Finding a positive association between paternal age and the incidence of aneuploidy is not difficult. A cursory analysis however reveals that any association is indirect, brought about by a close correlation between paternal age and maternal age. Approaches for dissecting out the confounding age effects of the mother has led to a lively exchange among epidemiologists, with perhaps a consensus for the absence of a paternal age effect, at least for trisomy 21. Molecular studies revealed the relatively minor contribution of paternal errors to trisomy, but even research on the paternally derived trisomies alone has been inconclusive; thus studies focussed directly on the sperm heads. Human-hamster fusion assays were superseded by FISH for establishing any possible link between age and the proportion of disomic sperm in an ejaculate. Despite innumerable microscope hours however, although convincing studies suggesting an age effect for disomies 1, 9, 18 and 21 and the sex chromosomes are in the literature, others failed to notice any association for these or other chromosomes. It is biologically plausible that chromosomal non-disjunction errors should increase with age. Male reproductive hormone production, testicular morphology and semen parameters all decline slowly with age and paternal age is implicated in congenital birth defects, such as achondroplasia and Apert syndromes and also linked to compromised DNA repair mechanisms. Despite several decades of epidemiological and molecular cytogenetic studies, however, we are still not close to a definitive answer of whether or not there is a paternal age effect for aneuploidy. In this review we conclude by questioning the efficacy of FISH because of difficulties in detecting nullisomy and because of evidence that the centromeres (from which most sperm-FISH probes are derived) cluster at the nuclear centre. Array-based approaches may well supersede FISH in addressing the question of a paternal age effect; for now, however, the jury is still out.

Keywords:
Age, Aneuploidy, Chromosome, Sperm, Trisomy
1.
Antonarakis SE: Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down syndrome collaborative group. N Engl J Med 324:872–876 (1991).
2.
Archer NP, Langlois PH, Suarez L, Brender J, Shanmugam R: Association of paternal age with prevalence of selected birth defects. Birth Defects Res A Clin Mol Teratol 79:27–34 (2007).
3.
Asada H, Sueoka K, Hashiba T, Kuroshima M, Kobayashi N, Yoshimura Y: The effects of age and abnormal sperm count on the nondisjunction of spermatozoa. J Assist Reprod Genet 17:51–59 (2000).
4.
Baumgartner A, Van Hummelen P, Lowe XR, Adler ID, Wyrobek AJ: Numerical and structural chromosomal abnormalities detected in human sperm with a combination of multicolor fish assays. Environ Mol Mutagen 33:49–58 (1999).
5.
Bosch M, Rajmil O, Martinez-Pasarell O, Egozcue J, Templado C: Linear increase of diploidy in human sperm with age: a four-colour fish study. Eur J Hum Genet 9:533–538 (2000).
6.
Bosch M, Rajmil O, Egozcue J, Templado C: Linear increase of structural and numerical chromosome 9 abnormalities in human sperm regarding age. Eur J Hum Genet 10:754–759 (2003).
7.
Brandriff B, Gordon L, Ashworth L, Watchmaker G, Moore D 2nd, et al: Chromosomes of human sperm: variability among normal individuals. Hum Genet 70:18–24 (1985).
8.
Bugge M, Collins A, Hertz JM, Eiberg H, Lundsteen C, et al: Non-disjunction of chromosome 13. Hum Mol Genet 16:2004–2010 (2007).
9.
Buwe A, Guttenbach M, Schmid M: Effect of paternal age on the frequency of cytogenetic abnormalities in human spermatozoa. Cytogenet Genome Res 111:213–228 (2005).
10.
Carothers AD, Frackiewicz A, De Mey R, Collyer S, Polani PE, et al: A collaborative study of the aetiology of Turner syndrome. Ann Hum Genet 43:355–368 (1980).
11.
Crow JF: The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet 1:40–47 (2000).
12.
Dakouane M, Bicchieray L, Bergere M, Albert M, Vialard F, et al: A histomorphometric and cytogenetic study of testis from men 29–102 years old. Fertil Steril 83:923–928 (2005).
13.
De Michelena MI, Burstein E, Lama JR, Vasquez JC: Paternal age as a risk factor for Down syndrome. Am J Med Genet 45:679–682 (1993).
14.
Eggermann T, Nothen MM, Eiben B, Hofmann D, Hinkel K, et al: Trisomy of human chromosome 18: molecular studies on parental origin and cell stage of nondisjunction. Hum Genet 97:218–223 (1996).
15.
