Sex-linked differences

High concentrations of radioactivity were observed in body fat and livers of rats, mice, and squirrel monkeys given oral doses of 60 mg/kg " C-labeled chloroform (Brown et al. 1974a). The maximum levels of radioactivity in the blood appeared within 1 hour and were 3 pg equivalents chloroform/mL for mice and 10 pg equivalents chloroform/mL for monkeys, which represented -0.35 and 1%, respectively, of the total radioactivity. In monkeys, bile concentrations peaked within 6 hours. The distribution of radioactively labeled chloroform was studied in three strains of mice (Taylor et al. 1974). No strain-related differences were observed however, higher levels of radioactivity were found in the renal cortex of males and in the liver of females. The renal binding of radioactive metabolites may have been altered by variations in the testosterone levels as a result of hormonal pretreatment in females or castration in males. Sex-linked differences in chloroform distribution were not observed in rats or monkeys (Brown et al. 1974a). Chloroform accumulates in the adipose tissue of rats after oral exposure of intermediate duration (Pfaffenberger et al. 1980). 

A higher incidence of ADRs has been reported for women in comparison to men. One reason for this observation is that women take more drugs than men. Yet, no sex-linked differences in drug pharmacokinetics have been documented. Other reports have not... 

The influence of selected heavy metals on the toxicity of some metabolites of selenite has been studied by Parizek et al, (1971). Cadmium had no effect on the toxicity of dimethylselenide, but a strong sex-linked interaction between mercury and this compound was found. The toxicity of both dimethylselenide and the trimethylselenium ion was greatly enhanced by the administration of mercuric compounds to male rats but was unaffected in females. Part of the reason for these sex-linked differences may be that the urinary excretion of trimethylselenium ions is under the control of anabolic steriods (Parizek et al., 1974). However, this does not fully explain all of these sex-linked effects. 

Deficiency of the VIIFC portion of the Factor VIII complex results in classic hemophilia or hemophilia A and is inherited as a sex-linked recessive disorder. Based on the degree of deficiency of the VIIFC molecule three different forms of hemophilia A are recognized. Less than 1% VIIFC activity equals severe hemophilia A. Two to 10% of normal VIIFC activity equals moderately severe hemophilia A. Ten to 25% of normal VIIFC activity equals minimal symptomatic disease. Deficiency of the VIIFvWFAg portion of the Factor VIII complex results in von WiUebrand disease. There are at present five principal types of von WiUebrand disease and numerous subtypes or variants. For the most part, von WiUebrand disease is inherited as an autosomal dominant, and a few subtypes may be inherited as an autosomal recessive trait. 

The genetic trait for MH is not sex-linked and both men and women can inherit MH. Inheritance in humans appears to be autosomal dominant with variable penetrance. Studies of large families have documented an autosomal dominant pattern. McPherson and Taylor (1982) studied 93 families in whom MH occurred. Even though various patterns of inheritance did emerge in the study we should assume that 50% of children are at risk in MH susceptible families. Kalow and Britt (1992) suggested that, in some families, at least two different non-allelic genes are likely to be present, one of which is probably autosomal dominant but rare, and the other autosomal recessive but common. 

It is well known, for example, that about 5 per cent of the people who become infected with typhoid germs become typhoid carriers and continue indefinitely to harbor an active colony (harmless to them) of typhoid bacilli in their intestinal tracts. There is abundant evidence of graded susceptibility there are many mild cases, and the incubation time in different individuals may be from 3 to 30 days, indicating variable resistance. The fact that about 70 per cent of the carriers are women suggests that the constitutional characteristics which make it possible for individuals to endure the presence of the organisms are in some way sex-linked in their inheritance. The evidence with respect to typhoid carriers, diphtheria carriers, scarlet-fever carriers, poliomyelitis-virus carriers, etc., makes it seem probable that "carriers" enter into the dissemination of many other milder infections, and... 

In a test for sex-linked recessive lethal mutations in Drosophila, Wild et al. 8 found no evidence of mutagenicity of CS. More than 9,000 chromosomes were tested, and the frequencies of mutations in the treated groups did not differ from those in the concurrent negative controls or the historical negative controls. The available information on the toxicity of CS under the treatment conditions is minimal. The actual dosages received by the flies are also uncertain, particularly because CS breaks down rapidly in water. Nevertheless, the available data give no indication of mutagenicity of CS in Drosophila. 

A second member of the ceruloplasmin family multicopper oxidases with six BCB domains was recently identified as the causative agent of sex-linked anemia (sla) in mice (Vulpe et al., 1993). It was named hephaes-tin and shown to be expressed mostly in the small intestine and the colon, where it is presumably involved in gastrointestinal iron uptake. Hephaes-tin displays a high level of sequence identity to ceruloplasmin and differs from it only by an additional C-terminal transmembrane domain, which anchors the protein to the cell membrane. A 582-nucleotide in-frame deletion in the mRNA for hephaestin sla mice has been identified compared to normal animals. The mice with such a mutation are unable to release iron from enterocytes (intestinal epithelial cells) into the circulation, which results in severe anemia. The GPI-anchored form of ceruloplasmin could potentially also mediate similar cellular iron efflux in the central nervous system. There is a transferrin-independent iron uptake system that requires Fe(III) to be reduced to Fe(II) at the cell surface for uptake to occur (DeSilva et al., 1996). Ceruloplasmin would oxidize Fe and prevent its uptake by this mechanism. Briefly, the role of ceruloplasmin is most likely to prevent excessive intracellular iron accumulation by tightly controlling iron efflux and inhibiting its uptake. 

D has been active in many different short-term genetic assays, including DNA damage and repair, mutations in yeast and human cells, sex-linked recessive mutations in fruit flies, and chromosome aberrations in vitro. 

Parizek J, Kalouskova J, Pavlik L, et al. 1992. Sex-linked, androgen-dependent differences in renal retention of trimethylselenonium ions. Biol Trace Elem Res 34(3) 257-263. 

Another method of monitoring heritable chromosomal abnormalities is the mouse sex chromosome-loss test. This assay differs from the dominant lethal test and heritable translocation test in that it is thought primarily to measure nondisjunctions. In this assay progeny of treated male and female mice are examined for sex-linked phenotypic differences. 

Ravindranath, V. and Anandatheerthavarada, H.K. (1989) High activity of cytochrome P-450 linked aminopyrine N-demethylase in mouse brain microsomes and associated sex-related differences. Biochem. J. 261 769-773. 

Existence of heterogeny may be proved by detection of different primary biochemical defects in individuals stricken with the disease. In other cases it can be detected, if the disease can be shown to follow different modes of inheritance in various families. This is most obvious, if e.g. one type with sex-linked inheritance can be found, where location of the mutated gene on the X-chromosome is prerequisite, and for another type autosomal inheritance can be proved. (As examples Pelizaeus-Merzbacher s disease or the mucopolysaccharidoses may serve.)... 

These considerations present no obstacle to the primary goal of this chapter, which is to use a variety of quantitative methods to assess whether differences can be detected between a priori defined morphological groups. Nevertheless, if consistent differences between sexual and parthe-nogenic cynipid taxa are found, they will need to be treated as provisional indications of possible sex-linked morphological differentiation that should be confirmed (or refuted) with subsequent analysis of data collected for that purpose. 

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