The disruption of human trophoblast functions by autophagy activation through PI3K/AKT/mTOR pathway induced by exposure to titanium carbide (Ti3C2) MXene

Yang, Limei; Hu, Le; Tang, Haibo; Liu, Xueqing; Zhang, Yue; Wen, Yixian; Yang, Yongxiu; Geng, Yanqing

doi:10.1016/j.fct.2022.113128

Cited by 11 publications

(5 citation statements)

References 42 publications

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“…Abnormal placental development and altered placental lipid metabolism following exposure to Ti 3 C 2 nanosheets cause neurodevelopmental disorders in offspring mice [ 21 ]. Previously, we found that Ti 3 C 2 nanosheet exposure inhibited the growth of villus explants and impaired the function of HTR-8/SVneo cells [ 22 ]. However, experimental studies on the biosafety of Ti 3 C 2 nanosheets are limited, and the effects of Ti 3 C 2 nanosheets on the male reproductive system have not been studied yet.…”

Section: Introductionmentioning

confidence: 99%

Ti3C2 (MXene) nanosheets disrupt spermatogenesis in male mice mediated by the ATM/p53 signaling pathway

Yang

Bao

et al. 2023

Biol Direct

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Background Two-dimensional ultrathin Ti3C2 nanosheets are increasingly being used in biomedical applications owing to their special physicochemical properties. But, the biological effects of its exposure on the reproductive system is still unclear. This study evaluated the reproductive toxicity of Ti3C2 nanosheets in the testes. Results Ti3C2 nanosheets at doses of 2.5 mg/kg bw and 5 mg/kg bw in mice caused defects in spermatogenic function, and we also clarified an underlying molecular mechanism of it in vivo and in vitro model. Ti3C2 nanosheets induced an increase of reactive oxygen species (ROS) in testicular and GC-1 cells, which in turn led to the imbalance in oxidative and antioxidant systems (also known as oxidative stress). Additionally, oxidative stress often induces cellular DNA strand damages via the oxidative DNA damages, which triggered cell cycle arrest in the G1/G0 phase, leading to cell proliferation inhibition and irreversible apoptosis. ATM/p53 signaling manifest key role in DNA damage repair (DDR), and we demonstrate that ATM/p53 signaling was activated, and mediated the toxic damage process caused by Ti3C2 nanosheet exposure. Conclusion Ti3C2 nanosheet-induced disruption of proliferation and apoptosis of spermatogonia perturbed normal spermatogenic function that was mediated by ATM/p53 signaling pathway. Our findings shed more light on the mechanisms of male reproductive toxicity induced by Ti3C2 nanosheets. Graphical abstract

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Section: Introductionmentioning

confidence: 99%

Ti3C2 (MXene) nanosheets disrupt spermatogenesis in male mice mediated by the ATM/p53 signaling pathway

Yang

Bao

et al. 2023

Biol Direct

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“…Specifically, Maroua Jalouli et al reported that allethrin may impair autophagy-related cell apoptosis and induce excessive oxidative stress, most likely via inhibiting the PI3K/AKT/mTOR signaling pathway, and these effects may result in ovarian dysfunction and reduced fertility in female offspring [ 64 ]. Our previous research revealed that cellular autophagy is activated via the PI3K/AKT/mTOR signaling pathway, eventually leading to functional impairment in HTR-8/SVneo cells [ 24 ]. We found that Ti 3 C 2 nanosheets treatment decreased the protein level of PI3K, p-AKT/ AKT, and p-mTOR/ mTOR.…”