Eskenazi B, Wyrobek AJ, Kidd SA, Lowe X, Moore D 2nd, et al: Sperm aneuploidy in fathers of children with paternally and maternally inherited Klinefelter syndrome. Hum Reprod 17:576–583 (2002).
16.
Ferguson-Smith MA, Yates JR: Maternal age specific rates for chromosome aberrations and factors influencing them: report of a collaborative European study on 52 965 amniocenteses. Prenat Diagn 4 Spec No:5–44 (1984).
17.
Finch KA, Fonseka KG, Abogrein A, Ioannou D, Handyside AH, et al: Nuclear organization in human sperm: preliminary evidence for altered sex chromosome centromere position in infertile males. Hum Reprod 23:1263–1270 (2008).
18.
Fisher JM, Harvey JF, Lindenbaum RH, Boyd PA, Jacobs PA: Molecular studies of trisomy 18. Am J Hum Genet 52:1139–1144 (1993).
19.
Fisher JM, Harvey JF, Morton NE, Jacobs PA: Trisomy 18: studies of the parent and cell division of origin and the effect of aberrant recombination on nondisjunction. Am J Hum Genet 56:669–675 (1995).
20.
Foster HA, Abeydeera LR, Griffin DK, Bridger JM: Non-random chromosome positioning in mammalian sperm nuclei, with migration of the sex chromosomes during late spermatogenesis. J Cell Sci 118:1811–1820 (2005).
21.
Goldstein H, Nielsen KG: Rates and survival of individuals with trisomy 13 and 18. Data from a 10-year period in Denmark. Clin Genet 34:366–372 (1988).
22.
Griffin DK: The incidence, origin, and etiology of aneuploidy. Int Rev Cytol 167:263–296 (1996).
23.
Griffin DK, Finch KA: The genetic and cytogenetic basis of male infertility. Hum Fertil (Camb) 8:19–26 (2005)
24.
Griffin DK, Abruzzo MA, Millie EA, Sheean LA, Feingold E, et al: Non-disjunction in human sperm: evidence for an effect of increasing paternal age. Hum Mol Genet 4:2227–2232 (1995).
25.
Guttenbach M, Schmid M: Determination of Y chromosome aneuploidy in human sperm nuclei by nonradioactive in situ hybridization. Am J Hum Genet 46:553–558 (1990).
26.
Guttenbach M, Schakowski R, Schmid M: Incidence of chromosome 3, 7, 10, 11, 17 and X disomy in mature human sperm nuclei as determined by nonradioactive in situ hybridization. Hum Genet 93:7–12 (1994).
27.
Guttenbach M, Martinez-Exposito MJ, Michelmann HW, Engel W, Schmid M: Incidence of diploid and disomic sperm nuclei in 45 infertile men. Hum Reprod 12:468–473 (1997).
28.
Guttenbach M, Kohn FM, Engel W, Schmid M: Meiotic nondisjunction of chromosomes 1, 17, 18, X, and Y in men more than 80 years of age. Biol Reprod 2000 6:1727–1729 (2000).
29.
Handelsman DJ, Staraj S: Testicular size: the effects of aging, malnutrition, and illness. J Androl 6:144–151 (1985).
30.
Handyside AH, Harton GL, Mariani B, Thornhill AR, Affara NA, et al: Karyomapping: a universal method for genome wide analysis of genetic disease based on mapping crossovers between parental haplotypes. J Med Genet 47:651–658 (2010).
31.
Hassold T, Hunt P: To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2:280–291 (2001).
32.
Hassold T, Chen N, Funkhouser J, Jooss T, Manuel B, et al: A cytogenetic study of 1,000 spontaneous abortions. Ann Hum Genet 44:151–178 (1980).
33.
Hassold T, Abruzzo M, Adkins K, Griffin D, Merrill M, et al: Human aneuploidy: incidence, origin, and etiology. Environ Mol Mutagen 28:167–175 (1996).
34.
Hassold T, Hall H, Hunt P: The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet 16 Spec No. 2: R203–R208 (2007).
35.
Hatch M, Kline J, Levin B, Hutzler M, Warburton D: Paternal age and trisomy among spontaneous abortions. Hum Genet 85:355–361 (1990).
36.
Hellstrom WJ, Overstreet JW, Sikka SC, Denne J, Ahuja S, et al: Semen and sperm reference ranges for men 45 years of age and older. J Androl 27:421–428 (2006).
37.
Hook EB: Issues in analysis of data on paternal age and 47,+21: implications for genetic counseling for Down syndrome. Hum Genet 77:303–306 (1987).
38.
