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Barbara F. Hales - One of the best experts on this subject based on the ideXlab platform.
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Paternal Exposure to testis cancer chemotherapeutics alters sperm fertilizing capacity and affects gene expression in the eight-cell stage rat embryo
Andrology, 2014Co-Authors: Jennifer Maselli, Barbara F. Hales, Bernard RobaireAbstract:Summary Treatment of testicular cancer includes the coadministration of bleomycin, etoposide and cis-platinum (BEP); however, along with its therapeutic benefit, BEP Exposure results in extensive reproductive chemotoxic effects, including alterations to sperm chromatin integrity. As an intact Paternal genome is essential for successful fertilization and embryogenesis, we assessed the effect of Paternal Exposure to BEP on sperm fertilization capacity and the resulting consequences on early embryonic gene expression. Adult male Brown Norway rats received a 9-week treatment with BEP or saline and then were sacrificed immediately or subject to a 9-week recovery period. HSP90AA1, HSP90B1 and PDIA3, involved in spermatozoa–egg interactions, were overexpressed in BEP-exposed spermatozoa after the 9-week treatment period; overexpression was also observed in spermatozoa from BEP-treated rats after 9 weeks of recovery. These proteins were localized to the plasma membrane of the sperm head; this localization may facilitate their role in spermatozoa–egg interactions as the highest staining intensities were observed in capacitated spermatozoa. The fertilization potential of spermatozoa was determined by in vitro fertilization with oocytes from unexposed naturally cycling female rats. Interestingly, the fertilization potential of spermatozoa following a 9-week recovery period from BEP treatment was significantly enhanced compared with controls. Moreover, stem cell transcription factors, involved in the regulation of a plethora of early embryonic events, were upregulated by more than twofold in eight-cell stage embryos sired by BEP recovery males compared with controls; this suggests that there are potential deleterious effects on embryo development well after termination of BEP Exposure.
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dna damage recognition in the rat zygote following chronic Paternal cyclophosphamide Exposure
Toxicological Sciences, 2007Co-Authors: Tara S. Barton, Bernard Robaire, Barbara F. HalesAbstract:The detrimental effects of preconceptional Paternal Exposure to the alkylating anticancer agent, cyclophosphamide, include aberrant epigenetic programming, dysregulated zygotic gene activation, and abnormalities in the offspring that are transmitted to the next generation. The adverse developmental consequences of genomic instabilities transmitted via the spermatozoon emphasize the need to elucidate the mechanisms by which the early embryo recognizes DNA damage in the Paternal genome. Little information exists on DNA damage detection in the zygote. We assessed the impact of Paternal cyclophosphamide Exposure on phosphorylated H2AX (gH2AX) and poly(ADP-ribose) polymerase-1(PARP-1), biomarkers of DNA damage, to determine the capacity in the rat zygote to recognize genomic damage and initiate a response to DNA lesions. An amplified biphasic gH2AX response was triggered in the Paternal pronucleus in zygotes sired by drug-treated males; the maternal genome was not affected. PARP-1 immunoreactivity was substantially elevated in both parental genomes, coincident with the second phase of gH2AX induction in embryos sired by cyclophosphamide-exposed spermatozoa. Thus, Paternal Exposure to a DNA damaging agent rapidly activates signals implemental for DNA damage recognition in the zygote. Inefficient repair of DNA lesions may lead to persistent alterations of the histone code and chromatin integrity, resulting in aberrant embryogenesis. We propose that the response of the early embryo to disturbances in spermatozoal genomic integrity plays a vital role in determining its outcome.
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epigenetic programming in the preimplantation rat embryo is disrupted by chronic Paternal cyclophosphamide Exposure
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Tara S. Barton, Bernard Robaire, Barbara F. HalesAbstract:Preconceptional Paternal Exposure to cyclophosphamide, a widely used anticancer agent, leads to increases in embryo loss, malformations, and behavioral deficits in offspring; these abnormalities are transmissible to subsequent generations [Auroux, M., Dulioust, E., Selva, J. & Rince, P. (1990) Mutat. Res. 229, 189–200]. Little information exists on the mechanisms underlying this male-mediated developmental toxicity. We assessed the impact of Paternal cyclophosphamide Exposure on the dynamic regulation of histone H4 acetylation at lysine 5 and DNA methylation in preimplantation rat embryos. Zygotes sired by drug-treated males displayed advanced developmental progression, increased pronuclear areas, and disruption of the epigenetic programming of both parental genomes. Early postfertilization zygotic pronuclei were hyperacetylated; by mid-zygotic development, male pronuclei were dramatically hypomethylated, whereas female pronuclei were hypermethylated. Micronuclei were substantially elevated, and histone H4 acetylation at lysine 5 localization to the nuclear periphery was disrupted in two-cell embryos fertilized by cyclophosphamide-exposed spermatozoa. This finding demonstrates that Paternal Exposure to this drug induces aberrant epigenetic programming in early embryos. We hypothesize that disturbances in epigenetic programming contribute to heritable instabilities later in development, emphasizing the importance of epigenetic risk assessment after chemotherapy.
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Paternal Exposure to cyclophosphamide induces dna damage and alters the expression of dna repair genes in the rat preimplantation embryo
Mutation Research-dna Repair, 2000Co-Authors: Wafa Harrouk, Bernard Robaire, Alexis M Codrington, Robert K Vinson, Barbara F. HalesAbstract:Abstract Chronic low dose treatment of male rats with cyclophosphamide, an anticancer alkylating agent, damages male germ cells, resulting in greater than 80% peri-implantation progeny loss. Little transcription or repair takes place in the DNA of post-meiotic male germ cells. The spermatozoal genome regains its transcriptional capacity in the fertilized oocyte. We hypothesized that as a consequence of Exposure of male rats to cyclophosphamide DNA damage to the male genome is transmitted to the conceptus; furthermore, this damage leads to alterations in the expression profiles of DNA repair genes during preimplantation development. Male rats were treated with either saline or cyclophosphamide (6 mg/kg/day, 4–6 weeks) and mated to control females; 1–8 cell stage embryos were collected. The alkaline comet assay was used to assess DNA damage in 1-cell embryos. A significantly higher percentage (68%) of the embryos fertilized by cyclophosphamide-exposed spermatozoa displayed a comet indicative of DNA damage, compared to those sired by control males (18%). The in situ transcription/antisense RNA approach was used to determine if DNA damage alters the expression of DNA repair genes in early embryos. Dramatic increases in the transcripts for selected members of the nucleotide excision repair family (XPC, XPE and PCNA), mismatch repair family (PMS1), and recombination repair family (RAD50) were found in 1-cell stage embryos sired by cyclophosphamide-treated males compared to controls, while decreases in the expression of base excision repair family members (UNG1, UNG2, and XRCC1) and in recombination repair transcripts (RAD54) were observed. By the 8-cell stage, transcripts for specific members of the nucleotide excision repair family (XPC) and mismatch repair family (MSH2, PMS2) were elevated greatly in control embryos compared to embryos sired by drug-treated males; in contrast, transcripts for other members of the nucleotide excision repair family (XPE, PCNA), as well as some of the base excision repair family (UNG1), were elevated in embryos sired by drug-treated males. Therefore, DNA damage incurred in spermatozoa, following cyclophosphamide Exposure is associated with alterations in the expression profiles of DNA repair genes in preimplantation embryos as early as the 1-cell stage. Genotoxic stress may disturb the nuclear remodeling and reprogramming events that follow fertilization and precede zygotic genome activation.
Eugène Van Puijenbroek - One of the best experts on this subject based on the ideXlab platform.
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the effect of Paternal Exposure to immunosuppressive drugs on sexual function reproductive hormones fertility pregnancy and offspring outcomes a systematic review
Human Reproduction Update, 2020Co-Authors: L F Perezgarcia, Saskia Vorstenbosch, Radboud Dolhain, Wichor M. Bramer, Eugène Van Puijenbroek, Johanna M W Hazes, Te B WinkelAbstract:BACKGROUND Information regarding the possible influence of immunosuppressive drugs on male sexual function and reproductive outcomes is scarce. Men diagnosed with immune-mediated diseases and a wish to become a father represent an important neglected population since they lack vital information to make balanced decisions about their treatment. OBJECTIVE AND RATIONALE The aim of this research was to systematically review the literature for the influence of Paternal immunosuppressive drug use on many aspects of male sexual health, such as sexual function, fertility, pregnancy outcomes and offspring health outcomes. SEARCH METHODS A systematic literature search was performed in the bibliographic databases: Embase (via Elsevier embase.com), MEDLINE ALL via Ovid, Cochrane Central Register of Trials (via Wiley) and Web of Science Core Collection. Additionally, Google Scholar and the Clinical trial registries of Europe and the USA were searched. The databases were searched from inception until 31 August 2019. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes and offspring health with a list of immunosuppressive drugs. Studies were included if they were published in English and if they included original data on male human Exposure to immunosuppressive drugs. A meta-analysis was not possible to perform due to the heterogeneity of the data. OUTCOMES A total of 5867 references were identified, amongst which we identified 161 articles fulfilling the eligibility criteria. Amongst these articles, 50 included pregnancy and offspring outcomes and 130 included sexual health outcomes. Except for large Scandinavian cohorts, most of the identified articles included a small number of participants. While a clear negative effect on sperm quality was evident for sulfasalazine and cyclophosphamide, a dubious effect was identified for colchicine, methotrexate and sirolimus. In three articles, Exposure to tumour necrosis factor-α inhibitors in patients diagnosed with ankylosing spondylitis resulted in improved sperm quality. The information regarding pregnancy and offspring outcomes was scant but no large negative effect associated with Paternal immunosuppressive drug Exposure was reported. WIDER IMPLICATIONS Evidence regarding the safety of immunosuppressive drugs in men with a wish to become a father is inconclusive. The lack of standardisation on how to evaluate and report male sexual function, fertility and reproduction as study outcomes in men exposed to immunosuppressive drugs is an important contributor to this result. Future research on this topic is needed and should be preferably done using standardised methods.
