Transcriptomic implications of low herbicide concentrations in hepatic cells: Insights into the individual and combined effects of 2,4-D, glyphosate, and AMPA

Autor(es)

Valente, Leticia Cardoso ; Riechelmann-Casarin, Luana ; Otton, Rosemari ; Delella, Flavia Karina ; Barbisan, Luis Fernando ; Romualdo, Guilherme Ribeiro

• Tipo de documento: Artigo Científico
• Fonte: Toxicology Letters; v. 409, p. 11-pg., 2025-06-01.

Resumo

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 populationalbased 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 mu g/mL; AMPA: 3.7 mu g/mL; 2,4-D: 0.56 mu g/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. (AU)

• Processo FAPESP: 22/06082-8 - Multimodel Drug Screening Platform (MDSP): insights pré-clínicos e moleculares para o gerenciamento dos Cânceres de Cólon e Fígado
• Beneficiário: Guilherme Ribeiro Romualdo
• Modalidade de apoio: Auxílio à Pesquisa - Projeto Geração
• Processo FAPESP: 23/05411-0 - Efeitos da combinação de compostos do café e agentes antitumorais sobre o Carcinoma Hepatocelular: investigação in vitro e in vivo
• Beneficiário: Leticia Cardoso Valente
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 23/08751-7 - Multimodel Drug Screening Platform (MDSP): insights pré-clínicos e moleculares para o gerenciamento dos cânceres de cólon e fígado
• Beneficiário: Guilherme Ribeiro Romualdo
• Modalidade de apoio: Bolsas no Brasil - Projeto Geração
• Processo FAPESP: 23/17585-3 - O Ácido Cafeico promove a resposta antitumoral do Sorafenibe sobre o Carcinoma Hepatocelular? Uma abordagem in vitro
• Beneficiário: Luana Riechelmann Casarin
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica