Long term exposure to benzo[b]fluoranthene does not induce mutations in Mutamouse male germ cells

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
Madison T. Stewart , Gu Zhou , Danielle P.M. LeBlanc , Annette E. Dodge , Matthew J. Meier , Andrew Williams , Alexandra S. Long , Paul A. White , Carole L. Yauk , Francesco Marchetti
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Abstract

Germ cell mutations can be inherited and lead to genetic disorders in the offspring. Thus, it is critical to identify environmental exposures that impact the germline. Polycyclic aromatic hydrocarbons (PAHs) are widespread combustion by-products found in food, tobacco smoke, and urban air. Benzo[b]fluoranthene (BbF) is a PAH that is classified as a possible human carcinogen. Studies using the transgenic mouse lacZ assay and duplex sequencing (DS), an error-corrected sequencing technology, have demonstrated that BbF robustly induces mutations in somatic tissues. However, the mutagenic effects of BbF on germ cells are unknown. We investigated whether long-term exposure to BbF induces mutations in male germ cells. Adult MutaMouse males were orally exposed to BbF in olive oil at doses of 0, 3.25, 6.25, 12.5, 25, or 50 mg/kg body weight per day (BW/day) for 90 days, or to 0, 1.56, 3.125, 6.25, 12.5, or 25 mg/kg BW/day for 180 days. Mutant frequencies were determined using the lacZ assay (n = 8 per group). Control and high dose groups at each time point were then sequenced to detect mutations using DS (n = 6 per group). Neither method detected significant increases in mutations following BbF exposure. Similarly, there was no increase in C:G > A:T transversions at either time point, the main mutation subtype induced by BbF in somatic tissues. These results suggest that BbF or its active metabolites are not present in germ cells at amounts sufficient to cause mutations, and/or DNA damage repair mechanisms in germ cells effectively repair BbF-induced damage.
长期接触苯并[b]氟蒽不会诱发突变小鼠雄性生殖细胞的突变
生殖细胞突变可以遗传并导致后代的遗传疾病。因此,确定影响生殖系的环境暴露是至关重要的。多环芳烃(PAHs)是广泛存在于食物、烟草烟雾和城市空气中的燃烧副产物。苯并[b]氟蒽(BbF)是一种多环芳烃,被列为可能的人类致癌物质。利用转基因小鼠lacZ试验和双工测序(DS)技术(一种错误校正测序技术)进行的研究表明,BbF可在体细胞组织中强烈诱导突变。然而,BbF对生殖细胞的诱变作用尚不清楚。我们研究了长期暴露于BbF是否会诱导男性生殖细胞发生突变。成年雄性MutaMouse以0、3.25、6.25、12.5、25或50 mg/kg体重/天(BW/天)的剂量口服橄榄油中的BbF,持续90天,或以0、1.56、3.125、6.25、12.5或25 mg/kg体重/天剂量口服180天。采用lacZ法测定突变频率(n = 8 /组)。然后在每个时间点对对照组和高剂量组进行测序,使用DS检测突变(每组n = 6)。两种方法均未检测到BbF暴露后突变的显著增加。同样,C:G >; A:T平移在任何时间点都没有增加,这是BbF在体细胞组织中诱导的主要突变亚型。这些结果表明,生殖细胞中BbF或其活性代谢物的含量不足以引起突变,生殖细胞中的DNA损伤修复机制可以有效地修复BbF诱导的损伤。
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来源期刊
Reproductive toxicology
Reproductive toxicology 生物-毒理学
CiteScore
6.50
自引率
3.00%
发文量
131
审稿时长
45 days
期刊介绍: Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.
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