Estrogenic endocrine disruptors: Molecular mechanisms of action.

Pyrethroids are now the fourth most used group of insecticides worldwide. Employed in agriculture and in urban areas, they are detected in waterways at concentrations that are lethally and sublethally toxic to aquatic organisms. Highly lipophilic, pyrethroids accumulate in sediments and bioaccumulate in fishes. Additionally, these compounds are demonstrated to act as endocrine disrupting compounds (or EDCs) in mammals and fishes, and therefore interfere with endocrine signaling by blocking, mimicking, or synergizing endogenous hormones through direct receptor interactions, and indirectly via upstream signaling pathways. Pyrethroid metabolites have greater endocrine activity than their parent structures, and this activity is dependent on the enantiomer present, as some pyrethroids are chiral. Many EDCs studied thus far in fish have known estrogenic or antiestrogenic effects, and as such cause the inappropriate or altered expression of genes or proteins (i.e., Vtg–vitellogenin, Chg–choriogenin), often leadi...

Pyrethroid Pesticides as Endocrine Disruptors: Molecular Mechanisms in Vertebrates with a Focus on Fishes.

Background: Epidemiological evidence suggests a link between pesticide exposure and the development of metabolic diseases. However, most experimental studies have evaluated the metabolic effects of...

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Metabolic Effects of a Chronic Dietary Exposure to a Low-Dose Pesticide Cocktail in Mice: Sexual Dimorphism and Role of the Constitutive Androstane Receptor

Prioritizing selected PPCPs on the basis of environmental and toxicogenetic concerns: A toxicity estimation to confirmation approach

The role of P450 metabolism in the estrogenic activity of bifenthrin in fish.

In vitro metabolism of cis- and trans-permethrin by rat liver microsomes, and its effect on estrogenic and anti-androgenic activities.

In vitro metabolism of methiocarb and carbaryl in rats, and its effect on their estrogenic and antiandrogenic activities

The oxidative, reductive, and hydrolytic metabolism of methiocarb and the hydrolytic metabolism of carbaryl by liver microsomes and plasma of rats or humans were examined. The effects of the metabolism of methiocarb and carbaryl on their nuclear receptor activities were also examined. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide, and a novel metabolite, methiocarb sulfone were detected. Methiocarb sulfoxide was oxidized to the sulfone by liver microsomes and reduced back to methiocarb by liver cytosol. Thus, the interconversion between methiocarb and the sulfoxide was found to be a new metabolic pathway for methiocarb by liver microsomes. The product of methiocarb hydrolysis, which is methylthio-3,5-xylenol (MX), was also oxidized to sulfoxide form by rat liver microsomes. The oxidations were catalyzed by human flavin-containing monooxygenase isoform (FMO1). CYP2C19, which is a human cytochrome P450 (CYP) isoform, catalyzed the sulfoxidations of methiocarb and MX, while CYP1A2 also exhibited oxidase activity toward MX. Methiocarb and carbaryl were not enzymatically hydrolyzed by the liver microsomes, but they were mainly hydrolyzed by plasma and albumin to MX and 1-naphthol, respectively. Both methiocarb and carbaryl exhibited PXR and PPARα agonistic activities; however, methiocarb sulfoxide and sulfone showed markedly reduced activities. In fact, when methiocarb was incubated with liver microsomes, the receptor activities were decreased. In contrast, MX and 1-naphthol showed nuclear receptor activities equivalent to those of their parent carbamates. Thus, the hydrolysis of methiocarb and carbaryl and the oxidation of methiocarb markedly modified their nuclear receptor activities.

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Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities.

【】 p-Hydroxyalkylbenzoates (parabens) have antimicrobial activity, and have been widely used as preservatives in food, cosmetic and pharmaceutical products. Phthalate diesters are commonly used as plasticizers for polyvinyl chloride-based products. In this study, we examined the arylhydrocarbon receptor (AhR) ligand activity, estrogen receptor (ER) ligand activity, and chytochrome P450-inhibitory (P450) activity of parabens and phthalates. We also studied the metabolism of parabens and phthalates in vitro in rat. Parabens with a mediumlength side chain (C4~C6) showed AhR ligand activity and ER ligand activity, but the phthalates examined here lacked these activities. Parabens and phthalates with a side chain of medium length (C6~C9) showed higher inhibitory effects on P450 activity than did those with a short (C1~C4) side chain. Benzyl-n-butylphthalate showed the gratest inhibitory effect on P450 activities among the phthalates tested in this study. It was found that carboxylesterase (CES) involved in the hydrolysis of parabens in liver, intestine and lung. The hydrolytic activity of liver microsomes toward parabens decreased with decreasing side chain length of the parabens. CES in the solubilized fraction of liver microsomes is involved in the hydrolysis of phthalates with the short side chain (C2~C4) , while an enzyme in the insoluble fraction is involved in the hydrolysis of phthalates with a long side chain (C6).

Satoko Tange

Papers

In vitro metabolism of cis- and trans-permethrin by rat liver microsomes, and its effect on estrogenic and anti-androgenic activities.

In vitro metabolism of methiocarb and carbaryl in rats, and its effect on their estrogenic and antiandrogenic activities

Metabolism of methiocarb and carbaryl by rat and human livers and plasma, and effect on their PXR, CAR and PPARα activities.

Parabens and phthalates: their metabolism, ahr ligand activity, estrogenic activity, and p450-inhibitory activity