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RESEARCH ARTICLE

SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity

Nicole O. Palmer A , Tod Fullston A , Megan Mitchell A , Brian P. Setchell B and Michelle Lane A C D
+ Author Affiliations
- Author Affiliations

A School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Frome Road, Adelaide, SA 5005, Australia.

B School of Medical Sciences, University of Adelaide, Frome Road, Adelaide, SA 5005, Australia.

C Repromed, 180 Fullarton Road, Dulwich, SA 5065, Australia.

D Corresponding author. Email: michelle.lane@adelaide.edu.au

Reproduction, Fertility and Development 23(7) 929-939 https://doi.org/10.1071/RD10326
Submitted: 1 December 2010  Accepted: 15 April 2011   Published: 26 August 2011

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.

Additional keywords: spermatozoa, subfertility.


References

Aggerholm, A. S., Thulstrup, A. M., Toft, G., Ramlau-Hansen, C. H., and Bonde, J. P. (2008). Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile? Fertil. Steril. 90, 619–626.
Is overweight a risk factor for reduced semen quality and altered serum sex hormone profile?Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXhtF2qsb7K&md5=7bd85e19b50f1225818eca9a2dde064eCAS | 18068160PubMed |

Aitken, R. J., and De Iuliis, G. N. (2010). On the possible origins of DNA damage in human spermatozoa. Mol. Hum. Reprod. 16, 3–13.
On the possible origins of DNA damage in human spermatozoa.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhsFOhtrrN&md5=1fa4dd702ac27779cd3f44139eeefcbfCAS | 19648152PubMed |

Al-Elq, A. H., Sadat-Ali, M., Al-Turki, H. A., Al-Mulhim, F. A., and Al-Ali, A. K. (2009). Is there a relationship between body mass index and serum vitamin d levels? Saudi Med. J. 30, 1542–1546.
| 19936417PubMed |

Aoki, V. W., Moskovtsev, S. I., Willis, J., Liu, L., Mullen, J. B., and Carrell, D. T. (2005). DNA integrity is compromised in protamine-deficient human sperm. J. Androl. 26, 741–748.
DNA integrity is compromised in protamine-deficient human sperm.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXhtF2msbfN&md5=ead85fed05006cabc32d1ca592d8141fCAS | 16291969PubMed |

Asquith, K. L., Harman, A. J., McLaughlin, E. A., Nixon, B., and Aitken, R. J. (2005). Localization and significance of molecular chaperones, heat shock protein 1, and tumor rejection antigen gp96 in the male reproductive tract and during capacitation and acrosome reaction. Biol. Reprod. 72, 328–337.
Localization and significance of molecular chaperones, heat shock protein 1, and tumor rejection antigen gp96 in the male reproductive tract and during capacitation and acrosome reaction.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXptFGmtQ%3D%3D&md5=922022be9e8b63e4d2fbd0152170cbe4CAS | 15456702PubMed |

Awe, S., and Renkawitz-Pohl, R. (2010). Histone h4 acetylation is essential to proceed from a histone- to a protamine-based chromatin structure in spermatid nuclei of drosophila melanogaster. Syst. Biol. Reprod. Med. 56, 44–61.
Histone h4 acetylation is essential to proceed from a histone- to a protamine-based chromatin structure in spermatid nuclei of drosophila melanogaster.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXitlWqu7s%3D&md5=07901696fefa1cc6dce04374bdd3d17dCAS | 20170286PubMed |

Bakos, H. W., Mitchell, M., Setchell, B. P., and Lane, M. (2010). The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model. Int. J. Androl. , .
The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model.Crossref | GoogleScholarGoogle Scholar | 20649934PubMed |

Bakos, H. W., Henshaw, R. C., Mitchell, M., and Lane, M. (2011). Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology. Fertil. Steril. 95, 1700–1704.
Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.Crossref | GoogleScholarGoogle Scholar | 21145051PubMed |

Bellvé, A. R. (1993). Purification, culture, and fractionation of spermatogenic cells. Methods Enzymol. 225, 84–113.
Purification, culture, and fractionation of spermatogenic cells.Crossref | GoogleScholarGoogle Scholar | 8231890PubMed |

