The Teratogenicity and the Action Mechanism of Gallic Acid Relating with Brain and Cervical Muscles

Abstract

Gallic acid (3,4,5-trihydroxybenzoic acid) (GA) and other flavanoids are extensively used in nutraceuticals because of their antioxidant and antiinflammatory properties. While examining whether GA is effective in alleviating valproic-acid-induced teratogenesis in a chicken embryo model (CEM), we observed embryo hemorrhage and liposis in the musculi longissimus cervicis. We conducted this study to determine whether GA is inherently teratogenic and the extent to which the risk can be transferred to fetuses. A CEM was used to administer GA at 2, 6, 10, and 14 μM. GA at 2 μM did not exhibit cytotoxicity. At 6, 10, and 14 μM, GA caused severe decreases in body and liver weights, causing -5.6%, -21.3%, and -27.5% body weights and 4.0, 3.8, and 3.2-g, liver weights, respectively, in day-1 chicks. The optimal alive birth rate (or damaging rate) reached 33.3%, 39.4%, and 29.2% at 6, 10, and 14 μM GA, respectively. The damaged tissue was primarily cervical muscle (musculi longissimus cervicis), as evidenced by liposis, Zenker’s necrosis, and hemolysis. The erythrocyte, hemoglobin, eosinophil, lymphocyte, and monocyte counts were severely reduced and PPAR-α was downregulated, whereas the Ras/Raf/JAK/STAT pathway was upregulated. The GA dose required to induce teratogenesis was ≥ 6 μM (1.02 mg/kg), which can be easily consumed by pregnant women in typical teas such as Chinese Pu-’Er and Chinese black teas, indicating a potential risk to human fetuses. GA at doses ≥ 1.02 mg/kg of body weight potentially causes characteristic cerebral hemolysis and liposis in the musculi longissimus cervicis. The mechanism of action of GA is multidisciplinary: The liposis can be ascribed to downregulation of PPAR-α; the erythrocyte hemolysis can be attributed to its unique autooxidative and prooxidant behavior and the inhibition of carbonic anhydrase; and the proliferation and differentiation deficits can be attributed to the upregulation of the Ras/Raf/JAK/STAT pathway.

Therapeutic Effects of Gallic Acid in Regulating Senescence and Diabetes; an In Vitro Study

“…Besides, new GA features, such as inhibition of aldose reductase, have been reported [ 21 ]. Although GA is believed to have a low risk of side effects, doses greater than 1.02 mg/kg might have teratogenic properties and pose a threat to the fetus in pregnant women [ 22 ]. So, choosing the best concentration and dose for GA is an essential concern in the studies.…”

In utero exposure of green coffee extract alters rat fetal neurodevelopment in a dose dependent manner

“…The present study showed that prenatal administration of the high dose of green coffee induced hemorrhage in the cerebral cortex, cerebellum, and spinal cord of the developing rat fetuses. Gallic acid has been reported to be teratogenic at early embryonic development and induced severe cerebral hemorrhage in E9.5 embryos in a dose-dependent manner (Hsieh et al 2015). This cerebral hemorrhage was attributed, partly, to the strong prooxidant nature of gallic acid (Lee et al, 2005;Eslami et al, 2010).…”

“…It has been reported that a small concentration of gallic acid, about 1.02 mg/kg or more, can induce teratogenicity and result in cerebral hemorrhage. This concentration of gallic acid could be easily consumed in tea or coffee, imposing risk to the developing fetus (Hsieh et al 2015). In addition to gallic acid, other polyphenols, present in the coffee extract, are considered to be ROS releasing compounds.…”

“…Moreover, Boots et al (2007) reported that orthoquinones from pyrogallol and catechol can produce ROS. All of these redox interactions can alter many biological functions during development, such as the cell cycle and apoptosis (Hsieh et al 2015).…”

Chromatographic Finger Printing and Quantification of Gallic Acid in Amla (Emblica Officinalis Gaertn.), Palasa (Butea Monosperma Taub.) and Amalaki Rasayana

“…Gallic acid, both natural and synthetic analogue having protocatechuic acid alkyl esters, inhibits HIV -1 protease 17 . The pro-oxidant and auto-oxidative behaviours of gallic acid have also been reported [18][19] .…”