Chromosomes, lead effects

Ethylene oxide has been shown to produce mutagenic and cytogenic effects in a variety of test systems (226). An increased frequency of chromosomal aberrations in peripheral lymphocytes of monkey exposed to ethylene oxide for 104 weeks has been reported (240). In mice, it is an effective inducer of chromosome breaks leading to dominant-lethal mutations. In addition, ethylene oxide has been shown to induce heritable effects in the heritable translocation test conducted in mice exposed to ethylene oxide by inhalation (241,242). In this study, male mice were exposed to ethylene oxide ranging from 165 to 300 ppm for 6 h per day 5 or 7 days/week for 8.5 weeks. Ethylene oxide has also been shown to bind to proteins (243) as well as to DNA (244). Several studies on ethylene oxide-exposed workers have demonstrated an increased incidence of chromosomal aberrations and sister chromatid exchanges the relevance of such effects to human health evaluation is currendy uncertain. 

Overproduction of the chromosomal genes for the dihydrofolate reductase (DHFR) and the dihydroptero-ate synthase (DHPS) leads to a decreased susceptibility to trimethoprim and sulfamethoxazol, respectively. This is thought to be the effect of titrating out the antibiotics. However, clinically significant resistance is always associated with amino acid changes within the target enzymes leading to a decreased affinity of the antibiotics. 

Besides unequal crossover and transposition, a third mechanism can effect rapid changes in the genetic material. Similar sequences on homologous or nonhomol-ogous chromosomes may occasionally pair up and eliminate any mismatched sequences between them. This may lead to the accidental fixation of one variant or another throughout a family of repeated sequences and thereby homogenize the sequences of the members of repetitive DNA families. This latter process is referred to as gene conversion. 

The chromatid separation process has also remained mysterious. It is an autonomous process that does not direcdy depend on the mitotic spindle (Wilson 1925, Mazia 1961). This is most vividly seen in cells whose spindles have been destroyed by spindle poisons such as colchicine. In many organisms, in particular in plant cells, the cell cycle delay induced by colchicine is only transient and chromatids eventually split apart in the complete absence of a mitotic spindle (Mole-Bajer 1958, Rieder Palazzo 1992) (Fig. 2). Mitosis in the presence of colchicine or colcemid (known as c-mitosis) leads to the production of daughter cells with twice the normal complement of chromosomes. This process is routinely used for manipulating plant genomes and may contribute to the therapeutic effects of taxol in treating breast cancer. 

Genotoxic Effects. Evaluation of the genotoxicity of lead in humans has focused on evaluations of lymphocytes from occupationally or environmentally exposed persons (Table 2-10) and in vitro studies of structural chromosomal aberrations and sister chromatid exchange in cultures of lymphocytes taken from healthy individuals (Table 2-11). Results of studies with human lymphocyte cultures exposed in vitro to lead acetate were nearly equally divided between positive (Beek and Obe 1974 Niebuhr and Wulf 1984) and negative (Beek and Obe 1975 Deknudt and Deminatti 1978 Gasiorek and Bauchinger 1981 Schmid etal. 1972). 

Beek B, Obe G. 1974. Effect of lead acetate on human leukocyte chromosomes in vitro. Experientia 30 1006-1007. 

Jacquet P, Tachon P. 1981. Effects of long-term lead exposure on monkey leukocyte chromosomes. Toxicol Lett 8 165-169. 

Kowalska-Wochna E, Moniuszko-Jakoniuk J, Kulikowska E, et al. 1988. The effect of orally applied aqueous solutions of lead and zinc on chromosome aberrations and induction of sister chromatid exchanges in the rat (Rattus sp). Genetica Polonice 29 181-189. 

Winder C. 1989. Reproductive and chromosomal effects of occupational exposure to lead in the male. Reprod Toxicol 3 221-233. 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

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