title: Poor maternal nutrition followed by accelerated postnatal growth leads to alterations in DNA damage and repair, oxidative and nitrosative stress, and oxidative defense capacity in rat heart.
abstract: Low birth weight and accelerated postnatal growth lead to increased risk of cardiovascular disease. We reported previously that rats exposed to a low-protein diet in utero and postnatal catch-up growth (recuperated) develop metabolic dysfunction and have reduced life span. Here we explored the hypothesis that cardiac oxidative and nitrosative stress leading to DNA damage and accelerated cellular aging could contribute to these phenotypes. Recuperated animals had a low birth weight (P<0.001) but caught up in weight to controls during lactation. At weaning, recuperated cardiac tissue had increased (P<0.05) protein nitrotyrosination and DNA single-stranded breaks. This condition was preceded by increased expression of DNA damage repair molecules 8-oxoguanine-DNA-glycosylase-1, nei-endonuclease-VIII-like, X-ray-repair-complementing-defective-repair-1, and Nthl endonuclease III-like-1 on d 3. These differences were maintained on d 22 and became more pronounced in the case of 8-oxoguanine-DNA-glycosylase-1 and nei-endonuclease-VIII-like. This was accompanied by increases in xanthine oxidase (P<0.001) and NADPH oxidase (P<0.05), major sources of reactive oxygen species (ROS). The detrimental effects of increased ROS in recuperated offspring may be exaggerated at 22 d by reductions (P<0.001) in the antioxidant enzymes peroxiredoxin-3 and CuZn-superoxide-dismutase. We conclude that poor fetal nutrition followed by accelerated postnatal growth results in increased cardiac nitrosative and oxidative-stress and DNA damage, which could contribute to age-associated disease risk.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Box 289, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Hills Rd., Cambridge, CB2 OQQ, UK. janeadkins@googlemail.com
authors.forename: Jane L
authors.initials: JL
authors.lastname: Tarry-Adkins
authors.forename: Malgorzata S
authors.initials: MS
authors.lastname: Martin-Gronert
authors.forename: Denise S
authors.initials: DS
authors.lastname: Fernandez-Twinn
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.forename: Maria Z
authors.initials: MZ
authors.lastname: Alfaradhi
authors.forename: John M
authors.initials: JM
authors.lastname: Land
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Aiken
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ozanne
mesh_terms: D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006128:Growth; D044342:Malnutrition / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D015538:Nitrosation; D009929:Organ Size; D018384:Oxidative Stress; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D016615:Telomere
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial