Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study

Membrane-Aminoglycoside Interactions as the Pathogenetic Pathway for Aminoglycoside Nephrotoxicity.

Gentamicin is an aminoglycoside antibiotic that is widely used in clinical settings for the treatment of infections caused by Gram negative bacteria. One of its major side effects is toxic damage to the renal proximal tubular cell resulting in nephrotoxicity and acute renal failure. Since growing evidence supports the view that toxin induced membrane dysfunction is the primary pathophysiologic pathway for nephrotoxic renal cell injury, these studies investigated the manner in which the aminoglycoside antibiotic, gentamicin, interacts with two critical membranes of the renal proximal tubule cell, the luminal brush border membrane (BBM) and the inner mitochondrial membrane. Initial studies characterized the aminoglycoside binding sites of isolated renal BBMs. Gentamicin bound to BBMs to a single class of non-interacting binding sites with a dissociation constant of 25 (mu)M. Experiments using protein modifying agents, phospholipases, and partitioning systems demonstrated that gentamicin bound to the acidic phospholipids of the membrane. This binding reaction is due to a charge interaction between the polycationic antibiotic and the anionic phospholipid. That this binding interaction affects BBM function was suggested by the influence of gentamicin on sodium-dependent D-glucose uptake by isolated renal BBMs. Both in vitro and in vivo exposure of BBMs to gentamicin inhibited sodium-dependent D-glucose uptake. The in vitro but not the in vivo effect of gentamicin was preventable with Mg('++), suggesting that the in vivo effects involved BBM alterations in addition to those produced acutely by gentamicin in vivo. To further characterize gentamicin-renal membrane interactions, the effect of gentamicin on Ca('++) uptake by renal cortical mitochondria was assessed in vitro. Gentamicin was found to be a competitive inhibitor of mitochondrial Ca('++) uptake and occurred at gentamicin concentrations below those that inhibit mitochondrial electron transport. These results demonstrated the potential for gentamicin to alter plasma and subcellular membrane function and thereby contribute to toxic cell injury via its interactions with divalent cations. In this regard, Ca('++) and Mg('++) were shown to be competitive inhibitors of the gentamicin-BBM binding interaction. Ca('++) was more effective than Mg('++). Furthermore, increasing delivery of Ca('++), as a competitive inhibitor of this binding reaction, to the kidney by giving rats 4 per cent calcium supplemented diets significantly ameliorated gentamicin-induced acute renal failure. These studies in clarifying the manner by which gentamicin interacts with renal membranes and interferes with membrane function have led to a logical means of preventing gentamicin nephrotoxicity in the experimental animal.Ph.D.PharmacologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/159451/1/8314352.pd