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fri0544 the effect of Paternal Exposure to immunosuppressive drugs on sexual function reproductive hormones fertility pregnancy and offspring outcomes a systematic review
Annals of the Rheumatic Diseases, 2020Co-Authors: Luis Fernando Perez, Saskia Vorstenbosch, Radboud Dolhain, Wichor M. Bramer, Eugène Van Puijenbroek, Johanna M W Hazes, Te B WinkelAbstract:Background: Low back pain (LBP) has become a major public health problem worldwide although the burden and underlying causes differ across locations and demographic groups. Objectives: To report the distribution, trend and risk factor in the burden of LBP from the Global Burden of Disease Study 2019 (GBD 2019). Methods: Based on GBD 2019, decomposition analyses were performed according to gender, age, geography and sociodemographic index (SDI). The number and age standardized rate of incidence, prevalence and disability adjusted life years (DALYs) with 95% uncertainty intervals (UI) were calculated. Results: In 2019, female patients have a slightly higher number of prevalence (17%), incidence (15%) and DALYs (16%) than male patients. Out of twenty 5-year age group, the number of incidences, prevalence, DALYs peak at 50-54 age group, while the rate of incidence, prevalence, DALYs peaked at 80-84 age group. From 5 SDI regions, the highest number and age-standardized rate of incidence, prevalence, DALYs were observed in middle and high SDI region, respectively. Considering 21 GBD regions, the highest number of incidence, prevalence, and DALYs were observed in East Asia, while the highest age standardized rate of incidence, prevalence and DALYs all found in Central Europe, High-income North America, High-income North America, respectively. In 204 countries and territories, the top 3 highest number of incidence, prevalence and DALYs were from China, India, United States of America. The top 3 highest age-standardized rate of prevalence, and DALYs were Georgia, United States of America, Denmark, while top 3 highest age-standardized rate of incidence were Poland, Vanuatu, Romania. From 1990 to 2019, globally, the number of incidence, prevalence, DALYs increased by 50%, 47%, 47% to 223,738,363 (95%UI 197,935,799-253,300,243), 569,089,727 (95% UI 505,632,980-641,256,710), 63,533,528 (95%UI 44,883,714-84,975,210), while age standardized rate of incidence, prevalence and DALYs decreased by 13%, 16%, 16% to 2,750 (95%UI 2,427-3,108), 6,974 (95%UI 6,192-7,862), 778 (95%UI 548-1,043). In 5 SDI regions, low SDI region has the highest percentage increases in number of incidence, prevalence and DALYs, the highest percentage decrease in age standardized rate of incidence, prevalence and DALYs were observed in High-middle SDI. In 21 GBD regions, the highest percentage increase in number of incidence, prevalence and DALYs were found in Central Sub-Saharan Africa, while East Asia has the highest percentage decrease in age standardized rate of incidence, prevalence and DALYs. In 204 countries and territories, the greatest percentage increase in number rate of incidence, prevalence, and DALYs were observed in Qatar, while the greatest percentage decrease in age-standardized rate of incidence, prevalence, and DALYs were found in China. In 2019, three risk factors account for 40% (95%UI:36%, 40%) DALYs due to LBP, including smoking (16%, 95%UI:12%, 20%), high body-mass index (7%,95%UI: 4%, 10%), occupational ergonomic factors (24%, 95%UI:22%, 26%). Conclusion: There is significant varied and increased disease burden of LBP by gender, age and geography, partly due to population growth and ageing. The age-standardized rate of prevalence, incidence and DALYs are decreasing, especially in countries such as China and India. Cost effective interventions targeted risk factors are required to minimize the ongoing burden of this condition. References: [1] Hoy D, et al. Ann Rheum Dis. 2014;73(6):968–974. [2] Maher C, et al. Lancet. 2017;389(10070):736–747. [3] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392(10159):1789–1858. [4] GBD 2017 Risk Factor Collaborators. Lancet. 2018;392(10159):1923–1994. Disclosure of Interests: Dongze WU: None declared, Xinyu WU: None declared, Jialing Wu: None declared, Lai-Shan Tam Grant/research support from: Janssen, Pfizer, Novartis, Speakers bureau: Abbvie, Lilly, Sanofi, Jieruo Gu: None declared
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35 Paternal Exposure to immunosuppressive drugs possible influence on pregnancy outcome and infant s health a systematic review
Reproductive Toxicology, 2019Co-Authors: Bernke Te Winkel, Saskia Vorstenbosch, Luis Fernando Perez, Radboud Dolhain, Wichor M. Bramer, Eugène Van PuijenbroekAbstract:Introduction: Although there are theoretical concerns about the possible influence on fertility, pregnancy outcome or complications and health of the offspring, preconceptional Paternal drug Exposure has not been studied significantly. This applies to immunosuppressive drugs like methotrexate and mycophenolic acid. As start of a research project on Paternal immunosuppressive drugs and/or autoimmune diseases and their possible influence on fertility, pregnancy outcomes and child health we performed two systematic reviews, one on drugs and one on diseases. Here we give an overview of the pregnancy and infant outcomes of immunosuppressive drugs from the initial search. Methods: The protocol for this systematic review is written according