Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, New York, United States of America.
PLoS Genet. 2024 Oct 24;20(10):e1011434. doi: 10.1371/journal.pgen.1011434. eCollection 2024 Oct.
Benzyl butyl phthalate (BBP), a plasticizer found in a wide range of consumer products including vinyl flooring, carpet backing, food packaging, personal care products, and children's toys, is an endocrine-disrupting chemical linked to impaired reproduction and development in humans. Despite evidence that BBP exposure perturbs the integrity of male and female gametes, its direct effect on early meiotic events is understudied. Here, using the nematode Caenorhabditis elegans, we show that BBP exposure elicits a non-monotonic dose response on the rate of X-chromosome nondisjunction measured using a high-throughput screening platform. From among the range of doses tested (1, 10, 100 and 500 μM BBP), we found that 10 μM BBP elicited the strongest effect on the germline, resulting in increased germ cell apoptosis and chromosome organization defects. Mass spectrometry analysis shows that C. elegans efficiently metabolizes BBP into its primary metabolites, monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP), and that the levels of BBP, MBP, and MBzP detected in the worm are within the range detected in human biological samples. Exposure to 10 μM BBP leads to germlines with enlarged mitotic nuclei, altered meiotic progression, activation of a p53/CEP-1-dependent DNA damage checkpoint, increased double-strand break levels throughout the germline, chromosome morphology defects in oocytes at diakinesis, and increased oxidative stress. RNA sequencing analysis indicates that BBP exposure results in the altered expression of genes involved in xenobiotic metabolic processes, extracellular matrix organization, oocyte morphogenesis, meiotic cell cycle, and oxidoreduction. Taken together, we propose that C. elegans exposure to BBP leads to increased oxidative stress and double-strand break formation, thereby compromising germline genomic integrity and chromosome segregation.
邻苯二甲酸丁基苄基酯（BBP）是一种广泛存在于各种消费品中的增塑剂，包括乙烯基地板、地毯衬背、食品包装、个人护理产品和儿童玩具，它是一种内分泌干扰化学物质，与人类生殖和发育受损有关。尽管有证据表明 BBP 暴露会破坏雄性和雌性配子的完整性，但它对早期减数分裂事件的直接影响仍未得到充分研究。在这里，我们使用线虫秀丽隐杆线虫（Caenorhabditis elegans）表明，暴露于 BBP 会导致 X 染色体非分离率呈非单调剂量反应，这是使用高通量筛选平台测量的。在所测试的一系列剂量（1、10、100 和 500 μM BBP）中，我们发现 10 μM BBP 对线粒体产生最强的影响，导致生殖细胞凋亡增加和染色体结构缺陷。质谱分析表明，秀丽隐杆线虫能够有效地将 BBP 代谢为其主要代谢物邻苯二甲酸单丁酯（MBP）和邻苯二甲酸单苄基酯（MBzP），并且在蠕虫中检测到的 BBP、MBP 和 MBzP 水平在人类生物样本中检测到的范围内。暴露于 10 μM BBP 会导致生殖细胞核增大、减数分裂进程改变、p53/CEP-1 依赖的 DNA 损伤检查点激活、整个生殖系中双链断裂水平增加、减数分裂双线期卵母细胞的染色体形态缺陷以及氧化应激增加。RNA 测序分析表明，暴露于 BBP 会导致参与外源性代谢过程、细胞外基质组织、卵母细胞形态发生、减数分裂细胞周期和氧化还原的基因表达发生改变。综上所述，我们提出，秀丽隐杆线虫暴露于 BBP 会导致氧化应激和双链断裂形成增加，从而损害生殖系基因组完整性和染色体分离。