Bener, A., Al-Ansari, A. A., Zirie, M., and Al-Hamaq, A. O. (2009). Is male fertility associated with Type 2 diabetes mellitus? Int. Urol. Nephrol. 41, 777–784.
Is male fertility associated with Type 2 diabetes mellitus?Crossref | GoogleScholarGoogle Scholar | 19381857PubMed |

Chavarro, J. E., Toth, T. L., Wright, D. L., Meeker, J. D., and Hauser, R. (2010). Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic. Fertil. Steril. 93, 2222–2231.
Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXms1yls7c%3D&md5=05452e5b2fdef0562d1a63ef3d9b0209CAS | 19261274PubMed |

Dixon, T., and Waters, A. M. (2003). ‘A growing problem. Trends and patterns in overweight and obesity among adults in Australia 1980 to 2001.’ AIHW Bulletin No. 8. (Australian Institute of Health and Welfare: Canberra.)

Du Plessis, S. S., Cabler, S., McAlister, D. A., Sabanegh, E., and Agarwal, A. (2010). The effect of obesity on sperm disorders and male infertility. Nat. Rev. Urol. 7, 153–161.
The effect of obesity on sperm disorders and male infertility.Crossref | GoogleScholarGoogle Scholar | 20157305PubMed |

Fejes, I., Koloszar, S., Szollosi, J., Zavaczki, Z., and Pal, A. (2005). Is semen quality affected by male body fat distribution? Andrologia 37, 155–159.
Is semen quality affected by male body fat distribution?Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD2MnjvFajtg%3D%3D&md5=57fc4a29942f55596c58b04da1175af1CAS | 16266392PubMed |

Fejes, I., Koloszar, S., Zavaczki, Z., Daru, J., Szollosi, J., and Pal, A. (2006). Effect of body weight on testosterone/estradiol ratio in oligozoospermic patients. Arch. Androl. 52, 97–102.
Effect of body weight on testosterone/estradiol ratio in oligozoospermic patients.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28XhtVGms70%3D&md5=78aab3a94f666e1ec5f8a387b6d8ae5fCAS | 16443585PubMed |

Fenic, I., Sonnack, V., Failing, K., Bergmann, M., and Steger, K. (2004). In vivo effects of histone-deacetylase inhibitor trichostatin-a on murine spermatogenesis. J. Androl. 25, 811–818.
| 1:CAS:528:DC%2BD2cXns1Ggtbs%3D&md5=7096cdd09f447688632c68eaddc9e0faCAS | 15292114PubMed |

Gatford, K. L., De Blasio, M. J., Roberts, C. T., Nottle, M. B., Kind, K. L., van Wettere, W. H., Smits, R. J., and Owens, J. A. (2009). Responses to maternal GH or ractopamine during early-mid pregnancy are similar in primiparous and multiparous pregnant pigs. J. Endocrinol. 203, 143–154.
Responses to maternal GH or ractopamine during early-mid pregnancy are similar in primiparous and multiparous pregnant pigs.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXht1Kku7fO&md5=f47224e36766d90d0661b0beaea4fe7eCAS | 19654144PubMed |

Gaudreault, C., El Alfy, M., Legare, C., and Sullivan, R. (2001). Expression of the hamster sperm protein p26h during spermatogenesis. Biol. Reprod. 65, 79–86.
Expression of the hamster sperm protein p26h during spermatogenesis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXkslWhtL8%3D&md5=93f52212383525376c3a4028d9e2ff3eCAS | 11420226PubMed |

Ghanayem, B. I., Bai, R., Kissling, G. E., Travlos, G., and Hoffler, U. (2010). Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. Biol. Reprod. 82, 96–104.
Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhs1WgsrrK&md5=e845c09bb9b7780ed47c410c017e1a42CAS | 19696015PubMed |

