Father Time: Children with Older Dads at Greater Risk for Mental Illness

The present trend of increasing paternal age is accompanied by concerns for the development of complex multi-gene diseases, e.g. autism and schizophrenia,

Biol Reprod. 2011 Aug 24. [Epub ahead of print]
Aging Results in Differential Regulation of DNA Repair Pathways in Pachytene Spermatocytes in the Brown Norway Rat.
Paul C, Nagano M, Robaire B.
Abstract
The present trend of increasing paternal age is accompanied by concerns for the development of complex multi-gene diseases, e.g. autism and schizophrenia, in progeny. Recent studies have established strong correlations between male age, increased oxidative stress, decreased sperm quality and structural aberrations of chromatin and DNA in spermatozoa. We tested the hypothesis that increasing age would result in altered gene expression relating to oxidative stress and DNA damage/repair in germ cells. To test this hypothesis, pachytene spermatocytes and round spermatids were isolated from Brown Norway (BN) rats at 4 (young) and 18 (aged) months of age. Microarray analysis was used to compare gene expression between the groups. The probe sets with significantly altered expression were linked to DNA damage/repair and oxidative stress in pachytene spermatocytes but not in round spermatids. Further analysis of pachytene spermatocytes demonstrated that genes involved in the base excision repair (BER) and nucleotide excision repair (NER) pathways were specifically altered. Quantitative RT-PCR confirmed that NER genes were upregulated (>1.5 fold) whereas BER genes were downregulated (>1.5 fold). At the protein level the members of the BER pathway were also altered by up to 2.3 fold; levels of NER proteins remained unchanged. Furthermore there was an increase in 8-oxo-2'-deoxyguanosine (8-oxodG) immunoreactivity in testes from aged males and in the number of spermatozoa positive for 8-oxodG. In conclusion, aging is associated with differential regulation of DNA repair pathways with a decrease in the BER pathway leading to deficient repair of 8-oxo-dG lesions in germ cells and spermatozoa.

Parental Age Effects on Cortical Morphology in Offspring.

Cereb Cortex. 2011 Aug 4. [Epub ahead of print]
Parental Age Effects on Cortical Morphology in Offspring.
Shaw P, Gilliam M, Malek M, Rodriguez N, Greenstein D, Clasen L, Evans A, Rapoport J, Giedd J.
SourceChild Psychiatry Branch, Intramural Program of the National Institute of Mental Health.

Abstract
The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = -2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes.

PMID:21817090[PubMed - as supplied by publisher]