Section: Discussionmentioning

confidence: 99%

Ti3C2 nanosheet-induced autophagy derails ovarian functions

Yang,

He,

et al. 2024

J Nanobiotechnol

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Background Two-dimensional ultrathin Ti3C2 (MXene) nanosheets have gained significant attention in various biomedical applications. Although previous studies have described the accumulation and associated damage of Ti3C2 nanosheets in the testes and placenta. However, it is currently unclear whether Ti3C2 nanosheets can be translocated to the ovaries and cause ovarian damage, thereby impairing ovarian functions. Results We established a mouse model with different doses (1.25, 2.5, and 5 mg/kg bw/d) of Ti3C2 nanosheets injected intravenously for three days. We demonstrated that Ti3C2 nanosheets can enter the ovaries and were internalized by granulosa cells, leading to a decrease in the number of primary, secondary and antral follicles. Furthermore, the decrease in follicles is closely associated with higher levels of FSH and LH, as well as increased level of E2 and P4, and decreased level of T in mouse ovary. In further studies, we found that exposure toTi3C2 nanosheets increased the levels of Beclin1, ATG5, and the ratio of LC3II/Ι, leading to autophagy activation. Additionally, the level of P62 increased, resulting in autophagic flux blockade. Ti3C2 nanosheets can activate autophagy through the PI3K/AKT/mTOR signaling pathway, with oxidative stress playing an important role in this process. Therefore, we chose the ovarian granulosa cell line (KGN cells) for in vitro validation of the impact of autophagy on the hormone secretion capability. The inhibition of autophagy initiation by 3-Methyladenine (3-MA) promoted smooth autophagic flow, thereby partially reduced the secretion of estradiol and progesterone by KGN cells; Whereas blocking autophagic flux by Rapamycin (RAPA) further exacerbated the secretion of estradiol and progesterone in cells. Conclusion Ti3C2 nanosheet-induced increased secretion of hormones in the ovary is mediated through the activation of autophagy and impairment of autophagic flux, which disrupts normal follicular development. These results imply that autophagy dysfunction may be one of the underlying mechanisms of Ti3C2-induced damage to ovarian granulosa cells. Our findings further reveal the mechanism of female reproductive toxicity induced by Ti3C2 nanosheets.

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“…Mitofusin-2 regulates mitochondrial autophagy, while low levels of mitofusin-2 expression increase trophoblast autophagy, which is associated with early unexplained miscarriages [ 52 ]. Excessive autophagy activation caused by decreased lei-7i expression or maternal exposure to nanoparticles, suppresses trophoblast migration and invasion [ 53 – 55 ].…”

Section: Involvement Of Rcd At the Maternal-fetal Interface In Pregnancymentioning

confidence: 99%

The regulated cell death at the maternal-fetal interface: beneficial or detrimental?

Chen,

Zheng

2024

Cell Death Discov.

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Regulated cell death (RCD) plays a fundamental role in placental development and tissue homeostasis. Placental development relies upon effective implantation and invasion of the maternal decidua by the trophoblast and an immune tolerant environment maintained by various cells at the maternal-fetal interface. Although cell death in the placenta can affect fetal development and even cause pregnancy-related diseases, accumulating evidence has revealed that several regulated cell death were found at the maternal-fetal interface under physiological or pathological conditions, the exact types of cell death and the precise molecular mechanisms remain elusive. In this review, we summarized the apoptosis, necroptosis and autophagy play both promoting and inhibiting roles in the differentiation, invasion of trophoblast, remodeling of the uterine spiral artery and decidualization, whereas ferroptosis and pyroptosis have adverse effects. RCD serves as a mode of communication between different cells to better maintain the maternal-fetal interface microenvironment. Maintaining the balance of RCD at the maternal-fetal interface is of utmost importance for the development of the placenta, establishment of an immune microenvironment, and prevention of pregnancy disorders. In addition, we also revealed an association between abnormal expression of key molecules in different types of RCD and pregnancy-related diseases, which may yield significant insights into the pathogenesis and treatment of pregnancy-related complications.

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The disruption of human trophoblast functions by autophagy activation through PI3K/AKT/mTOR pathway induced by exposure to titanium carbide (Ti3C2) MXene

Cited by 11 publications

References 42 publications

Ti3C2 (MXene) nanosheets disrupt spermatogenesis in male mice mediated by the ATM/p53 signaling pathway

Ti3C2 (MXene) nanosheets disrupt spermatogenesis in male mice mediated by the ATM/p53 signaling pathway

Ti3C2 nanosheet-induced autophagy derails ovarian functions

The regulated cell death at the maternal-fetal interface: beneficial or detrimental?

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