Bifenthrin is a pyrethroid insecticide used in urban and agricultural applications. Previous studies have shown that environmentally relevant (ng/L) concentrations of bifenthrin increased plasma concentrations of 17b-estradiol (E2) and altered the expression of dopaminergic pathway components. The dopaminergic neurons can indirectly regulate E2 biosynthesis, suggesting that bifenthrin may disrupt the hypothalamic-pituitary-gonadal (HPG) axis. Because embryos do not have a complete HPG axis, the hypothesis that bifenthrin impairs dopamine regulation was tested in embryonic and 1-mo-old juvenile zebrafish (Danio rerio) with exposure to measured concentrations of 0.34 and 3.1 mg/L bifenthrin for 96 h. Quantitative reverse transcriptase polymerase chain reaction was used to investigate transcripts of tyrosine hydroxylase (TH), dopamine receptor 1 (DR1) and 2A (DR2A), dopamine active transporter (DAT), estrogen receptor a (ERa), ERb1, ERb2, luteinizing hormone b (LHb), follicle-stimulating hormone b (FSHb), vitellogenin (VTG), cytochrome P450 cyp19a1a, and cyp19a1b. Levels of E2 were measured by enzyme-linked immunosorbent assay (ELISA). Dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations were measured by liquid chromatrography-tandem mass spectrometry (LC-MS/MS). Significant decreases in TH and DR1 transcripts and HVA levels, as well as ratios of HVA/dopamine and HVAþDOPAC/dopamine, in zebrafish embryos were observed after bifenthrin treatment. In juveniles, a significant increase in the expression of ERb1 and the DOPAC to dopamine ratio was noted. These results show a possible antiestrogenic effect of bifenthrin in embryos, and estrogenicity in juveniles, indicating life-stage-dependent toxicity in developing fish. Environ Toxicol Chem 2018;37:236-246. C 2017 SETAC

The dopaminergic effect of PAH and PFAS mixtures, prepared based on environmental levels has been studied in juvenile female Atlantic cod (Gadus morhua). Benzo[a]pyrene, dibenzothiophene, fluorene, naphthalene, phenanthrene and pyrene were used to prepare a PAH mixture, while PFNA, PFOA, PFOS and PFTrA were used to prepare PFAS mixture. Cod were injected intraperitoneally twice, with either a low (1x) or high dose (20x) of each compound mixture or various combinations. After two week of exposure, levels of plasma 17β-estradiol (E2) were significantly high in high PAH/high PFAS treated groups. Dopamine: metabolite ratios (DOPAC/dopamine and HVA+DOPAC/dopamine) in brain homogenate changes with the levels of E2 in plasma except for high PAH/low PFAS and low PAH/high PFAS treated groups. In general, th mRNA levels inversely correlated with dopamine: metabolite ratios and gnrh2 mRNA levels. Respective decreases and increases of dr1 and dr2a after exposure to the high PAH dose were observed. Whereas, high PFAS exposure decreased both drs, leading to high plasma E2 concentrations. Other investigated endpoints suggest that these compounds at different doses and combinations have different toxicity threshold and mode of actions. These effects indicate potential alternations in feedback signalling processes within dopaminergic pathway by these contaminants.

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Effects-directed analyses of water extracts from the San Francisco Bay Delta of California using estrogenic activity indicated that the pesticides, bifenthrin, and diuron, as well as alkylphenol surfactants, were observed in active fractions. To determine whether the estrogenic activity of the mixture had any impacts on sexual development, Japanese medaka (Oryzias latipes) embryos were exposed to an ambient concentration of the compounds, individually and as mixtures, using components of the US Environmental Protection Agency (USEPA), Endocrine Disruptor Screening Program, and Organisation for Economic Cooperation and Development (OECD) assay. In medaka exposed to diuron, or surfactants alone, the percentages of phenotypic females were 88.9 ± 19.2% and 66.4 ± 3.8%, respectively. When diuron was combined with surfactants, 93.3 ± 5.8% of the animals were female. To evaluate whether phenotypic females were changed from genetically male animals, the expression of the male-specific gene (DMY) was measured in animals following treatment. Treatments with ambient concentrations of surfactants and diuron had animals with higher percentages (78 ± 19%) of phenotypic females that were derived from genotypic males. Our results demonstrated that mixtures of pesticides and surfactants may alter sexual development after embryonic exposure in fish.

Post‐traumatic stress disorder (PTSD), which can affect 1 in 11 adults during their lifetime, is often comorbid with chronic alcohol use problems and increases alcohol relapse risk. PTSD and alcohol‐use phenotypes are associated with variants in the FKBP propyl isomerase 5 (FKBP5) gene, which encodes FK506‐binding protein 5 (FKBP5), a chaperone modulator of glucocorticoid receptors (GR) that is functionally implicated in stress‐related psychiatric disorders and alcohol withdrawal severity. Data suggests that FKBP5 inhibition may decrease alcohol intake, but its role in the post‐traumatic recurrence of alcohol drinking is unknown. Here, we tested the hypotheses that amygdala Fkbp5 expression is increased in rats with a history of traumatic stress and is associated with greater reacquisition of ethanol self‐administration. Then, we tested the hypothesis that benztropine mesylate, an FDA‐approved drug that disrupts FKBP5‐GR binding, reduces reacquisition of ethanol self‐administration in rats with a history of traumatic stress. Separate cohorts (for mRNA vs. benztropine studies) of male (n = 43) and female (n = 20) Wistar rats received 3 sessions of light‐cued footshock stress (30 min session, 60 footshocks, 1‐s 0.4 mA) before acquiring operant ethanol (10% v/v) self‐administration (1‐h sessions, fixed ratio1‐3), followed by extinction (16 sessions), and then renewed alcohol access. Amygdala Fkbp5 expression correlated significantly with increased ethanol self‐administration (rs(23) = 0.463, p = 0.023) during renewal of ethanol access. Subchronic (3 days) benztropine pretreatment (‐2 h, i.p., 0, 5, and 10 mg/kg [n = 10, 14, and 14]) significantly reduced the reacquisition of ethanol self‐administration. On days 2 and 3 of reacquisition, self‐administration was significantly reduced in drug treated animals (Dose x Day: F(4,64)=2.83, p < 0.04), culminating in a 68% reduction in males (0.78±0.16 vs. 0.25±0.13 g/kg) and a 41% reduction in females (0.88±0.14 vs. 0.52±0.13 g/kg) at the 10 mg/kg dose. Overall, the results warrant further study of benztropine and its potential inhibition of FKBP5 to reduce post‐traumatic alcohol relapse risk.