Pteridium aquilinum and Its Ptaquiloside Toxin Induce DNA Damage Response in Gastric Epithelial Cells, a Link With Gastric Carcinogenesis

Abstract

The multifactorial origin of gastric cancer encompasses environmental factors mainly associated with diet. Pteridium aquilinum-bracken fern-is the only higher plant known to cause cancer in animals. Its carcinogenic toxin, ptaquiloside, has been identified in milk of cows and groundwater. Humans can be directly exposed by consumption of the plant, contaminated water or milk, and spore inhalation. Epidemiological studies have shown an association between bracken exposure and gastric cancer. In the present work, the genotoxicity of P. aquilinum and ptaquiloside, including DNA damaging effects and DNA damage response, was characterized in human gastric epithelial cells and in a mouse model. In vitro, the highest doses of P. aquilinum extracts (40 mg/ml) and ptaquiloside (60 μg/ml) decreased cell viability and induced apoptosis. γH2AX and P53-binding protein 1 analysis indicated induction of DNA strand breaks in treated cells. P53 level also increased after exposure, associated with ATR-Chk1 signaling pathway activation. The involvement of ptaquiloside in the DNA damage activity of P. aquilinum was confirmed by deregulation of the expression of a panel of genes related to DNA damage signaling pathways and DNA repair, in response to purified ptaquiloside. Oral administration of P. aquilinum extracts to mice increased gastric cell proliferation and led to frameshift events in intron 2 of the P53 gene. Our data demonstrate the direct DNA damaging and mutagenic effects of P. aquilinum. These results are in agreement with the carcinogenic properties attributed to this fern and its ptaquiloside toxin and support their role in promoting gastric carcinogenesis.

Tissue damage and embryonic malformation induced by aqueous extract of Pteridium aquilinum on chorioallantoic membrane of chick embryo (CAM)

“…Corroborating with our study the literature described desmoplasia that on fibrosis formation there is excessive synthesis of extracellular matrix (including collagen and other proteins) (SEANDEL et al, 2001;CHUN et al, 2004), as well as histological changes such as increased number of inflammatory cells in the gastric mucosa of C57B/6 in mice that received aqueous extract of BF (COUSSENS, WERB, 2002;GOMES et al, 2012;LOTERSZTAJN, INSEL, 2013). As a result of this inflammatory process could trigger the formation of neoplastic tissue (COUSSENS, WERB, 2002;EIRO, VIZOSO, 2012).…”

Efficacy of certain common ferns against red spider mite Oligonychus coffeae and tea mosquito bug Helopeltis theivora infesting tea

“…infesting groundnut. Moreover, the DNA damage caused by P. aquilinum was proved at a higher concentration of 40 mg/ml in rats (Gomes et al 2011); while the concentration evaluated in our study was at a lower level. On comparing with standard treatments, d. linearis and P. aquilinum require continuous application at a seven-day interval for better control.…”

“…The above-mentioned factors corroborate the low persistence of fern extracts in our study. Even though the bracken fern P. aquilinum proved its carcinogenic compound ptaquiloside (Gomes et al 2011), it is used in traditional medicine in many countries of the world for its substantial antibacterial, antifungal, antiviral, and cytotoxic properties (Wink 2015); it was also evaluated for its insecticidal activity by various authors. Jbilou et al (2008) reported 66% mortality in Tribolium castaneum caused by P. aquilinum.…”

Effects of copaene, a tricyclic sesquiterpene, on human lymphocytes cells in vitro

“…Likewise, nivalenol (a sesquiterpene mycotoxin) showed organ specific genotoxicity in cultured Chinese hamster ovary (CHO) cells and in several mouse organs and tissues like liver, kidney, thymus, bone marrow and mucosa of stomach, jejunum, and colon using single cell gel electrophoresis (SCGE) assay (Tsuda et al1998). In addition, ptaquiloside increased DNA damage in human gastric epithelial cells as well as in a mouse model (Gomes et al 2012). Furthermore, Aquino et al (2011) reported that artesunate showed weak genotoxic effects at low doses and clastogenic effects at high doses in bone marrow cells from male Swiss mice.…”