence is increasing. The previous study showing a major effect of paternal obesity on metabolic health of offspring is confounded by comorbidity with diabetes. Therefore, we investigated the effect of diet-induced paternal obesity, in the absence of diabetes, on the metabolic health of two resultant generations and the molecular profiles of the testes and sperm. Founder (F0) male C57BL6 mice were fed either a high-fat diet (HFD) or a control diet (CD) n = 10/diet for a period of 10 wk. Testis expression of mRNA/microRNAs was analyzed by microarray and qPCR and sperm microRNA abundance by qPCR. Two subsequent generations were generated by mating F0 and then F1 mice to CD mice, and their metabolic health was investigated. All mice, other than F0 males, were maintained on a CD. HFD feeding induced paternal obesity with a 21% increase in adiposity, but not overt diabetes, and initiated intergenerational transmission of obesity and insulin resistance in two generations of offspring. This distinct phenotypic constellation is either partially or fully transmitted to both female and male F1 offspring and further transmitted through both parental lineages to the F2 generation, with a heightened effect on female F1 offspring (+67% in adiposity) and their F2 sons (+24% in adiposity). Founder male obesity altered the testes expression of 414 mRNAs by microarray and 11 microRNAs by qPCR, concomitant with alterations in sperm microRNA content and a 25% reduction in global methylation of germ cell DNA. Diet-induced paternal obesity modulates sperm microRNA content and germ cell methylation status, which are potential signals that program offspring health and initiate the transmission of obesity and impaired metabolic health to future generations. This study implicates paternal obesity in the transgenerational lification of obesity and type 2 diabetes in humans.
Publisher: Bioscientifica
Date: 12-2022
DOI: 10.1530/REP-22-0121
Abstract: Reactive oxygen species are generated throughout the pre-implantation period and are necessary for normal embryo formation. However, at pathological levels, they result in reduced embryo viability which can be mediated through factors delivered by sperm and eggs at conception or from the external environment. Reactive oxygen species (ROS) occur naturally in pre-implantation embryos as a by-product of ATP generation through oxidative phosphorylation and enzymes such as NADPH oxidase and xanthine oxidase. Biological concentrations of ROS are required for crucial embryonic events such as pronuclear formation, first cleavage and cell proliferation. However, high concentrations of ROS are detrimental to embryo development, resulting in embryo arrest, increased DNA damage and modification of gene expression leading to aberrant fetal growth and health. In vivo embryos are protected against oxidative stress by oxygen scavengers present in follicular and oviductal fluids, while in vitro , embryos rely on their own antioxidant defence mechanisms to protect against oxidative damage, including superoxide dismutase, catalase, glutathione and glutamylcysteine synthestase. Pre-implantation embryonic ROS originate from eggs, sperm and embryos themselves or from the external environment (i.e. in vitro culture system, obesity and ageing). This review examines the biological and pathological roles of ROS in the pre-implantation embryo, maternal and paternal origins of embryonic ROS, and from a clinical perspective, we comment on the growing interest in combating increased oxidative damage in the pre-implantation embryo through the addition of antioxidants.
Publisher: American Physiological Society
Date: 04-2012
DOI: 10.1152/AJPENDO.00401.2011
Abstract: Male obesity is associated with reduced sperm motility and morphology and increased sperm DNA damage and oxidative stress however, the reversibility of these phenotypes has never been studied. Therefore, the aim of this study was to assess the reversibility of obesity and its associated sperm physiology and function in mice in response to weight loss through diet and exercise. C57BL6 male mice ( n = 40) were fed either a control diet (CD 6% fat) or a high-fat diet (HFD 21% fat) for 10 wk before allocation to either diet and/or swimming exercise interventions for 8 wk. Diet alone reduced adiposity (1.6-fold) and serum cholesterol levels (1.7-fold, P 0.05), while exercise alone did not alter these, but exercise plus diet also improved glucose tolerance (1.3-fold, P 0.05). Diet and/or exercise improved sperm motility (1.2-fold) and morphology (1.1-fold, P 0.05), and reduced sperm DNA damage (1.5-fold), reactive oxygen species (1.1-fold), and mitochondrial membrane potential (1.2-fold, P 0.05) and increased sperm binding (1.4-fold) ( P 0.05). Sperm parameters were highly correlated with measures of glycemia, insulin action, and serum cholesterol (all P 0.05) regardless of adiposity or intervention, suggesting a link between systemic metabolic status and sperm function. This is the first study to show that the abnormal sperm physiology resulting from obesity can be reversed through diet and exercise, even in the presence of ongoing obesity, suggesting that diet and lifestyle interventions could be a combined approach to target subfertility in overweight and obese men.