Grimes, S. R. (1984). Release of ribonucleoprotein during digestion of rat testis chromatin with deoxyribonuclease ii (3.1.4.6). Comp. Biochem. Physiol. B 78, 633–641.
Release of ribonucleoprotein during digestion of rat testis chromatin with deoxyribonuclease ii (3.1.4.6).Crossref | GoogleScholarGoogle Scholar | 6478794PubMed |

Grimes, S. R., and Henderson, N. (1984). Acetylation of rat testis histones h2b and th2b. Dev. Biol. 101, 516–521.
Acetylation of rat testis histones h2b and th2b.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaL2cXhtlKgurw%3D&md5=8e7ff89ef5a28b2aa237eada51d22dd3CAS | 6692994PubMed |

Guarente, L., and Picard, F. (2005). Calorie restriction: the sir2 connection. Cell 120, 473–482.
Calorie restriction: the sir2 connection.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXitVWnuro%3D&md5=814ca4f7ac899553c344ac870741b99dCAS | 15734680PubMed |

Hammoud, A. O., Gibson, M., Peterson, C. M., Meikle, A. W., and Carrell, D. T. (2008a). Impact of male obesity on infertility: a critical review of the current literature. Fertil. Steril. 90, 897–904.
Impact of male obesity on infertility: a critical review of the current literature.Crossref | GoogleScholarGoogle Scholar | 18929048PubMed |

Hammoud, A. O., Wilde, N., Gibson, M., Parks, A., Carrell, D. T., and Meikle, A. W. (2008b). Male obesity and alteration in sperm parameters. Fertil. Steril. 90, 2222–2225.
Male obesity and alteration in sperm parameters.Crossref | GoogleScholarGoogle Scholar | 18178190PubMed |

Hazzouri, M., Pivot-Pajot, C., Faure, A. K., Usson, Y., Pelletier, R., Sele, B., Khochbin, S., and Rousseaux, S. (2000). Regulated hyperacetylation of core histones during mouse spermatogenesis: involvement of histone deacetylases. Eur. J. Cell Biol. 79, 950–960.
Regulated hyperacetylation of core histones during mouse spermatogenesis: involvement of histone deacetylases.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3MXot1Srsg%3D%3D&md5=3d5af3d375988b1e6d49becc3a71e3feCAS | 11152286PubMed |

Hegsted, D. M., McGandy, R. B., Myers, M. L., and Stare, F. J. (1965). Quantitative effects of dietary fat on serum cholesterol in man. Am. J. Clin. Nutr. 17, 281–295.
| 1:STN:280:DyaF28%2FkslartA%3D%3D&md5=cbc92d3f6bedd1eaf0a81db9617a2f5aCAS | 5846902PubMed |

Hofny, E. R., Ali, M. E., Abdel-Hafez, H. Z., Kamal Eel, D., Mohamed, E. E., Abd El-Azeem, H. G., and Mostafa, T. (2010). Semen parameters and hormonal profile in obese fertile and infertile males. Fertil. Steril. 94, 581–584.
Semen parameters and hormonal profile in obese fertile and infertile males.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXpvFansLY%3D&md5=5e9e64a329a1d3aea938ab279954b3d3CAS | 19423100PubMed |

Jamsai, D., Bianco, D. M., Smith, S. J., Merriner, D. J., Ly-Huynh, J. D., Herlihy, A., Niranjan, B., Gibbs, G. M., and O’Bryan, M. K. (2008). Characterization of gametogenetin 1 (GGN1) and its potential role in male fertility through the interaction with the ion channel regulator, cysteine-rich secretory protein 2 (CRISP2) in the sperm tail. Reproduction 135, 751–759.
Characterization of gametogenetin 1 (GGN1) and its potential role in male fertility through the interaction with the ion channel regulator, cysteine-rich secretory protein 2 (CRISP2) in the sperm tail.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXnsVOksrw%3D&md5=683184de2d69723fc1bf87e1cf73504dCAS | 18502891PubMed |

Jensen, T. K., Andersson, A. M., Jorgensen, N., Andersen, A. G., Carlsen, E., Petersen, J. H., and Skakkebaek, N. E. (2004). Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil. Steril. 82, 863–870.
Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXhvFOjtrg%3D&md5=581f59ada5a62fef697173e6db0d8e01CAS | 15482761PubMed |

