Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

• Published in: Cell death & disease Vol. 10; no. 4; p. 307
• Main Authors: Li, Ran, Xing, Qian-wei, Wu, Xiao-lu, Zhang, Lei, Tang, Min, Tang, Jing-yuan, Wang, Jing-zi, Han, Peng, Wang, Shang-qian, Wang, Wei, Zhang, Wei, Zhou, Guo-ping, Qin, Zhi-qiang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.04.2019; Springer Nature B.V
• Subjects: 13/1; 13/109; 13/2; 13/31; 13/89; 45/91; 631/337/176/1988; 631/80/82/23; AKT protein; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line; Cell Proliferation - drug effects; Demethylation; Dibutyl Phthalate - toxicity; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA damage; DNA Damage - drug effects; DNA Demethylation; DNA methylation; DNA Methyltransferase 3B; Flagella; Flagella - genetics; Flagella - metabolism; Germ cells; Immunology; Life Sciences; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; n-Butyl phthalate; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; PTEN Phosphohydrolase - chemistry; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Reproductive system; Signal Transduction - drug effects; Sperm; Sperm Motility - drug effects; Sperm Motility - genetics; Spermatozoa - drug effects; Spermatozoa - metabolism; Testis - cytology; Testis - drug effects; Testis - metabolism; Toxicity
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1547-8

Di-n-butyl phthalate (DBP) is a kind of ubiquitous chemical linked to hormonal disruptions that affects male reproductive system. However, the mechanism of DBP-induced germ cells toxicity remains unclear. Here, we demonstrate that DBP induces reduction of proliferation, increase of apoptosis and DNA damage dependent on the PTEN/AKT pathway. Mechanistically, DBP decreases PTEN promoter methylation and increases its transcriptional activity, leading to increased PTEN expression. Notably, DNMT3b is confirmed as a target of miR-29b and miR-29b-mediated status of PTEN methylation is involved in the effects of DBP treatment. Meanwhile, DBP decreases AKT pathway expression via increasing PTEN expression. In addition, the fact that DBP decreases the sperm number and the percentage of motile and progressive sperm is associated with downregulated AKT pathway and sperm flagellum-related genes. Collectively, these findings indicate that DBP induces aberrant PTEN demethylation, leading to inhibition of the AKT pathway, which contributes to the reproductive toxicity.