Normal pregnancy is essential for human reproduction. However, BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene‐7,8‐dihydrodiol‐9,10‐epoxide) could cause dysfunctions of human trophoblast cells and might further induce miscarriage. Yet, the underlying mechanisms remain largely unknown. Herein, we identified a novel upregulated lnc‐HZ04 and a novel downregulated miR‐hz04 in villous tissues of unexplained recurrent miscarriage (RM) relative to those in healthy control tissues and also in BPDE‐treated human trophoblast cells. Lnc‐HZ04 directly and specifically bound with miR‐hz04, diminished the reduction effects of miR‐hz04 on IP3R1 mRNA expression level and on IP3R1 mRNA stability, and then activated the Ca2+‐mediated IP3R1/p‐CaMKII/SGCB pathway, which further promoted trophoblast cell apoptosis. The miR‐hz04 target site on lnc‐HZ04 played crucial roles in these regulations. In normal trophoblast, relatively less lnc‐HZ04 and more miR‐hz04 suppressed this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in RM tissues, p53 was upregulated, which might promote p53‐mediated lnc‐HZ04 transcription. Relatively more lnc‐HZ04 and less miR‐hz04 activated this apoptosis pathway and might further induce miscarriage. BaP could also induce mice miscarriage by upregulating its corresponding murine apoptosis pathway. Therefore, BPDE‐induced apoptosis of human trophoblast cells was associated with the occurrence of miscarriage. This work discovered the regulation roles of lnc‐HZ04 and miR‐hz04 and provided scientific and clinical understanding of the occurrence of unexplained miscarriage.
Aflatoxin B (AFB) causes hepatotoxic, genotoxic, and immunotoxic effects in a variety of species. Although various neutralizing agents of AFB toxicity have been studied, the egg yolk immunoglobulin (IgY) detoxification of small molecular toxins and the mechanisms underlying such effects have not yet been reported. In this investigation, anti-AFB IgY against AFB was successfully raised, and a competitive indirect enzyme-linked immunosorbent assay was established with a sensitive half-maximal inhibitory concentration (IC 2.4 ng/mL) and dynamic working range (0.13-43.0 ng/mL). The anti-AFB IgY obtained reduced AFB-induced cytotoxicity, cellular dysfunction, and genotoxicity by protecting cells against apoptotic body formation and DNA strand breaks, preventing G2/M phase cell cycle arrest, reducing AFB-DNA adduct and reactive oxygen species production and maintaining cell migration and invasion and the mitochondrial membrane potential. Anti-AFB IgY significantly inhibited the AFB-induced expression of proteins related to antioxidative, pro-apoptotic, and antiapoptotic processes in a strong dose-dependent manner. These experiments demonstrated that the anti-AFB IgY-bound AFB could not enter cells. This is the first time that IgY has been found to reduce the effects of small molecular toxins, which will be beneficial for the development of antibodies as detoxication agents.
Egg yolk immunoglobulins (IgY), as nutraceutical supplement for therapeutic or prophylactic intervention, have been extensively studied. The effects of IgY on small molecular toxin-induced toxicity in animals are unclear. In the present study, the protection of highly purified and specific anti-AFB1 IgY against AFB1-induced genotoxicity and oxidative damage on the rat liver model were investigated. Our results revealed that AFB1 induced significant oxidative damage markers, as well as AFB1-induced protein expression in antioxidant, pro- and antiapoptosis processes in rat liver. These effects could be significantly inhibited by cogavage with anti-AFB1 IgY in a dose-dependent manner. However, anti-AFB1 IgY did not significantly induce hepatic CAT and SOD1. To explore mechanisms, metabolite experiments were established to evaluate the influence of anti-AFB1 IgY on the absorption of AFB1 in rats. Middle and high doses of anti-AFB1 IgY reduced hepatic AFB1-DNA adducts by 43.3% and 52.9%, AFB1-N 7-guanine urinary adducts by 19.6% and 34.4%, and AFB1-albumin adducts by 10.5% and 21.1%, respectively. The feces of high dose anti-AFB1 IgY cogavaged rats contained approximately 2-fold higher AFB1 equivalents at 3–6 h after ingestion than AFB1 group feces, indicating IgY inhibited AFB1 uptake. These results had provided insight that anti-AFB1 IgY could prevent animal organs from damage caused by AFB1 and will be beneficial for the application of detoxification antibody as a supplement in food.
BackgroundMiscarriage seriously hinders human reproduction. BaP (benzo(a)pyrene) and its metabolite BPDE (benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide) could cause trophoblast cell dysfunctions and might further induce human miscarriage. However, the underlying mechanisms remain largely unknown. ResultsHerein, we identified a novel lnc-HZ04 up-regulated and a novel miR-hz04 down-regulated in the unexplained recurrent miscarriage (RM) villous tissues relative to the healthy control tissues and also in the BPDE-exposed trophoblast cells. Lnc-HZ04 served as competing endogenous RNA (ceRNA), directly and specifically bound with miR-hz04 on its target site, and diminished the inhibition effects of miR-hz04 on IP3R1 mRNA expression level and its mRNA stability, thus activated Ca2+-mediated IP3R1/p-CaMKII/SGCB apoptosis pathway, which further promoted trophoblast cell apoptosis. The miR-hz04 target site, but not its mutant, on lnc-HZ04 played important roles in these regulations. In normal trophoblast, relatively less lnc-HZ04 and more miR-hz04 inhibited this apoptosis pathway and gave normal pregnancy. After exposure to BPDE or in the RM tissues, relatively more lnc-HZ04 and less miR-hz04 activated this apoptosis pathway and induced miscarriage. BaP could also induce mice miscarriage by up-regulating this corresponding murine apoptosis pathway. ConclusionsThis work discovered that lnc-HZ04 served as a ceRNA for miR-hz04 and up-regulated IP3R1/CaMKII/SGCB pathway, which promoted the BPDE-induced human trophoblast cell apoptosis and the occurrence of miscarriage, providing novel scientific and clinical understanding in the occurrence of unexplained miscarriage.
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