to the PRISMA-P statement and registered in PROSPERO. A systematic literature search was performed in Embase and MEDLINE. Additional sources included Cochrane Central register of Controlled Trials, Web of Science and Google Scholar. The initial search was done in April 2018. For each database a search profile was developed including keywords regarding male fertility, Paternal Exposure, pregnancy outcomes and complications and infant's health. This was combined with immunosuppressive drugs. The literature search was limited to the English language and human subjects. The following type of studies were included: case control studies, cohort studies, cross-sectional studies, case reports and case series. The methodological quality of the studies was assessed with the Newcastle Ottawa Scale. Results: After deduplication 3720 publications were eligible for title and abstract screening. Full text reading was done for 260 publications, which resulted in inclusion of 41 references on pregnancy and infant related outcomes. Since 2016, 7 population-based cohort studies were published based on the Danish registries, with potential overlap in included pregnancies. The Norwegian registries were used in 2 population-based cohort studies. Other cohort studies used data from Teratology Information Services, the USA National Transplant Pregnancy Registry or hospitals. Case series were mostly based on hospital records. Most studies looked at azathioprine and/or 6-mercaptopurine (n = 8) or methotrexate (n = 5). Other drugs in studies were TNA-alpha blockers, calcineurin inhibitors, mycophenolic acid or colchicine. The most frequently reported outcomes were pregnancy outcome (e.g. miscarriage, live birth), preterm birth (gestational age), low birthweight (birth weight) and congenital abnormalities, in general no major differences between exposed and the comparison group were reported. Conclusions: Paternal use of immunosuppressive drugs preconceptionally has received more attention in the last years. Preliminary data of the systematic review implies that the reported outcomes after immunosuppressive drug use do not differ significantly from the comparison group. The numbers in the different publications, and also the total number of pregnancies included, are still low. The quality of the publications ranges between high and low.
Te B Winkel - One of the best experts on this subject based on the ideXlab platform.
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the effect of Paternal Exposure to immunosuppressive drugs on sexual function reproductive hormones fertility pregnancy and offspring outcomes a systematic review
Human Reproduction Update, 2020Co-Authors: L F Perezgarcia, Saskia Vorstenbosch, Radboud Dolhain, Wichor M. Bramer, Eugène Van Puijenbroek, Johanna M W Hazes, Te B WinkelAbstract:BACKGROUND Information regarding the possible influence of immunosuppressive drugs on male sexual function and reproductive outcomes is scarce. Men diagnosed with immune-mediated diseases and a wish to become a father represent an important neglected population since they lack vital information to make balanced decisions about their treatment. OBJECTIVE AND RATIONALE The aim of this research was to systematically review the literature for the influence of Paternal immunosuppressive drug use on many aspects of male sexual health, such as sexual function, fertility, pregnancy outcomes and offspring health outcomes. SEARCH METHODS A systematic literature search was performed in the bibliographic databases: Embase (via Elsevier embase.com), MEDLINE ALL via Ovid, Cochrane Central Register of Trials (via Wiley) and Web of Science Core Collection. Additionally, Google Scholar and the Clinical trial registries of Europe and the USA were searched. The databases were searched from inception until 31 August 2019. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes and offspring health with a list of immunosuppressive drugs. Studies were included if they were published in English and if they included original data on male human Exposure to immunosuppressive drugs. A meta-analysis was not possible to perform due to the heterogeneity of the data. OUTCOMES A total of 5867 references were identified, amongst which we identified 161 articles fulfilling the eligibility criteria. Amongst these articles, 50 included pregnancy and offspring outcomes and 130 included sexual health outcomes. Except for large Scandinavian cohorts, most of the identified articles included a small number of participants. While a clear negative effect on sperm quality was evident for sulfasalazine and cyclophosphamide, a dubious effect was identified for colchicine, methotrexate and sirolimus. In three articles, Exposure to tumour necrosis factor-α inhibitors in patients diagnosed with ankylosing spondylitis resulted in improved sperm quality. The information regarding pregnancy and offspring outcomes was scant but no large negative effect associated with Paternal immunosuppressive drug Exposure was reported. WIDER IMPLICATIONS Evidence regarding the safety of immunosuppressive drugs in men with a wish to become a father is inconclusive. The lack of standardisation on how to evaluate and report male sexual function, fertility and reproduction as study outcomes in men exposed to immunosuppressive drugs is an important contributor to this result. Future research on this topic is needed and should be preferably done using standardised methods.
