Bisphenol A (BPA), one of the chemicals with the highest volume of production worldwide, has been demonstrated to cause testicular toxicity via different pathways. However, there is little evidence concerning the mechanism of BPA exposure induced histone modification alterations, especially regarding the effect on the histone H3 lysine 4 (H3K4) epigenetic modification. Our results demonstrated a new epigenetic regulation of BPA exposure on testicular damage using both cell culture and mouse models. With BPA treatment, disordered and shrunken seminiferous tubules and poor sperm quality were observed in vivo, and mouse spermatogonial germ cell proliferation was inhibited in vitro. BPA attenuated PI3K expression inducing phospho-AKT inhibition in vivo and in vitro. DPY30 was the only downregulated subunit in BPA and MEK2206 (AKT inhibitor) treated cells, which contributed to reducing H3K4me3 recruitment at the PIK3CA transcriptional start site (TSS) in BPA treated cells. The toxicity caused by BPA exposure was relieved after the transduction of adenoviruses expressing DPY30 transgenes, which resulted in the stimulation of PI3K/AKT with H3K4me3 enriched at the PI3KCA TSS. DPY30 promoted cell glycolysis via AMPK and proliferation through AKT/P21. DPY30 was mainly located in the round and elongated spermatids for energy accumulation in mature sperm in AD-DPY30-treated mice which showed higher sperm quality. Overall, our results indicated that BPA exposure causes testicular toxicity through a DPY30-mediated H3K4me3 epigenetic modification, which serves to regulate the PI3K/AKT/P21 pathway.

The trans-10,cis-12 isomer of conjugated linoleic acid (t10c12-CLA) is a biohydrogenation intermediate in the rumen and has been shown to cause milk fat depression in dairy goats. However, few studies have focused on the in vitro molecular mechanisms involved in the response of the goat mammary gland to t10c12-CLA. In the present study, RNA sequencing technology was used to investigate the effects of t10c12-CLA on goat mammary epithelial cells. From the data, 25,153 annotated transcripts were obtained, and differentially expressed genes were selected based on a false discovery rate <0.05. Candidate genes and potent cellular signaling pathways were identified through Gene Ontology (GO) and pathway analysis. Next, real-time quantitative PCR and Western blot analyses were used to verify the results of the RNA sequencing data. The results indicated that t10c12-CLA inhibits fatty acid synthesis through downregulation of genes involved in de novo fatty acid synthesis, and this process is likely correlated with the activation of the AMP-activated protein kinase signaling pathways.

Delta-5 desaturase (D5D), encoded by the fatty acid desaturase 1 (FADS1) gene, is a rate-limiting enzyme in polyunsaturated fatty acid (PUFA) synthesis that influences the PUFA levels in milk fat. However, the function and molecular mechanism of FADS1 in milk fat metabolism remain largely unknown. The FADS1 overexpression increased the triglyceride content, lipid droplet size, and expression of genes related to fatty acid de novo synthesis (SREBP1 and ACC), intracellular fatty acid transporters (FABP3 and FABP4) and triacylglycerol synthesis gene (DGAT2). It also significantly promoted the SREBP1 nuclear translocation by inhibiting the AMPK activation. In addition, FADS1 overexpression inhibited cell proliferation and arrested cell cycle at the G1 phase. These findings reveal a novel FADS1-AMPK-SREBP1 pathway regulating milk fat production in the goat mammary gland.