RESUMEN
Hydroxylation of polyaromatic compounds through cytochromes P450 (CYPs) is known to result in potentially estrogenic transformation products. Recently, there has been an increasing awareness of the importance of alternative pathways such as aldehyde oxidases (AOX) or N-methyltransferases (NMT) in bioactivation of small molecules, particularly N-heterocycles. Therefore, this study investigated the biotransformation and activity of methylated quinolines, a class of environmentally relevant N-heterocycles that are no native ligands of the estrogen receptor (ER), in the estrogen-responsive cell line ERα CALUX. We found that this widely used cell line overexpresses AOXs and NMTs while having low expression of CYP enzymes. Exposure of ERα CALUX cells to quinolines resulted in estrogenic effects, which could be mitigated using an inhibitor of AOX/NMTs. No such mitigation occurred after coexposure to a CYP1A inhibitor. A number of N-methylated but no hydroxylated transformation products were detected using liquid chromatography-mass spectrometry, which indicated that biotransformations to estrogenic metabolites were likely catalyzed by NMTs. Compared to the natural ER ligand 17ß-estradiol, the products formed during the metabolization of quinolines were weak to moderate agonists of the human ERα. Our findings have potential implications for the risk assessment of these compounds and indicate that care must be taken when using in vitro estrogenicity assays, for example, ERα CALUX, for the characterization of N-heterocycles or environmental samples that may contain them.
Asunto(s)
Metiltransferasas/metabolismo , Quinolinas/metabolismo , Receptores de Estrógenos/metabolismo , Biocatálisis , Línea Celular Tumoral , Humanos , Metiltransferasas/química , Modelos Moleculares , Estructura Molecular , Quinolinas/química , Proteínas Recombinantes/metabolismoRESUMEN
OBJECTIVE: This study examines the effect of economic recession on the suicide differential between rural and urban counties. METHODS: A negative binomial regression model and county mortality data are used to estimate the effect of recession and rurality on county-level suicides from 2002-2016. RESULTS: After accounting for differences in population, urban counties have more female suicides than rural counties, but urban counties experience smaller increases in female suicide numbers during periods of recession than rural counties. Long-term factors such as high chronic poverty or unemployment have a greater impact on male suicide rates, while short-term economic crises have a larger impact on female suicides. Higher percentages of children in the county have an increasing effect on male suicides, but a decreasing effect on female suicides. Finally, farm-dependent counties have fewer suicides than non-farm-dependent counties. This holds true for both males and females. CONCLUSIONS: Periods of recession impact suicide numbers; however, this effect is most noticeable for females, with rural counties having larger increases in female suicide numbers than their urban counterparts during recession years.