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fri0544 the effect of Paternal Exposure to immunosuppressive drugs on sexual function reproductive hormones fertility pregnancy and offspring outcomes a systematic review
Annals of the Rheumatic Diseases, 2020Co-Authors: Luis Fernando Perez, Saskia Vorstenbosch, Radboud Dolhain, Wichor M. Bramer, Eugène Van Puijenbroek, Johanna M W Hazes, Te B WinkelAbstract:Background: Low back pain (LBP) has become a major public health problem worldwide although the burden and underlying causes differ across locations and demographic groups. Objectives: To report the distribution, trend and risk factor in the burden of LBP from the Global Burden of Disease Study 2019 (GBD 2019). Methods: Based on GBD 2019, decomposition analyses were performed according to gender, age, geography and sociodemographic index (SDI). The number and age standardized rate of incidence, prevalence and disability adjusted life years (DALYs) with 95% uncertainty intervals (UI) were calculated. Results: In 2019, female patients have a slightly higher number of prevalence (17%), incidence (15%) and DALYs (16%) than male patients. Out of twenty 5-year age group, the number of incidences, prevalence, DALYs peak at 50-54 age group, while the rate of incidence, prevalence, DALYs peaked at 80-84 age group. From 5 SDI regions, the highest number and age-standardized rate of incidence, prevalence, DALYs were observed in middle and high SDI region, respectively. Considering 21 GBD regions, the highest number of incidence, prevalence, and DALYs were observed in East Asia, while the highest age standardized rate of incidence, prevalence and DALYs all found in Central Europe, High-income North America, High-income North America, respectively. In 204 countries and territories, the top 3 highest number of incidence, prevalence and DALYs were from China, India, United States of America. The top 3 highest age-standardized rate of prevalence, and DALYs were Georgia, United States of America, Denmark, while top 3 highest age-standardized rate of incidence were Poland, Vanuatu, Romania. From 1990 to 2019, globally, the number of incidence, prevalence, DALYs increased by 50%, 47%, 47% to 223,738,363 (95%UI 197,935,799-253,300,243), 569,089,727 (95% UI 505,632,980-641,256,710), 63,533,528 (95%UI 44,883,714-84,975,210), while age standardized rate of incidence, prevalence and DALYs decreased by 13%, 16%, 16% to 2,750 (95%UI 2,427-3,108), 6,974 (95%UI 6,192-7,862), 778 (95%UI 548-1,043). In 5 SDI regions, low SDI region has the highest percentage increases in number of incidence, prevalence and DALYs, the highest percentage decrease in age standardized rate of incidence, prevalence and DALYs were observed in High-middle SDI. In 21 GBD regions, the highest percentage increase in number of incidence, prevalence and DALYs were found in Central Sub-Saharan Africa, while East Asia has the highest percentage decrease in age standardized rate of incidence, prevalence and DALYs. In 204 countries and territories, the greatest percentage increase in number rate of incidence, prevalence, and DALYs were observed in Qatar, while the greatest percentage decrease in age-standardized rate of incidence, prevalence, and DALYs were found in China. In 2019, three risk factors account for 40% (95%UI:36%, 40%) DALYs due to LBP, including smoking (16%, 95%UI:12%, 20%), high body-mass index (7%,95%UI: 4%, 10%), occupational ergonomic factors (24%, 95%UI:22%, 26%). Conclusion: There is significant varied and increased disease burden of LBP by gender, age and geography, partly due to population growth and ageing. The age-standardized rate of prevalence, incidence and DALYs are decreasing, especially in countries such as China and India. Cost effective interventions targeted risk factors are required to minimize the ongoing burden of this condition. References: [1] Hoy D, et al. Ann Rheum Dis. 2014;73(6):968–974. [2] Maher C, et al. Lancet. 2017;389(10070):736–747. [3] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392(10159):1789–1858. [4] GBD 2017 Risk Factor Collaborators. Lancet. 2018;392(10159):1923–1994. Disclosure of Interests: Dongze WU: None declared, Xinyu WU: None declared, Jialing Wu: None declared, Lai-Shan Tam Grant/research support from: Janssen, Pfizer, Novartis, Speakers bureau: Abbvie, Lilly, Sanofi, Jieruo Gu: None declared
Jörns Fickel - One of the best experts on this subject based on the ideXlab platform.