Kanfi, Y., Shalman, R., Peshti, V., Pilosof, S. N., Gozlan, Y. M., Pearson, K. J., Lerrer, B., Moazed, D., Marine, J. C., de Cabo, R., and Cohen, H. Y. (2008). Regulation of sirt6 protein levels by nutrient availability. FEBS Lett. 582, 543–548.
Regulation of sirt6 protein levels by nutrient availability.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXisVSqs7c%3D&md5=0a6cd25886bed9695e6fbc6758fd5c68CAS | 18242175PubMed |

Kanfi, Y., Peshti, V., Gil, R., Naiman, S., Nahum, L., Levin, E., Kronfeld-Schor, N., and Cohen, H. Y. (2010). SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 9, 162–173.
SIRT6 protects against pathological damage caused by diet-induced obesity.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXktFOns70%3D&md5=804b71ffbf73484f0b69c3c899f097a5CAS | 20047575PubMed |

Kimmins, S., and Sassone-Corsi, P. (2005). Chromatin remodelling and epigenetic features of germ cells. Nature 434, 583–589.
Chromatin remodelling and epigenetic features of germ cells.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXislCmsr4%3D&md5=15a3d7583ee1637c8d51bd7a03786dccCAS | 15800613PubMed |

Koloszár, S., Fejes, I., Zavaczki, Z., Daru, J., Szollosi, J., and Pal, A. (2005). Effect of body weight on sperm concentration in normozoospermic males. Arch. Androl. 51, 299–304.
Effect of body weight on sperm concentration in normozoospermic males.Crossref | GoogleScholarGoogle Scholar | 16036638PubMed |

Koltai, E., Szabo, Z., Atalay, M., Boldogh, I., Naito, H., Goto, S., Nyakas, C., and Radak, Z. (2010). Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats. Mech. Ageing Dev. 131, 21–28.
Exercise alters SIRT1, SIRT6, NAD and NAMPT levels in skeletal muscle of aged rats.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXnt1GgsQ%3D%3D&md5=1f0956b253c269e734afabd3835336a5CAS | 19913571PubMed |

Kolthur-Seetharam, U., Teerds, K., de Rooij, D. G., Wendling, O., McBurney, M., Sassone-Corsi, P., and Davidson, I. (2009). The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic–pituitary gonadotropin signaling. Biol. Reprod. 80, 384–391.
The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic–pituitary gonadotropin signaling.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtFOiur8%3D&md5=f42caa10e72998eb8f943495f957db89CAS | 18987333PubMed |

Kort, H. I., Massey, J. B., Elsner, C. W., Mitchell-Leef, D., Shapiro, D. B., Witt, M. A., and Roudebush, W. E. (2006). Impact of body mass index values on sperm quantity and quality. J. Androl. 27, 450–452.
Impact of body mass index values on sperm quantity and quality.Crossref | GoogleScholarGoogle Scholar | 16339454PubMed |

Kriegel, T. M., Heidenreich, F., Kettner, K., Pursche, T., Hoflack, B., Grunewald, S., Poenicke, K., Glander, H. J., and Paasch, U. (2009). Identification of diabetes- and obesity-associated proteomic changes in human spermatozoa by difference gel electrophoresis. Reprod. Biomed. Online 19, 660–670.
Identification of diabetes- and obesity-associated proteomic changes in human spermatozoa by difference gel electrophoresis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXisVaqtw%3D%3D&md5=e748dac7ab8f95c47fdf0bd839bf145bCAS | 20021714PubMed |

Kurtz, K., Ausio, J., and Chiva, M. (2009). Preliminary study of sperm chromatin characteristics of the Brachyuran crab Maja brachydactyla. Histones and nucleosome-like structures in decapod crustacean sperm nuclei previously described without snbps. Tissue Cell 41, 334–344.
Preliminary study of sperm chromatin characteristics of the Brachyuran crab Maja brachydactyla. Histones and nucleosome-like structures in decapod crustacean sperm nuclei previously described without snbps.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtFGkt73N&md5=e557e6d2dc64df90f4a890c3b1f25dc0CAS | 19324386PubMed |