Hook EB, Regal RR: A search for a paternal-age effect upon cases of 47, +21 in which the extra chromosome is of paternal origin. Am J Hum Genet 36:413–421 (1984).
39.
Hook EB, Cross PK, Lamson SH, Regal RR, Baird PA, et al: Paternal age and Down syndrome in British Columbia. Am J Hum Genet 33:123–128 (1981).
40.
Jacobs PA, Hassold TJ, Whittington E, Butler G, Collyer S, et al: Klinefelter’s syndrome: an analysis of the origin of the additional sex chromosome using molecular probes. Ann Hum Genet 52:93–109 (1988).
41.
Johnson L, Grumbles JS, Bagheri A, Petty CS: Increased germ cell degeneration during postprophase of meiosis is related to increased serum follicle-stimulating hormone concentrations and reduced daily sperm production in aged men. Biol Reprod 42:281–287 (1990).
42.
Kaufman JM, Vermeulen A: The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocr Rev 26:833–876 (2005).
43.
Kidd SA, Eskenazi B, Wyrobek AJ: Effects of male age on semen quality and fertility: a review of the literature. Fertil Steril 75:237–248 (2001).
44.
Kondoh T, Tonoki H, Matsumoto T, Tsukahara M, Niikawa N: Origin of the extra chromosome in trisomy 18. A study on five patients using a restriction fragment length polymorphism. Hum Genet 79:377–378 (1988).
45.
Kuhnert B, Nieschlag E: Reproductive functions of the ageing male. Hum Reprod Update 10:327–339 (2004).
46.
Kupke KG, Muller U: Parental origin of the extra chromosome in trisomy 18. Am J Hum Genet 45:599–605 (1989).
47.
Lahdetie J, Ajosenpaa-Saari M, Mykkanen J: Detection of aneuploidy in human spermatozoa of normal semen donors by fluorescence in situ hybridization. Environ Health Perspect 104:629–632 (1996).
48.
Lian ZH, Zack MM, Erickson JD: Paternal age and the occurrence of birth defects. Am J Hum Genet 39:648–660 (1986).
49.
Lorda-Sanchez I, Binkert F, Maechler M, Robinson WP, Schinzel AA: Reduced recombination and paternal age effect in Klinefelter syndrome. Hum Genet 89:524–530 (1992).
50.
Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A, et al: Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. Am J Hum Genet 69:1046–1054 (2001).
51.
Luetjens CM, Rolf C, Gassner P, Werny JE, Nieschlag E: Sperm aneuploidy rates in younger and older men. Hum Reprod 17:1826–1832 (2002).
52.
MacDonald M, Hassold T, Harvey J, Wang LH, Morton NE, et al: The origin of 47,XXY and 47,XXX aneuploidy: heterogeneous mechanisms and role of aberrant recombination. Hum Mol Genet 3:1365–1371 (1994).
53.
Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, et al: Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet 114:299–303 (2002).
54.
Martin RH, Rademaker AW: The effect of age on the frequency of sperm chromosomal abnormalities in normal men. Am J Hum Genet 41:484–492 (1987).
55.
Martin RH, Spriggs E, Ko E, Rademaker AW: The relationship between paternal age, sex ratios, and aneuploidy frequencies in human sperm, as assessed by multicolor fish. Am J Hum Genet 57:1395–1399 (1995).
56.
Martin RH, Ernst S, Rademaker A, Barclay L, Ko E, et al: Chromosomal abnormalities in sperm from testicular cancer patients before and after chemotherapy. Hum Genet 99:214–218 (1997).
57.
Martinez-Pasarell O, Nogues C, Bosch M, Egozcue J, Templado C: Analysis of sex chromosome aneuploidy in sperm from fathers of Turner syndrome patients. Hum Genet 104:345–349 (1999).
58.
Mathur A, Stekol L, Schatz D, MacLaren NK, Scott ML, et al: The parental origin of the single X chromosome in Turner syndrome: lack of correlation with parental age or clinical phenotype. Am J Hum Genet 48:682–686 (1991).
59.
Matsunaga E, Tonomura A, Oishi H, Kikuchi Y: Reexamination of paternal age effect in Down’s syndrome. Hum Genet 40:259–268 (1978).
60.
McInnes B, Rademaker A, Martin R: Donor age and the frequency of disomy for chromosomes 1, 13, 21 and structural abnormalities in human spermatozoa using multicolour fluorescence in-situ hybridization. Hum Reprod 13:2489–2494 (1998).
61.
McIntosh G, Olshan A, Baird P: Paternal age and the risk of birth defects in offspring. Epidemiology 6:282–288 (1995).