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Tissue-specific epigenetic inheritance after Paternal heat Exposure in male wild guinea pigs
Mammalian Genome, 2020Co-Authors: Alexandra Weyrich, Selma Yasar, Dorina Lenz, Jörns FickelAbstract:External temperature change has been shown to modify epigenetic patterns, such as DNA methylation, which regulates gene expression. DNA methylation is heritable, and as such provides a mechanism to convey environmental information to subsequent generations. Studies on epigenetic response to temperature increase are still scarce in wild mammals, even more so studies that compare tissue-specific epigenetic responses. Here, we aim to address differential epigenetic responses on a gene and gene pathway level in two organs, liver and testis. We chose these organs, because the liver is the main metabolic and thermoregulation organ, and epigenetic modifications in testis are potentially transmitted to the F2 generation. We focused on the transmission of DNA methylation changes to naive male offspring after Paternal Exposure to an ambient temperature increase of 10 °C, and investigated differential methylated regions of sons sired before and after the Paternal Exposure using Reduced Representation Bisulfite Sequencing. We detected both a highly tissue-specific epigenetic response, reflected in genes involved in organ-specific metabolic pathways, and a more general regulation of single genes epigenetically modified in both organs. We conclude that genomes are context-specifically differentially epigenetically regulated in response to temperature increase. These findings emphasize the epigenetic relevance in cell differentiation, which is essential for the specific function(s) of complex organs, and is represented in a diverse molecular regulation of genes and gene pathways. The results also emphasize the Paternal contribution to adaptive processes.
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environmental change dependent inherited epigenetic response
Genes, 2018Co-Authors: Alexandra Weyrich, Dorina Lenz, Jörns FickelAbstract:Epigenetic modifications are a mechanism conveying environmental information to subsequent generations via parental germ lines. Research on epigenetic responses to environmental changes in wild mammals has been widely neglected, as well as studies that compare responses to changes in different environmental factors. Here, we focused on the transmission of DNA methylation changes to naive male offspring after Paternal Exposure to either diet (~40% less protein) or temperature increase (10 °C increased temperature). Because both experiments focused on the liver as the main metabolic and thermoregulation organ, we were able to decipher if epigenetic changes differed in response to different environmental changes. Reduced representation bisulfite sequencing (RRBS) revealed differentially methylated regions (DMRs) in annotated genomic regions in sons sired before (control) and after the fathers’ treatments. We detected both a highly specific epigenetic response dependent on the environmental factor that had changed that was reflected in genes involved in specific metabolic pathways, and a more general response to changes in outer stimuli reflected by epigenetic modifications in a small subset of genes shared between both responses. Our results indicated that fathers prepared their offspring for specific environmental changes by Paternally inherited epigenetic modifications, suggesting a strong Paternal contribution to adaptive processes.
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Paternal intergenerational epigenetic response to heat Exposure in male wild guinea pigs
Molecular Ecology, 2016Co-Authors: Alexandra Weyrich, Dorina Lenz, Jörns Fickel, Marie Jeschek, Tzu Hung Chung, Kathrin Rubensam, Frank Goritz, Katarina JewgenowAbstract:Epigenetic modifications, of which DNA methylation is the best studied one, can convey environmental information through generations via parental germ lines. Past studies have focused on the maternal transmission of epigenetic information to the offspring of isogenic mice and rats in response to external changes, whereas heterogeneous wild mammals as well as Paternal epigenetic effects have been widely neglected. In most wild mammal species, males are the dispersing sex and have to cope with differing habitats and thermal changes. As temperature is a major environmental factor we investigated if genetically heterogeneous Wild guinea pig (Cavia aperea) males can adapt epigenetically to an increase in temperature and if that response will be transmitted to the next generation(s). Five adult male guinea pigs (F0) were exposed to an increased ambient temperature for 2 months, i.e. the duration of spermatogenesis. We studied the liver (as the main thermoregulatory organ) of F0 fathers and F1 sons, and testes of F1 sons for Paternal transmission of epigenetic modifications across generation(s). Reduced representation bisulphite sequencing revealed shared differentially methylated regions in annotated areas between F0 livers before and after heat treatment, and their sons’ livers and testes, which indicated a general response with ecological relevance. Thus, Paternal Exposure to a temporally limited increased ambient temperature led to an ‘immediate’ and ‘heritable’ epigenetic response that may even be transmitted to the F2 generation. In the context of globally rising temperatures epigenetic mechanisms may become increasingly relevant for the survival of species.
Saskia Vorstenbosch - One of the best experts on this subject based on the ideXlab platform.
