Letters to the editor |
The child of problems
Andrologie et Biologie de la Procréation, CHU de Bicêtre, 94275, Le Kremlin-Bicêtre, Cedex, France
E-mail: auroux.mauriceetmichel{at}neuf.fr
Sir,
Numerous publications have regularly made the point about possible harmful effects of assisted reproductive technologies (ART) on human progeny. Several factors of risk are reviewed, but conclusions are relatively reassuring (Golombok, 2005
; Sutcliffe, 2005). However, authors are guarded about long-term effects. From this point of view, experimental results (for a review, see Auroux, 2000; Walker et al., 2000) are rarely taken into account because comparison between species is known to be difficult and often uncertain. Nevertheless, medicines have to be experimented on animals before they have to be tested in human.
Faced with these still unknown long-term effects, it seems pertinent to recall some experimental works carried out by different groups either on mice or on rats. Reik et al. (1993) showed, in mice, that epigenetic manipulations in early embryo could affect the adult phenotype through methylation alteration of some genes in the liver, as well as growth deficiency. In 1995, we found, in mice, that pre-embryo cryopreservation could lead to anomalies in preweaning development and, in adults, behavioural disturbances depending on strain and sex (Dulioust et al. 1995). Kwong et al. (2000) observed, in the rat, that maternal malnutrition during the preimplantation embryonic period resulted in arterial hypertension in adults, male and female. Ecker et al. (2004) showed that the culture of preimplantation mouse embryos induced behavioural troubles in derived adults. Finally, we published ourselves that cryopreservation of mouse pre-embryo led to protection of adults from induced urinary bladder cancer depending on strain and sex (Auroux et al., 2004).
Though these five results display dissimilar pathologies, they show a common characteristic: whatever the long-term effect may be, alterations noted in adults follow after varied epigenetic events in the early embryo. Even if cautiousness is required, to know whether it is possible to draw a parallel between animal and human ART situations is, for this reason, especially important. This is all the more because some authors have shown, in humans, that ART could lead to long-term anomalies, particularly in relation to genomic imprinting disorders, such as Beckewith–Wiedemann syndrome (Sutcliffe et al., 1995a,b; Olivennes et al., 2001; DeBaun et al., 2003; Maher et al., 2003), Angelman syndrome (Cox et al., 2002) and retinoblastoma (Moll et al., 2003). In connection with these long-term effects, it is interesting to notice that if, in the USA general population, major malformations concern about 3% of children at birth, developmental functional disorders affect 6–7% of 1-year-old infants and 12–14% of school-age children (Kimmel et al., 1993). Other developmental disabilities were noticed in 17% of a 17-year-old population, the aetiology being unknown in about 70% of these cases (Boyle et al., 1994). In this context, the possible influence of ART on the continuum of development takes a special importance. Finally, regarding children conceived from ART (at least 1% of the population in rich countries according to Sutcliffe, 2005), we hold to what we have been saying for nearly twenty years (Auroux, 1987, 1997, 2000; Auroux et al., 2004; Dulioust et al., 1995) and we take up the recent Sutcliffe’s conclusion: ‘Some questions are unresolved concerning their progress into adult life (...). If their ART conception has exposed them to undue risks because these factors were not studied when the techniques were first introduced, they may well take a very different view of the justifications of ART than the reader of this chapter. Further studies need to be performed. The ideal one has yet to be done.’ (Sutcliffe, 2005). Experimental results speak for this warning.
References
Auroux M. (1987) L’enfant des problèmes. XXXIIIe Assises Françaises de Gynécologie (Masson, Paris) pp. 285–296.
Auroux M. (1997) Behavioral teratogenesis: An extension to the teratogenesis of functions. Biol Neonate 71:137–147.[Web of Science][Medline]
Auroux M. (2000) Long-term effects in progeny of paternal environment and of gamete/embryo cryopreservation. Hum Reprod Update 6. 550–563.
Auroux M, Cerutti I, Ducot B, Loeuillet A. (2004) Is embryo-cryopreservation really neutral? A new long-term effect of embryo freezing in mice: protection of adults from induced cancer according to strain and sex. Reprod Toxicol 18:813–818.[CrossRef][Web of Science][Medline]
Boyle CA, Decoufle P, Yeargig-Allsopp M. (1994) Prevalence and health impact of developmental disabilities in US children. Pediatrics 93:399–403.
Cox GF, Burger J, Lip V, Mau UA, Sperling K, Wu BL, Horsthemke B. (2002) Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 71:161–164.
DeBaun MR, Niemitz EL, Feinberg AP. (2003) Association of in vitro fertilization with Beckwith–Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 72:156–160.[CrossRef][Web of Science][Medline]
Dulioust E, Toyama K, Busnel MC, Moutier R, Carlier M, Marchaland C, Ducot B, Roubertoux P, Auroux M. (1995) Long-term effects of embryo freezing in mice. Proc Natl Acad Sci USA 92:589–593.
Ecker DJ, Stein P, Xu Z, Williams CJ, Kopf GS, Bilker WB, Abel T, Schultz RM. (2004) Long-term effects of culture of preimplantation mouse embryos on behavior. Proc Natl Acad Sci USA 101:1595–1600.
Golombok S. (2005) New family forms. In Brinsden PR (Ed.). Textbook of In Vitro Fertilization and Assisted Reproduction 3rd edn. (Taylor & Francis, London, UK) pp. 541–555.
Kimmel CA, Generoso WM, Thomas RD, Bakshi KS. (1993) A new frontier in understanding the mechanisms of developmental abnormalities. Toxicol Appl Pharmacol 119:159–165.[CrossRef][Web of Science][Medline]
Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. (2000) Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of post-natal hypertension. Development 127:4195–4202.[Abstract]
Maher ER, Brueton LA, Bowdin SC, Luharia A, Cooper W, Cole TR, Macdonald F, Sampson JR, Baratt CR, Reik W, et al. (2003) Beckwith–Wiedemann syndrome and assisted reproduction technology (ART). J Med Genet 40:62–64.
Moll AC, Imhof S, Cruysbert JRM, Schouten-van Meeteren AYN, Boers M, Van Leeuwen FE. (2003) Incidence of retinoblastoma in children born after in vitro fertilization. Lancet 361:309–310.[CrossRef][Web of Science][Medline]
Olivennes F, Mannaerts B, Struijs M, Bonduelle M, Devroey P. (2001) Perinatal outcome of pregnancy after GnRH antagonist (ganirelix) treatment during ovarian stimulation for conventional IVF or ICSI: a preliminary report. Hum Reprod 16:1588–1591.
Reik W, Römer I, Barton SC, Surani MA, Klose J, Howlett SK. (1993) Adult phenotype in the mouse can be affected by epigenetic events in the early embryo. Development 119:933–942.[Abstract]
Sutcliffe AG. (2005) The health of children born after assisted reproductive technologies. In Brinsden PR (Ed.). Textbook of In Vitro Fertilization and Assisted Reproduction 3rd edn. (Taylor & Francis, London, UK) pp. 529–539.
Sutcliffe AG, D’Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B. (1995a) Outcome in children from cryopreserved embryos. Arch Dis Child 72:290–293.
Sutcliffe AG, D’Souza SW, Cadman J, Richards B, McKinlay IA, Lieberman B. (1995b) Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. Hum Reprod 10:3332–3337.
Walker SK, Hartwich KM, Robinson JS. (2000) Long-term effects on offspring of exposure of oocytes and embryos to chemical and physical agents. Hum Reprod Update 6:564–577.
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