62.
Mirone V, Ricci E, Gentile V, Basile Fasolo C, Parazzini F: Determinants of erectile dysfunction risk in a large series of Italian men attending andrology clinics. Eur Urol 45:87–91 (2004).
63.
Naguib KK, Al-Awadi SA, Moussa MA, Bastaki L, Gouda S, et al: Trisomy 18 in Kuwait. Int J Epidemiol 28:711–716 (1999).
64.
Nicolaidis P, Petersen MB: Origin and mechanisms of non-disjunction in human autosomal trisomies. Hum Reprod 13:313–319 (1998).
65.
Nothen MM, Eggermann T, Erdmann J, Eiben B, Hofmann D, et al: Retrospective study of the parental origin of the extra chromosome in trisomy 18 (Edwards syndrome). Hum Genet 92:347–349 (1993).
66.
Nybo Andersen AM, Hansen KD, Andersen PK, Davey Smith G: Advanced paternal age and risk of fetal death: a cohort study. Am J Epidemiol 160:1214–1222 (2004).
67.
Olshan AF, Ananth CV, Savitz DA: Intrauterine growth retardation as an endpoint in mutation epidemiology: an evaluation based on paternal age. Mutat Res 344:89–94 (1995).
68.
Penrose LS: The relative effects of paternal and maternal age in mongolism. J Genet 27:219 (1933).
69.
Penrose LS: Parental age and mutation. Lancet 269:312–313 (1955).
70.
Petersen MB, Antonarakis SE, Hassold TJ, Freeman SB, Sherman SL, et al: Paternal nondisjunction in trisomy 21: excess of male patients. Hum Mol Genet 2:1691–1695 (1993).
71.
Regal RR, Cross PK, Lamson SH, Hook EB: A search for evidence for a paternal age effect independent of a maternal age effect in birth certificate reports of Down’s syndrome in New York State. Am J Epidemiol 112:650–655 (1980).
72.
Robbins WA, Baulch JE, Moore D 2nd, Weier HU, Blakey D, et al: Three-probe fluorescence in situ hybridization to assess chromosome X, Y, and 8 aneuploidy in sperm of 14 men from two healthy groups: evidence for a paternal age effect on sperm aneuploidy. Reprod Fertil Dev 7:799–809 (1995).
73.
Robbins WA, Vine MF, Truong KY, Everson RB: Use of fluorescence in situ hybridization (fish) to assess effects of smoking, caffeine, and alcohol on aneuploidy load in sperm of healthy men. Environ Mol Mutagen 30:175–183 (1997).
74.
Robinson WP, Bernasconi F, Dutly F, Lefort G, Romain DR, et al: Molecular studies of translocations and trisomy involving chromosome 13. Am J Med Genet 61:158–163 (1996).
75.
Rochebrochard E, Thonneau P: Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Hum Reprod 17:1649–1656 (2002).
76.
Rolf C, Nieschlag E: Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes 109:68–74 (2001).
77.
Rolf C, Behre HM, Nieschlag E: Reproductive parameters of older compared to younger men of infertile couples. Int J Androl 19:135–142 (1996).
78.
Rosenbusch B, Strehler E, Abt M, Sterzik K: Correlation between cytogenetic anomalies of human spermatozoa and sperm morphology as well as age of patients studied. Zentralbl Gynäkol 115:113–116 (1993).
79.
Roth MP, Stoll C, Taillemite JL, Girard S, Boue A: Paternal age and Down’s syndrome diagnosed prenatally: no association in French data. Prenat Diagn 3:327–335 (1983).
80.
Rousseaux S, Hazzouri M, Pelletier R, Monteil M, Usson Y, et al: Disomy rates for chromosomes 14 and 21 studied by fluorescent in-situ hybridization in spermatozoa from three men over 60 years of age. Mol Hum Reprod 4:695–699 (1998).
81.
Sartorelli EM, Mazzucatto LF, de Pina-Neto JM: Effect of paternal age on human sperm chromosomes. Fertil Steril 76:1119–1123 (2001).
82.
Sartorius GA, Nieschlag E: Paternal age and reproduction. Hum Reprod Update 16:65–79 (2010).
83.
Savage AR, Petersen MB, Pettay D, Taft L, Allran K, et al: Elucidating the mechanisms of paternal non-disjunction of chromosome 21 in humans. 7:1221–1227 (1998).
84.
