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Metabolism and Toxicity of Occupational Neurotoxicants: Genetic, Physiological, and Environmental Determinants
Published in Lucio G. Costa, Luigi Manzo, Occupatinal Neurotoxicology, 2020
Stefano M. Candura, Luigi Manzo, Anna F. Castoldi, Lucio G. Costa
Genetic factors also determine important intersubject variations in the metabolism and neurotoxicity of ethanol and industrial alcohols.38,39 ADH is a dimeric enzyme whose subunit chains are determined by at least six genetic loci, of which at least two, ADH2 and ADH3, are polymorphic. The isoenzymes vary markedly in their kinetic properties, and the frequency of the alleles encoding them vary across ethnic group.54 Both polymorphic ADH loci have been localized to the long arm of chromosome 4.55 ALDH is present in at least four forms, whose characteristics and activity vary substantially.56 Acetaldehyde oxidation is mostly catalyzed by ALDH2, encoded by a gene localized to chromosome 12.57 In Asians and American Indians, a null allele at the ALDH2 locus causes impaired elimination of acetaldehyde and flushing reactions following ingestion or inhalation of relatively small amounts of ethanol. The null allele is dominant, and heterozygotes exhibit ALDH deficiency.38
Animal studies
Published in C M Langton, C F Njeh, The Physical Measurement of Bone, 2016
Jenny Zhao, Yebin Jiang, Christopher F Njeh, Roger Bouillon, Piet Geusens, Harry K Genant
The wide availability of genetically altered mice has increased the usefulness of the murine model for investigating osteoporosis and other skeletal disorders. Independent genetic regulation of three-dimensional vertebral trabecular microstructure in 12BXH recombinant inbred mice as measured by μCT contributed information regarding the variation in biomechanical properties among the strains [82]. Mice homozygous for a null mutation of the PTHrP gene die at birth with severe skeletal deformities. Heterozygotes survive and by 3 months of age develop osteopenia characterized by decreased trabecular bone volume and increased bone marrow adiposity. PTHrP wild type and heterozygous-null mice were ovariectomized at 4 months of age and sacrificed at 5 weeks. Three-dimensional μCT was use to examine the trabecular structure of the mice, with an isotropic resolution of 9 μm3. Bone specimens from mice heterozygous for the PTHrP null allele demonstrate significant changes as compared with wild-type litter mates in most parameters examined. However, measurements of trabecular number and trabecular thickness were not significantly different between the two groups. These findings support the notion that PTHrP haplo-insufficiency leads to abnormal bone formation in the adult mouse skeleton.
Pneumonitis induced by non-cytotoxic agents
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Umair A Gauhar, J Allen D Cooper
Gold therapy can cause interstitial pneumonitis, bronchiolitis obliterans (BO) and bronchiolitis obliterans organizing pneumonia (BOOP). Gold-induced pneumonitis is seen in about 1 per cent of patients. It was first described by Savilahti in 1948 but brought to greater attention in 1976 by Winterbauer.56,57 Sixty cases had been reported before 1986.58 Tomioka and King in 1997 analysed a cohort of 140 patients with suspected chrysotherapy-induced pulmonary toxicity (from 1966 to December 1994).54 Their analysis showed that there was no clear relationship between the total dose of gold received and the onset of symptoms or their severity. Women outnumbered men four to one and mean age of onset was 53.1 ± 12.3 years. Interestingly, fewer than 4 per cent of the patients had simultaneous acute rheumatoid flare and gold-induced pulmonary toxicity. In a study of 85 gold-treated RA patients (compared to 283 healthy controls), Hakala et al. found a positive correlation between gold-induced interstitial pneumonitis and the presence of HLA-B40 (relative risk 10.5) and HLA-Dw1 (relative risk 6.2).59 RA patients with gold-induced pneumonitis have also been found to express two extended HLA haplotypes, HLA-A3 B35 Dw1 BfF C4A3,2(BO) and HLA-B40 with a C4 null allele at higher frequency than controls.60 Adverse effects are more commonly seen with gold sodium thiomalate compared with auranofin.61 Symptoms usually begin within 2–6 months after therapy, but Hafejee and Burke have reported a case of acute pneumonitis occurring within 2 hours of intramuscular gold administration.62
Human leucocyte antigen – G gene polymorphism in laryngeal squamous cell carcinoma patients in Mansoura University Hospitals
Published in Egyptian Journal of Basic and Applied Sciences, 2021
Ghada Barakat, Asser Elsharkawy, Yasmin Nabiel
The null allele termed HLA-G*0105 N is one of the fifteen HLA-G gene alleles. It represents a single base pair deletion in exon 3 [17] where the deletion of cytosine at codon 130 disrupts the open reading frame, and then inhibits the translation of HLA-G1 and G5. But it can translate HLA-G2, HLA-G3 (membrane-bound isoforms) and HLA-G6, HLA-G7 (soluble isoforms), such variable effects over HLA-G translation are found to be a hindering factor for pregnancy occurrence through affecting fertilization and implantation, and show some effect over tumor development [18,19].
The individual and combined effects of spaceflight radiation and microgravity on biologic systems and functional outcomes
Published in Journal of Environmental Science and Health, Part C, 2021
Jeffrey S. Willey, Richard A. Britten, Elizabeth Blaber, Candice G.T. Tahimic, Jeffrey Chancellor, Marie Mortreux, Larry D. Sanford, Angela J. Kubik, Michael D. Delp, Xiao Wen Mao
Initiatives to study bone health in space have predominantly focused on how spaceflight negatively impacts skeletal structure and biomechanical properties with the overarching goal of understanding how they contribute to fracture risk. While it is important to address remaining knowledge gaps on fracture risk in follow-up studies, investigations by the space research community also need to broaden to reflect our growing understanding of skeletal function. Beyond providing structural support, the skeleton is an endocrine organ that can crosstalk with other tissues to maintain health and homeostasis. A number of studies demonstrate the ability of bone to function as an endocrine organ (reviewed in 104–106 to regulate a variety of physiological processes including glucose metabolism,107–109 appetite suppression,110 cognition and behavior.111,112 The organism’s ability to coordinate the function of multiple tissues via bone-derived factors is essential to keep up with the demands of daily living. For example, bone-derived lipocalin-2 (LCN2) regulates glucose homeostasis via endocrine action on major metabolic organs, and also can cross the blood-brain barrier to control appetite via its binding to the melanocortin receptor (MC4R) in the hypothalamus.110 In addition, LCN2 can exert pro-inflammatory actions on a variety of cell types including vascular cells.113 Osteocalcin (OCN), another bone-derived hormone can modulate cognition and anxiety-like behavior. 111,112 Mice heterozygous for an OCN null allele showed deficits in cognition while administration of OCN improved memory and decreased anxiety-like behaviors.112 In addition, OCN has been shown to mediate aspects of the acute stress response. In the presence of stressors, it is thought that OCN participates in signaling to inhibit the parasympathetic branch of the autonomic nervous system to allow the sympathetic pathway to predominate, in turn promoting flight or fight responses.114 The biological processes regulated by these bone-derived hormones are critical for human health and performance in space missions. Hence, it is important to begin to address whether combined spaceflight factors can perturb signaling mediated by bone-derived hormones. More studies also are needed to understand the role of bone crosstalk with other organs in mediating the physiological changes attributed to spaceflight.