title: Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis.
abstract: Triazines are herbicides that are widely used worldwide, and we previously observed that the maternal exposure of mice to simazine (50 or 500μg/kg) resulted in smaller ovaries and uteri of their female offspring. Here, we investigated the underlying mechanism that may account for the reproductive dysfunction induced by simazine. We found that following maternal exposure, simazine is transmitted to the offspring, as evidenced by its presence in the offspring ovaries. Analyses of the simazine-exposed offspring revealed that the expression of the relaxin hormone receptor, relaxin-family peptide receptor 1 (RXFP1), prominently decreased in their ovaries and uteri. In addition, downstream target genes of the relaxin pathway including nitric oxide (NO) synthase 2 (Nos2), Nos3, matrix metallopeptidase 9 (Mmp9), and vascular endothelial growth factor (Vegf) were downregulated in their ovaries. Moreover, AKT and extracellular signal-regulated kinases (ERK) levels and their phosphorylated active forms decreased in simazine-exposed ovaries. In vitro exposure of the human ovarian granulosa cells (KGN) and uterine endometrium cells (Hec-1A) to very low concentrations (0.001 to 1nM) of triazines including atrazine, terbuthylazine, and propazine repressed NO production with a concurrent reduction in RXFP1, NOS2, and NOS3. The inhibitory action of triazines on NO release was dependent on RXFP1, phosphoinositol 3-kinase (PI3K)/AKT, and ERK. Radioligand-binding assay also confirmed that triazines competitively inhibited the binding of relaxin to its receptor. Therefore, the present study suggests that triazine herbicides act as endocrine disrupters by interfering with relaxin hormone signaling. Thus, further evaluation of their impact on human health is imperative.
authors.affiliation: School of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Si Eun
authors.initials: SE
authors.lastname: Park
authors.affiliation: School of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Sa Rang
authors.initials: SR
authors.lastname: Lim
authors.affiliation: School of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Hyung-Kyoon
authors.initials: HK
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. Electronic address: jeehyeon@cau.ac.kr.
authors.forename: Jeehyeon
authors.initials: J
authors.lastname: Bae
mesh_terms: D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012065:Relaxin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014227:Triazines / Q000633:toxicity*; D014599:Uterus / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D006540:Herbicides; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D043562:Receptors, G-Protein-Coupled; D012065:Relaxin; D014227:Triazines; C478103:RXFP1 protein, mouse
keywords: Antagonist; Atrazine; RXFP1; Relaxin signaling; Reproductive toxicity; Simazine