Publisher: MDPI AG
Date: 05-07-2021
Abstract: Advanced paternal age is associated with increased sperm reactive oxygen species (ROS) and decreased fertilization and pregnancy rates. Sperm washing during infertility treatment provides an opportunity to reduce high sperm ROS concentrations associated with advanced paternal age through the addition of idebenone. Sperm from men aged years and older CBAF1 mice (12–18 months), were treated with 5 µM and 50 µM of idebenone and intracellular and superoxide ROS concentrations assessed. Following in vitro fertilization (IVF), embryo development, blastocyst differentiation, DNA damage and cryosurvival, pregnancy and implantation rates and fetal and placental weights were assessed. Five µM of idebenone given to aged human and mouse sperm reduced superoxide concentrations ~20% (p 0.05), while both 5 and 50 µM reduced sperm intracellular ROS concentrations in mice ~30% (p 0.05). Following IVF, 5 µM of idebenone to aged sperm increased fertilization rates (65% vs. 60%, p 0.05), blastocyst total, trophectoderm and inner cell mass cell numbers (73 vs. 66, 53 vs. 47 and 27 vs. 24, respectively, p 0.01). Treatment with idebenone also increased blastocyst cryosurvival rates (96% vs. 78%, p 0.01) and implantation rates following embryo transfer (35% vs. 18%, p 0.01). Placental weights were smaller (107 mg vs. 138 mg, p 0.05), resulting in a larger fetal to placental weight ratio (8.3 vs. 6.3, p = 0.07) after sperm idebenone treatment. Increased sperm ROS concentrations associated with advanced paternal age are reduced with the addition of idebenone in vitro, and are associated with improved fertilization rates, embryo quality and implantation rates after IVF.
Publisher: MDPI AG
Date: 09-02-2017
DOI: 10.3390/NU9020122
Publisher: Elsevier BV
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 04-10-2017
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.FERTNSTERT.2013.12.007
Abstract: To determine whether dietary and exercise regimes in obese males can provide a novel intervention window for improving the reproductive health of the next generation. Experimental animal study. University research facilities. C57BL6 male and female mice. Mice were fed a control diet (6% fat) or high-fat diet (21% fat) for 9 weeks. After the initial feeding, high-fat-diet males were allocated to diet and/or exercise interventions for a further 9 weeks. After intervention males were mated with females fed standard chow (4% fat) before and during pregnancy. F1 sperm motility, count, morphology, capacitation, mitochondrial function, and sperm binding and weight of reproductive organs. Our primary finding was that diet intervention alone in founders improved offspring sperm motility and mitochondrial markers of sperm health (decreased reactive oxygen species and mitochondrial membrane potential), ultimately improving sperm binding. Sperm binding and capacitation was also improved in F1 males born to a combined diet and exercise intervention in founders. Founder sperm parameters and metabolic measures as a response to diet and/or exercise (i.e., lipid/glucose homeostasis, sperm count and morphology) correlated with offspring's sperm function, independent of founder treatment. This implicates paternal metabolic and reproductive status in predicting male offspring's reproductive function. This is the first study to show that improvements to both metabolic (lipids, glucose and insulin sensitivity) and reproductive function (sperm motility and morphology) in obese fathers via diet and exercise interventions can improve subsequent reproductive health in offspring.
Publisher: No publisher found
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 03-06-2016
DOI: 10.1038/SREP27010
Abstract: There is an ever increasing body of evidence that demonstrates that paternal over-nutrition prior to conception programs impaired metabolic health in offspring. Here we examined whether paternal under-nutrition can also program impaired health in offspring and if any detrimental health outcomes in offspring could be prevented by micronutrient supplementation (vitamins and antioxidants). We discovered that restricting the food intake of male rodents reduced their body weight, fertility, increased sperm oxidative DNA lesions and reduced global sperm methylation. Under-nourished males then sired offspring with reduced postnatal weight and growth but somewhat paradoxically increased adiposity and dyslipidaemia, despite being fed standard chow. Paternal vitamin/antioxidant food fortification during under-nutrition not only normalised founder oxidative sperm DNA lesions but also prevented early growth restriction, fat accumulation and dyslipidaemia in offspring. This demonstrates that paternal under-nutrition reduces postnatal growth but increases the risk of obesity and metabolic disease in the next generation and that micronutrient supplementation during this period of under-nutrition is capable of restoring offspring metabolic health.
Publisher: Frontiers Media SA
Date: 10-11-2021
Publisher: Springer Science and Business Media LLC
Date: 10-02-2021
Publisher: Wiley
Date: 03-03-2017
DOI: 10.1002/MRD.22784
Abstract: Gene expression and/or epigenetic deregulation may have consequences for sperm and blastocysts, as well as for the placenta, together potentially contributing to problems observed in offspring. We previously demonstrated specific perturbations of fertilization, blastocyst formation, implantation, as well as aberrant glucose metabolism and adiposity in offspring using a mouse model of paternal obesity. The current investigation analyzed gene expression and methylation of specific CpG residues in F1 placentas of pregnancies fathered by obese and normal-weight male mice, using real-time PCR and bisulfite pyrosequencing. Our aim was to determine if paternal obesity deregulated placental gene expression and DNA methylation when compared to normal-weight males. Gene methylation of sperm DNA was analyzed and compared to placentas to address epigenetic transmission. Of the 10 paternally expressed genes (Pegs), 11 genes important for development and transport of nutrients, and the long-terminal repeat Intracisternal A particle (IAP) elements, derived from a member of the class II endogenous retroviral gene family, we observed a significant effect of paternal diet-induced obesity on deregulated expression of Peg3, Peg9, Peg10, and the nutrient transporter gene Slc38a2, and aberrant DNA methylation of the Peg9 promoter in F1 placental tissue. Epigenetic changes in Peg9 were also found in sperm from obese fathers. We therefore propose that paternal obesity renders changes in gene expression and/or methylation throughout the placental genome, which could contribute to the reproductive problems related to fertility and to the metabolic, long-term health impact on offspring.
Publisher: Informa UK Limited
Date: 10-2012
DOI: 10.4161/SPMG.21362
Publisher: Wiley
Date: 03-2015
DOI: 10.14814/PHY2.12336
Start Date: 2022
End Date: 12-2024
Amount: $463,399.00
Funder: Australian Research Council
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