Schmid TE, Brinkworth MH, Hill F, Sloter E, Kamischke A, et al: Detection of structural and numerical chromosomal abnormalities by ACM-FISH analysis in sperm of oligozoospermic infertility patients. Hum Reprod 19:1395–1400 (2004).
85.
Shah K, Sivapalan G, Gibbons N, Tempest H, Griffin DK: The genetic basis of infertility. Reproduction 126:13–25 (2003).
86.
Sherman SL, Takaesu N, Freeman SB, Grantham M, Phillips C, et al: Trisomy 21: association between reduced recombination and nondisjunction. Am J Hum Genet 49:608–620 (1991).
87.
Shi Q, Martin RH: Spontaneous frequencies of aneuploid and diploid sperm in 10 normal chinese men: assessed by multicolor fluorescence in situ hybridization. Cytogenet Cell Genet 90:79–83 (2000).
88.
Sloter ED, Lowe X, Moore ID, Nath J, Wyrobek AJ: Multicolor FISH analysis of chromosomal breaks, duplications, deletions, and numerical abnormalities in the sperm of healthy men. Am J Hum Genet 67:862–872 (2000).
89.
Sloter ED, Nath J, Eskenazi B, Wyrobek AJ: Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents. Fertil Steril 81:925–943 (2004).
90.
Sloter ED, Schmid TE, Marchetti F, Eskenazi B, Nath J, et al: Quantitative effects of male age on sperm motion. Hum Reprod 21:2868–2875 (2006).
91.
Spriggs EL, Rademaker AW, Martin RH: Aneuploidy in human sperm: the use of multicolor FISH to test various theories of nondisjunction. Am J Hum Genet 58:356–362 (1996).
92.
Stene J, Stene E, Stengel-Rutkowski S, Murken JD: Paternal age and Down’s syndrome: data from prenatal diagnoses (DFG). Hum Genet 59:119–124 (1981).
93.
Tellier AL, Cormier-Daire V, Abadie V, Amiel J, Sigaudy S, et al: Charge syndrome: report of 47 cases and review. Am J Med Genet 76:402–409 (1998).
94.
Tempest HG, Homa ST, Dalakiouridou M, Christopikou D, Wright D, et al: The association between male infertility and sperm disomy: evidence for variation in disomy levels among individuals and a correlation between particular semen parameters and disomy of specific chromosome pairs. Reprod Biol Endocrinol 2:82–90 (2004).
95.
Templado C, Marquez C, Munne S, Colls P, Martorell MR, et al: An analysis of human sperm chromosome aneuploidy. Cytogenet Cell Genet 74:194–200 (1996).
96.
Thepot F, Wack T, Selva J, Czyglik F, Mayaux M: Paternal age and pregnancy issues the cecos experience. Contracept Fertil Sex 21:388–390. (1993).
97.
Thomas NS, Collins AR, Hassold TJ, Jacobs PA: A reinvestigation of non-disjunction resulting in 47, XXY males of paternal origin. Eur J Hum Genet 8:805–808 (2000).
98.
Weinstein M, Stark M: Behavioral and biological determinants of fecundability. Ann NY Acad Sci 709:128–144 (1994).
99.
Williams BJ, Ballenger CA, Malter HE, Bishop F, Tucker M, et al: Non-disjunction in human sperm: results of fluorescence in situ hybridization studies using two and three probes. Hum Mol Genet 2:1929–1936 (1993).
100.
Wyrobek A, Marchetti F, Sloter E, Bishop J: Chromosomally defective sperm and their developmental consequences, in Anderson D, Karakaya AE, Sram RJ (eds): Human Monitoring After Environmental and Occupational Exposure to Chemical and Physical Agents. NATO science Series 313:134–150 (IOS Press, Amsterdam 2000).
101.
Ya-gang X, Robinson WP, Spiegel R, Binkert F, Ruefenacht U, et al: Parental origin of the supernumerary chromosome in trisomy 18. Clin Genet 44:57–61 (1993).
102.
Zalensky AO, Breneman JW, Zalenskaya IA, Brinkley BR, et al: Organization of centromeres in the decondensed nuclei of mature human sperm. Chromosoma 102:509–518 (1993).
103.
Zaragoza MV, Jacobs PA, James RS, Rogan P, Sherman S, et al: Nondisjunction of human acrocentric chromosomes: studies of 432 trisomic fetuses and liveborns. Hum Genet 94:411–417 (1994).
104.
Zhang Y, Kreger BE, Dorgan JF, Cupples LA, Myers RH, et al: Parental age at child’s birth and son’s risk of prostate cancer. The Framingham Study. Am J Epidemiol 150:1208–1212 (1999).
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