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the effect of Paternal Exposure to immunosuppressive drugs on sexual function reproductive hormones fertility pregnancy and offspring outcomes a systematic review
Human Reproduction Update, 2020Co-Authors: L F Perezgarcia, Saskia Vorstenbosch, Radboud Dolhain, Wichor M. Bramer, Eugène Van Puijenbroek, Johanna M W Hazes, Te B WinkelAbstract:BACKGROUND Information regarding the possible influence of immunosuppressive drugs on male sexual function and reproductive outcomes is scarce. Men diagnosed with immune-mediated diseases and a wish to become a father represent an important neglected population since they lack vital information to make balanced decisions about their treatment. OBJECTIVE AND RATIONALE The aim of this research was to systematically review the literature for the influence of Paternal immunosuppressive drug use on many aspects of male sexual health, such as sexual function, fertility, pregnancy outcomes and offspring health outcomes. SEARCH METHODS A systematic literature search was performed in the bibliographic databases: Embase (via Elsevier embase.com), MEDLINE ALL via Ovid, Cochrane Central Register of Trials (via Wiley) and Web of Science Core Collection. Additionally, Google Scholar and the Clinical trial registries of Europe and the USA were searched. The databases were searched from inception until 31 August 2019. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes and offspring health with a list of immunosuppressive drugs. Studies were included if they were published in English and if they included original data on male human Exposure to immunosuppressive drugs. A meta-analysis was not possible to perform due to the heterogeneity of the data. OUTCOMES A total of 5867 references were identified, amongst which we identified 161 articles fulfilling the eligibility criteria. Amongst these articles, 50 included pregnancy and offspring outcomes and 130 included sexual health outcomes. Except for large Scandinavian cohorts, most of the identified articles included a small number of participants. While a clear negative effect on sperm quality was evident for sulfasalazine and cyclophosphamide, a dubious effect was identified for colchicine, methotrexate and sirolimus. In three articles, Exposure to tumour necrosis factor-α inhibitors in patients diagnosed with ankylosing spondylitis resulted in improved sperm quality. The information regarding pregnancy and offspring outcomes was scant but no large negative effect associated with Paternal immunosuppressive drug Exposure was reported. WIDER IMPLICATIONS Evidence regarding the safety of immunosuppressive drugs in men with a wish to become a father is inconclusive. The lack of standardisation on how to evaluate and report male sexual function, fertility and reproduction as study outcomes in men exposed to immunosuppressive drugs is an important contributor to this result. Future research on this topic is needed and should be preferably done using standardised methods.
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fri0544 the effect of Paternal Exposure to immunosuppressive drugs on sexual function reproductive hormones fertility pregnancy and offspring outcomes a systematic review
Annals of the Rheumatic Diseases, 2020Co-Authors: Luis Fernando Perez, Saskia Vorstenbosch, Radboud Dolhain, Wichor M. Bramer, Eugène Van Puijenbroek, Johanna M W Hazes, Te B WinkelAbstract:Background: Low back pain (LBP) has become a major public health problem worldwide although the burden and underlying causes differ across locations and demographic groups. Objectives: To report the distribution, trend and risk factor in the burden of LBP from the Global Burden of Disease Study 2019 (GBD 2019). Methods: Based on GBD 2019, decomposition analyses were performed according to gender, age, geography and sociodemographic index (SDI). The number and age standardized rate of incidence, prevalence and disability adjusted life years (DALYs) with 95% uncertainty intervals (UI) were calculated. Results: In 2019, female patients have a slightly higher number of prevalence (17%), incidence (15%) and DALYs (16%) than male patients. Out of twenty 5-year age group, the number of incidences, prevalence, DALYs peak at 50-54 age group, while the rate of incidence, prevalence, DALYs peaked at 80-84 age group. From 5 SDI regions, the highest number and age-standardized rate of incidence, prevalence, DALYs were observed in middle and high SDI region, respectively. Considering 21 GBD regions, the highest number of incidence, prevalence, and DALYs were observed in East Asia, while the highest age standardized rate of incidence, prevalence and DALYs all found in Central Europe, High-income North America, High-income North America, respectively. In 204 countries and territories, the top 3 highest number of incidence, prevalence and DALYs were from China, India, United States of America. The top 3 highest age-standardized rate of prevalence, and DALYs were Georgia, United States of America, Denmark, while top 3 highest age-standardized rate of incidence were Poland, Vanuatu, Romania. From 1990 to 2019, globally, the number of incidence, prevalence, DALYs increased by 50%, 47%, 47% to 223,738,363 (95%UI 197,935,799-253,300,243), 569,089,727 (95% UI 505,632,980-641,256,710), 63,533,528 (95%UI 44,883,714-84,975,210), while age standardized rate of incidence, prevalence