Salient points. What does the sperm bring to the egg? A very sophisticated toolbox

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1 What does the sperm bring to the egg? Christopher LR Barratt A very sophisticated toolbox The optimally elected cell High quality DNA PLC Zeta1 (PLCZ1) Centrosome RNA Histone code As yet unknown Salient points The best quality cell - Millions of years of evolution have adapted females (and males) to select the highest quality sperm cells but in ART this may not always be so. Does it make a difference? A sophisticated tool kit not just DNA The obvious : Phospholipase zeta, haploid undamaged DNA, mitochondria (and its DNA),centrosome The less obvious : epigenetic information in form of post translational modifications (e.g. histones), various forms of RNA (e.g. mrna, MiRNA), and unknown e.g. key proteins? We may not be able to robustly select a high quality cell as yet but the requirement to do so is absolute. 3

2 Selecting the optimal cell 4 Embryologists and clinicians (male or female) know selection of sperm is critical The whole paradigm of investigation and treatment relies on the quality of the sperm cell. IUI IVF ICSI [semen parameters critical] The incredible journey selection of the best cells 1:14,000,000 reach site of fertilisation Adapted from Publicover, Harper & Barratt 2007 Nature Cell Biology 9,

3 Mate (gamete) selection in animals Very sophisticated with somewhat of an evolutionary arms race pre and post copulation. All aimed at selection of the fittest sperm cell Dramatic and fierce competition once in female tract : selection by sperm and female Removal of rival cell Induction of response in female tract -gene expression From Manier et al., 2010 Science 328: Sophistication even more refined in some mammals Sperm find their mates and stick to them to increase the chances of fertilisation. From Foster & Pizzari (2010) Current Biology 20: R and Fisher and Hoekstra (2010) Nature 463:

4 Guidance system chemotaxis Eisenbach & Giojalas (2006) Nat Rev Mole Cell Biol 7, More obvious selection of healthy sperm cells An example - Give us the young man with high quality sperm A typical Scottish male without the kilt. Marlon Brando But what about the toolbox? 12

5 A sophisticated toolbox High quality DNA A common question What about DNA? Ward (2010) Mol Hum Reprod 16, 30-6 Delbes et al., (2010) Mol Hum Reprod 16, Special Issue Damaging the paternal genome (sperm) and effects on fertilisation, pregnancy and health Experimental data in animals Numerous robust lines of evidence show negative effects on early embryo development, pregnancy outcome and live births from damage to paternal genome e.g. post implantation pregnancy loss (Delbes et al., (2010) Mol Hum Reprod 16:14-22). Interesting example negative effects of DNA fragmentation (from freezing) on health of offspring (survival, aberrant growth, premature aging, incidence of cancer) Fernandez-Gonzales et al., (2008) Biol Reprod 78: But : What about humans?

6 DNA damage in sperm has a negative influence of Blastocyst development Increased pregnancy loss associated with sperm DNA damage meta analaysis Zini et al., (2008) Hum Reprod. 23: Further data supports this e.g. Speyer et al., 2010 Hum Reprod May 22. [Epub ahead of print] Origin is also important Pregnancy rates significantly lower in men with NOA Additionally strong tendency towards lower gestational age amongst singletons in NOA Vernaeve et al (2003) Hum Reprod 18,

7 Egg activation PLC Zeta1 (PLCZ1) Starting a new life: Sperm PLC zeta mobilizes the Ca2+ signal that induces egg activation and embryo development BioEssays Volume 34, Issue 2, pages , 16 NOV 2011 DOI: /bies Abnormalities in PLC-zeta affect fertilisation rates and possibly development 21 From Yoon et al., J Clin Invest (2008) 118,

8 Centrosome Centrosome From Schatten & Sun (2009) Mol Hum Reprod 15, RNA and its variants mrna (potential translation), mirna, SiRNA Hamatani (2012) Fertil Steril 97, ; Gan et al. (2012) RNA ; Mclver et al., Hum Reprod Update (2011) Advanced access 11 th October.

9 Paramutation.. 25 Epigentic code potentially via resident Histones From Li et al., (2008) Asian J Androl 10, Histones may impart specific imprints especially as it relates to developmentally important genes Brykczynska et al., (2010) Nat Str & Mol Biol Hammoud et al., (2009) Nature 460: Arpanahi et al., (2009) Genome Res 19: Others

10 Hidden key factors the sperm proteome. We ve identified ~2300 proteins $ So What s interesting/or odd?. Significant number of histones [?epigenetic pg modification] Full proteosome [implying turnover?] Significant complement of heat shock proteins (25 +) [chaperone, stress] Potential transcription factors??? 28 Unpublished So the question we ask is : will any sperm do? Adapted from WHO 2010; No Crucial selection of sperm naturally Women certainly want high quality cells

11 Salient points Millions of years of evolution have adapted females (and males) to select the highest quality sperm cells. Women when selecting a partner - understand this... So do clinicians and embryologists... Example of DNA integrity as a critical factors but the sperm is not just DNA (with a tail) it contains a very sophisticated toolkit. We may not be able to robustly select a high quality cell as yet but the requirement to do so is absolute. 31 Members of Group in Dundee Steve Tardif, Sarah Martins Da Silva, Senga Oxenham, Vanessa Kay Wardah Alasmari, Stephen Mansell Collaborators in Dundee Paul Wyatt Stuart Wilson. Steve Publicover - University of Birmingham TENOVUS Scotland Scottish Enterprise 32