The in vivo estrogenic and in vitro anti‐estrogenic activity of permethrin and bifenthrin

Abstract

Pyrethroids are highly toxic to fish at parts per billion or parts per trillion concentrations. Their intended mechanism is prolonged sodium channel opening, but recent studies reveal that pyrethroids such as permethrin and bifenthrin also have endocrine activity. Additionally, metabolites may have greater endocrine activity than parent compounds. We evaluated the in vivo concentration-dependent ability of bifenthrin and permethrin to induce choriogenin (an estrogen-responsive protein) in Menidia beryllina, a fish species known to reside in pyrethroid contaminated aquatic habitats. We then compared the in vivo response to an in vitro assay: CALUX (Chemical Activated Luciferase Gene Expression). Juvenile Menidia beryllina exposed to bifenthrin (1, 10, 100 ng/L), permethrin (0.1, 1, 10 µg/L), and ethinylestradiol (1, 10, 50 ng/L) had significantly higher ng/mL choriogenin (Chg) measured in whole body homogenate than controls. While Chg expression in fish exposed to ethinylestradiol (EE2) exhibited a traditional sigmoidal concentration-response, curves fit to Chg expressed in fish exposed to pyrethroids suggest a unimodal response, decreasing slightly as concentration increases. While the in vivo response indicated that bifenthrin and permethrin or their metabolites act as estrogen agonists, the CALUX assay demonstrated estrogen antagonism by the pyrethroids. Our results, supported by evidence from previous studies, suggest that bifenthrin and permethrin, and/or their metabolites, appear to act as estrogen receptor (ER) agonists in vivo, and that the unmetabolized pyrethroids, particularly bifenthrin, act as an ER antagonists in cultured mammalian cells.

Exploring the Impacts of Two Separate Mixtures of Pesticide and Surfactants on Estrogenic Activity in Male Fathead Minnows and Rainbow Trout

“…Bifenthrin increased estrogen associated choriogenin and VTG plasma protein in Menidia beryllina as well as plasma estradiol-17b (E2) at 0.1 and 1.5 lg/L in juvenile RT (Brander et al 2012;Forsgren et al 2013). It also increased VTG in larval (0.07 lg L -1 ) and adult (0.140 lg L -1 ) FHM (Beggel et al 2011).…”

“…In fish, diuron has been shown to act as a weak antiandrogen by competitively binding to the androgen receptor (Thibaut and Porte 2004). Bifenthrin is a pyrethroid pesticide that binds the voltage-gated sodium channels in neurons, and it has been shown to be estrogenic in several species of fish (Brander et al 2012;Wang et al 2007). Recent monitoring studies have identified bifenthrin in concentrations ranging from 1 to 106 ng/L in northern California (Weston and Lydy 2012;Weston et al 2013).…”

Effects of salinity acclimation on the endocrine disruption and acute toxicity of bifenthrin in freshwater and euryhaline strains of Oncorhynchus mykiss

“…Other in vitro studies have shown that these metabolites have demonstrated estrogen receptor binding and activation [14]. Recent studies in Menidia berylina demonstrated antiestrogenic activity of bifenthrin in vitro, but estrogenic activity at ng/L concentrations in vivo [8], indicating that biotransformation may have contributed to the estrogenic response [8]. Liver microsomes from humans, rats, steelhead, and rainbow trout catalyzed NADPH-dependent turnover of bifenthrin.…”

“…Recent studies have shown that pyrethroids cause estrogenic activity in fish [8,10–13] and cell lines [14]. Hydroxylated metabolites of permethrin produced stereoselectively from liver microsomes of rainbow trout had more estrogenic activity than the parent compound, as measured by vitellogenin (VTG) mRNA [12].…”

Developmental exposure to environmentally relevant concentrations of bifenthrin alters transcription of mTOR and ryanodine receptor-dependent signaling molecules and impairs predator avoidance behavior across early life stages in inland silversides (Menidia beryllina)

“…Bioaccumulation of bifenthrin in tissues has also been demonstrated (Munaretto et al, 2013) potentially leading to long-term, or delayed effects resulting from developmental exposure. Endocrine disruption in response to bifenthrin (ng/L) has been repeatedly determined in inland silversides ( Menidia beryllina ), with significant impacts at concentrations ranging from 0.5 to 50 ng/L (Brander et al, 2012b; DeGroot and Brander, 2014; Brander et al, 2016; DeCourten and Brander, 2017). Interestingly, bifenthrin metabolites appear to contribute most to the estrogenic effects (DeGroot and Brander, 2014), and responses can be greater at lower concentrations.…”