and DALYs decreased by 13%, 16%, 16% to 2,750 (95%UI 2,427-3,108), 6,974 (95%UI 6,192-7,862), 778 (95%UI 548-1,043). In 5 SDI regions, low SDI region has the highest percentage increases in number of incidence, prevalence and DALYs, the highest percentage decrease in age standardized rate of incidence, prevalence and DALYs were observed in High-middle SDI. In 21 GBD regions, the highest percentage increase in number of incidence, prevalence and DALYs were found in Central Sub-Saharan Africa, while East Asia has the highest percentage decrease in age standardized rate of incidence, prevalence and DALYs. In 204 countries and territories, the greatest percentage increase in number rate of incidence, prevalence, and DALYs were observed in Qatar, while the greatest percentage decrease in age-standardized rate of incidence, prevalence, and DALYs were found in China. In 2019, three risk factors account for 40% (95%UI:36%, 40%) DALYs due to LBP, including smoking (16%, 95%UI:12%, 20%), high body-mass index (7%,95%UI: 4%, 10%), occupational ergonomic factors (24%, 95%UI:22%, 26%). Conclusion: There is significant varied and increased disease burden of LBP by gender, age and geography, partly due to population growth and ageing. The age-standardized rate of prevalence, incidence and DALYs are decreasing, especially in countries such as China and India. Cost effective interventions targeted risk factors are required to minimize the ongoing burden of this condition. References: [1] Hoy D, et al. Ann Rheum Dis. 2014;73(6):968–974. [2] Maher C, et al. Lancet. 2017;389(10070):736–747. [3] GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392(10159):1789–1858. [4] GBD 2017 Risk Factor Collaborators. Lancet. 2018;392(10159):1923–1994. Disclosure of Interests: Dongze WU: None declared, Xinyu WU: None declared, Jialing Wu: None declared, Lai-Shan Tam Grant/research support from: Janssen, Pfizer, Novartis, Speakers bureau: Abbvie, Lilly, Sanofi, Jieruo Gu: None declared
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35 Paternal Exposure to immunosuppressive drugs possible influence on pregnancy outcome and infant s health a systematic review
Reproductive Toxicology, 2019Co-Authors: Bernke Te Winkel, Saskia Vorstenbosch, Luis Fernando Perez, Radboud Dolhain, Wichor M. Bramer, Eugène Van PuijenbroekAbstract:Introduction: Although there are theoretical concerns about the possible influence on fertility, pregnancy outcome or complications and health of the offspring, preconceptional Paternal drug Exposure has not been studied significantly. This applies to immunosuppressive drugs like methotrexate and mycophenolic acid. As start of a research project on Paternal immunosuppressive drugs and/or autoimmune diseases and their possible influence on fertility, pregnancy outcomes and child health we performed two systematic reviews, one on drugs and one on diseases. Here we give an overview of the pregnancy and infant outcomes of immunosuppressive drugs from the initial search. Methods: The protocol for this systematic review is written according to the PRISMA-P statement and registered in PROSPERO. A systematic literature search was performed in Embase and MEDLINE. Additional sources included Cochrane Central register of Controlled Trials, Web of Science and Google Scholar. The initial search was done in April 2018. For each database a search profile was developed including keywords regarding male fertility, Paternal Exposure, pregnancy outcomes and complications and infant's health. This was combined with immunosuppressive drugs. The literature search was limited to the English language and human subjects. The following type of studies were included: case control studies, cohort studies, cross-sectional studies, case reports and case series. The methodological quality of the studies was assessed with the Newcastle Ottawa Scale. Results: After deduplication 3720 publications were eligible for title and abstract screening. Full text reading was done for 260 publications, which resulted in inclusion of 41 references on pregnancy and infant related outcomes. Since 2016, 7 population-based cohort studies were published based on the Danish registries, with potential overlap in included pregnancies. The Norwegian registries were used in 2 population-based cohort studies. Other cohort studies used data from Teratology Information Services, the USA National Transplant Pregnancy Registry or hospitals. Case series were mostly based on hospital records. Most studies looked at azathioprine and/or 6-mercaptopurine (n = 8) or methotrexate (n = 5). Other drugs in studies were TNA-alpha blockers, calcineurin inhibitors, mycophenolic acid or colchicine. The most frequently reported outcomes were pregnancy outcome (e.g. miscarriage, live birth), preterm birth (gestational age), low birthweight (birth weight) and congenital abnormalities, in general no major differences between exposed and the comparison group were reported. Conclusions: Paternal use of immunosuppressive drugs preconceptionally has received more attention in the last years. Preliminary data of the systematic review implies that the reported outcomes after immunosuppressive drug use do not differ significantly from the comparison group. The numbers in the different publications, and also the total number of pregnancies included, are still low. The quality of the publications ranges between high and low.