La Vignera, S., Calogero, A. E., Condorelli, R., Lanzafame, F., Giammusso, B., and Vicari, E. (2009). Andrological characterization of the patient with diabetes mellitus. Minerva Endocrinol. 34, 1–9.
| 1:STN:280:DC%2BD1M7jsVGnsw%3D%3D&md5=5b7ed7ad9d3aac3c0502490581d559abCAS | 19209124PubMed |

Liszt, G., Ford, E., Kurtev, M., and Guarente, L. (2005). Mouse sir2 homolog sirt6 is a nuclear adp-ribosyltransferase. J. Biol. Chem. 280, 21 313–21 320.
Mouse sir2 homolog sirt6 is a nuclear adp-ribosyltransferase.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2MXks1elsLs%3D&md5=07212283e8998be11e649bdd05b2ceedCAS |

Lombard, D. B. (2009). Sirtuins at the breaking point: Sirt6 in DNA repair. Aging 1, 12–16.
| 1:CAS:528:DC%2BD1MXht1GkurrM&md5=1ab8ad7eba1bb566e3b6f89a7c7bf992CAS | 20157593PubMed |

Lombard, D. B., Schwer, B., Alt, F. W., and Mostoslavsky, R. (2008). SIRT6 in DNA repair, metabolism and ageing. J. Intern. Med. 263, 128–141.
SIRT6 in DNA repair, metabolism and ageing.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjtFKktb0%3D&md5=b4f3462d3befcd30503983937bb4a9e4CAS | 18226091PubMed |

MacDonald, A. A., Herbison, G. P., Showell, M., and Farquhar, C. M. (2010). The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Hum. Reprod. Update 16, 293–311.
The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXks1Kms74%3D&md5=b6337e03069cdca27c7a9ac4a7311477CAS | 19889752PubMed |

Marcon, L., and Boissonneault, G. (2004). Transient DNA strand breaks during mouse and human spermiogenesis new insights in stage specificity and link to chromatin remodeling. Biol. Reprod. 70, 910–918.
Transient DNA strand breaks during mouse and human spermiogenesis new insights in stage specificity and link to chromatin remodeling.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2cXis1Sitbo%3D&md5=08e0f14d1a9160ca742c4adc7af7b850CAS | 14645105PubMed |

Martini, A. C., Tissera, A., Estofan, D., Molina, R. I., Mangeaud, A., de Cuneo, M. F., and Ruiz, R. D. (2010). Overweight and seminal quality: a study of 794 patients. Fertil. Steril. 94, 1739–1743.
Overweight and seminal quality: a study of 794 patients.Crossref | GoogleScholarGoogle Scholar | 20056217PubMed |

McCord, R. A., Michishita, E., Hong, T., Berber, E., Boxer, L. D., Kusumoto, R., Guan, S., Shi, X., Gozani, O., Burlingame, A. L., Bohr, V. A., and Chua, K. F. (2009). Sirt6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging 1, 109–121.
| 1:CAS:528:DC%2BD1MXht1GkurrF&md5=d10a4653bc5fc8ff00a51635ac2e8e47CAS | 20157594PubMed |

Meistrich, M. L., Trostle-Weige, P. K., Lin, R., Bhatnagar, Y. M., and Allis, C. D. (1992). Highly acetylated h4 is associated with histone displacement in rat spermatids. Mol. Reprod. Dev. 31, 170–181.
Highly acetylated h4 is associated with histone displacement in rat spermatids.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DyaK38XktVCqs7g%3D&md5=e17b03f67f3c0b13cca41e708c3922e9CAS | 1372808PubMed |

Metoyer, C. F., and Pruitt, K. (2008). The role of sirtuin proteins in obesity. Pathophysiology 15, 103–108.
The role of sirtuin proteins in obesity.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXpt1Kjur0%3D&md5=f48ac517118fcf11fa910440bef48921CAS | 18599274PubMed |

Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L., Barrett, J. C., Chang, H. Y., Bohr, V. A., Ried, T., Gozani, O., and Chua, K. F. (2008). SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496.
SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXjslCnurs%3D&md5=37268f31c006b66857a1eeb55cb99abeCAS | 18337721PubMed |

Minge, C. E., Bennett, B. D., Norman, R. J., and Robker, R. L. (2008). Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality. Endocrinology 149, 2646–2656.
Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone reverses the adverse effects of diet-induced obesity on oocyte quality.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1cXht1Gmsb%2FO&md5=c300ee70125853a914f07c599717216aCAS | 18276752PubMed |

Mitchell, M., Bakos, H. W., and Lane, M. (2011). Paternal diet-induced obesity impairs embryo development and implantation in the mouse. Fertil. Steril. 95, 1349–1353.
Paternal diet-induced obesity impairs embryo development and implantation in the mouse.Crossref | GoogleScholarGoogle Scholar | 21047633PubMed |

Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., Mills, K. D., Patel, P., Hsu, J. T., Hong, A. L., Ford, E., Cheng, H. L., Kennedy, C., Nunez, N., Bronson, R., Frendewey, D., Auerbach, W., Valenzuela, D., Karow, M., Hottiger, M. O., Hursting, S., Barrett, J. C., Guarente, L., Mulligan, R., Demple, B., Yancopoulos, G. D., and Alt, F. W. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329.
Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD28Xht1KktLc%3D&md5=facdb285cee9d6ad3cff0f00aea689edCAS | 16439206PubMed |

Ng, S. K., Tan, S. H., and Sundararajan, V. S. (2003). On combining multiple microarray studies for improved functional classification by whole-dataset feature selection. Genome Inform. 14, 44–53.
| 1:CAS:528:DC%2BD2cXitV2isbY%3D&md5=99e848cdf04741fbfc67fae7dc7a49d0CAS | 15706519PubMed |

Ng, S. F., Lin, R. C., Laybutt, D. R., Barres, R., Owens, J. A., and Morris, M. J. (2010). Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963–966.
Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhtlWlsr%2FF&md5=2e25e65e017d1d9fab58f4ec3d143ae6CAS | 20962845PubMed |

Ohta, H., Sakaide, Y., and Wakayama, T. (2009). Functional analysis of male mouse haploid germ cells of various differentiation stages: early and late round spermatids are functionally equivalent in producing progeny. Biol. Reprod. 80, 511–517.
Functional analysis of male mouse haploid germ cells of various differentiation stages: early and late round spermatids are functionally equivalent in producing progeny.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXis1amtLc%3D&md5=9c8fc6a9143f0f38656be3ebb5ce215dCAS | 19073998PubMed |

Paasch, U., Grunewald, S., Kratzsch, J., and Glander, H. J. (2010). Obesity and age affect male fertility potential. Fertil. Steril. 94, 2898–2901.
Obesity and age affect male fertility potential.Crossref | GoogleScholarGoogle Scholar | 20667533PubMed |

Roth, M. Y., Amory, J. K., and Page, S. T. (2008). Treatment of male infertility secondary to morbid obesity. Nat. Clin. Pract. Endocrinol. Metab. 4, 415–419.
Treatment of male infertility secondary to morbid obesity.Crossref | GoogleScholarGoogle Scholar | 18523426PubMed |

Schwer, B., Schumacher, B., Lombard, D. B., Xiao, C., Kurtev, M. V., Gao, J., Schneider, J. I., Chai, H., Bronson, R. T., Tsai, L. H., Deng, C. X., and Alt, F. W. (2010). Neural sirtuin 6 (sirt6) ablation attenuates somatic growth and causes obesity. Proc. Natl Acad. Sci. USA 107, 21 790–21 794.
Neural sirtuin 6 (sirt6) ablation attenuates somatic growth and causes obesity.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhs1WisLrF&md5=fa6baa0c423e00051966bfd7529e08c3CAS |

