👤 Rosemari Otton

Glyphosate and 2,4-D are among the most widely used herbicides globally, leading to environmental presence, food contamination, and human contact. Investigations based on current toxicological limits or populational-based herbicide exposures are warranted, and in vitro bioassays provide useful tools for toxicological screening. Thus, this study evaluated the transcriptomic implications of non-cytotoxic exposures to glyphosate, its metabolite aminomethylphosphonic acid (AMPA), or 2,4-D - or to their mixes - on hepatic cells. The half maximal effective concentration (IC50) of each herbicide was calculated (cell viability) in human hepatic C3A cells and 1000-fold lower concentrations were used for transcriptomic analysis (RNA-Seq) after 48 h exposure, resembling current toxicological limits and considering herbicide water levels (glyphosate: 0.95 µg/mL; AMPA: 3.7 µg/mL; 2,4-D: 0.56 µg/mL). Glyphosate exposure enriched MAPK-related biological processes (upregulated TNF, FOS, IGF1, and PDGFB), and downregulated genes associated with lipid metabolism (CD36 and PPARA). Many AMPA exposure-related differentially expressed genes (DEGs, such as PFKFB3, HK2, and ALDOA) were associated with glucose metabolic pathways. Glyphosate and its metabolite yielded a common molecular signature, as illustrated by principal component analysis and the function of 212 shared DEGs. The exposure to 2,4-D was associated with the JNK cascade and the solute carrier family annotations. The herbicide mixtures had a discrete effect on enhancing the impact of individual herbicides, although important epithelial-mesenchymal transition genes were exclusively modified by the mixes (COL11A2, LOXL3, SNAI1). Altogether, our data reveals new perspectives on the short-term molecular effects of herbicide exposure in liver cells, emphasizing potential avenues for further exploration. Show less

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome. It is currently the most common chronic liver disease with complex pathogenesis and challenging treatment. Here, we investigated the hepatoprotective role of green tea (GT) and determined the involvement of miRNAs and its mechanism of action. Male C57Bl/6 mice were fed with a high-fat diet for 4 weeks. After this period, the animals received gavage with GT (500 mg/kg body weight) over 12 weeks (5 days/week). HepG2 cell lines were transfected with miR-34a or miR-194 mimetics and inhibitors to validate the GT supplementation protects against NAFLD development by altering lipid metabolism, increasing gene expression involved in triglycerides and fatty acid catabolism, and decreasing uptake and lipid accumulation. This phenotype was accompanied by miR-34a downregulation and an increase in their mRNA targets Our study identified for the first time that the beneficial effects of GT in the liver can be due to the modulation of miRNAs, opening new perspectives for the treatment of NAFLD focusing on epigenetic regulation of miR-34a and miR-194 as green tea targets. Show less

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. Show less