Sharpe, R. M. (2000). Environment, lifestyle and male infertility. Baillieres Best Pract. Res. Clin. Endocrinol. Metab. 14, 489–503.
Environment, lifestyle and male infertility.Crossref | GoogleScholarGoogle Scholar | 1:STN:280:DC%2BD3MvmslajsA%3D%3D&md5=1c133cb8a85fdd88af82360b2581cc1bCAS | 11097788PubMed |

Sullivan, R., Frenette, G., and Girouard, J. (2007). Epididymosomes are involved in the acquisition of new sperm proteins during epididymal transit. Asian J. Androl. 9, 483–491.
Epididymosomes are involved in the acquisition of new sperm proteins during epididymal transit.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD2sXptVSlsb0%3D&md5=1a312d56543951c9cbc8b7e6e218a39cCAS | 17589785PubMed |

Tennen, R. I., Berber, E., and Chua, K. F. (2010). Functional dissection of SIRT6: Identification of domains that regulate histone deacetylase activity and chromatin localization. Mech. Ageing Dev. 131, 185–192.
Functional dissection of SIRT6: Identification of domains that regulate histone deacetylase activity and chromatin localization.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjvFeqtrs%3D&md5=80ceb974955ac094c7c06f604d07f108CAS | 20117128PubMed |

Vaquero, A. (2009). The conserved role of sirtuins in chromatin regulation. Int. J. Dev. Biol. 53, 303–322.
The conserved role of sirtuins in chromatin regulation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXptVekur0%3D&md5=0d8ef35569392d3c03c562fe4440a2c3CAS | 19378253PubMed |

Vaquero, A., and Reinberg, D. (2009). Calorie restriction and the exercise of chromatin. Genes Dev. 23, 1849–1869.
Calorie restriction and the exercise of chromatin.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD1MXhtVegurnE&md5=f36945de3bc378df18e2bf487a0052ffCAS | 19608767PubMed |

Wang, A., Dean, J., and Sullivan, A. (2007). Assisted reproduction technology in Australia and New Zealand 2005. In ‘Assisted Reproduction Technology’. Series No. 11. pp. 6–8. (Australian Institute of Health and Welfare National Perinatal Statistics Unit: Sydney.)

Wegner, C. C., Clifford, A. L., Jilbert, P. M., Henry, M. A., and Gentry, W. L. (2010). Abnormally high body mass index and tobacco use are associated with poor sperm quality as revealed by reduced sperm binding to hyaluronan-coated slides. Fertil. Steril. 93, 332–334.
Abnormally high body mass index and tobacco use are associated with poor sperm quality as revealed by reduced sperm binding to hyaluronan-coated slides.Crossref | GoogleScholarGoogle Scholar | 19733846PubMed |

World Health Organization. (1999). ‘WHO Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction.’ 4th edn. (Cambridge University Press: Cambridge.)

Xiao, C., Kim, H. S., Lahusen, T., Wang, R. H., Xu, X., Gavrilova, O., Jou, W., Gius, D., and Deng, C. X. (2010). SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J. Biol. Chem. 285, 36 776–36 784.
SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXhsVWgsrvO&md5=5733f9704df25f01278ba3179e46a84eCAS |

Yang, B., Zwaans, B. M., Eckersdorff, M., and Lombard, D. B. (2009). The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability. Cell Cycle 8, 2662–2663.
The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BC3cXjsl2ls7g%3D&md5=14cd8752f9e1bc528498f2dc170b4e47CAS | 19597350PubMed |

Yoshinaga, K., and Toshimori, K. (2003). Organization and modifications of sperm acrosomal molecules during spermatogenesis and epididymal maturation. Microsc. Res. Tech. 61, 39–45.
Organization and modifications of sperm acrosomal molecules during spermatogenesis and epididymal maturation.Crossref | GoogleScholarGoogle Scholar | 1:CAS:528:DC%2BD3sXjslymt7o%3D&md5=5544a885ba120ac60bea01d7dcc36a83CAS | 12672121PubMed |

Zhu, P. Y., Huang, Y. F., and Xu, J. P. (2002). [Isolation and identification of spermatids from mouse testis.] Zhonghua Nan Ke Xue 8, 28–31.
| 12479043PubMed |