Antiestrogens Inhibit Xenoestrogen-Induced Brain Aromatase Activity but Do Not Prevent Xenoestrogen-Induced Feminization in Japanese Medaka ( Oryzias latipes )

Abstract

In fish, exposure to estrogen or estrogen-mimicking chemicals (xenoestrogens) during a critical period of development can irreversibly invert sex differentiation. In medaka, a male-to-female reversal upon exposure to a xenoestrogen is accompanied by an increase in brain aromatase expression and activity. However, whether this increase is the direct cause of sex reversal is unknown. In this study we further examined the role brain aromatase plays in genesis of developmental abnormalities in response to endocrine-disrupting chemicals (EDCs). Further, the effects of a mixture of apparent antagonistic environmentally relevant EDCs on development were examined to determine if their combined actions could lessen each other’s impacts. To this end, hatchling medaka were subjected in a 2-week flow-through immersion exposure to an estrogen mimic [dichlorodiphenyltrichloroethane (o,p′-DDT)] and to pharmaceutical [fadrozole (FAD)] and environmental aromatase inhibitors [tributyltin (TBT)] alone and in combination. Brain aromatase expression and enzyme activity were measured on exposure days 5, 9, and 14 by real-time reverse-transcriptase polymerase chain reaction and tritiated water release assay, respectively. We recorded sex reversals at sexual maturity by examining the phenotypic and genotypic sex of d-rR–strain medaka. Results indicate that FAD and TBT inhibit aromatase activity in o,p′-DDT–treated fish but do not prevent feminization, indicating that increased brain aromatase activity is not critical to EDC-induced male-to-female sex inversion. The observation that estradiol biosynthesis inhibitors do not block the effect of the xenoestrogen suggests that in the environment, exposure to seemingly antagonistic EDCs does not necessarily lessen the harmful impacts of these compounds.

Neuroendocrine Effects of Endocrine Disruptors in Teleost Fish

“…In agreement, many studies reported impact of various xenoestrogens on brain aromatase expression in fish (Halm et al 2002;Cheshenko et al 2008;Hallgren and Olsen 2009;Hinfray et al 2006;Kortner et al 2009;Kuhl and Brouwer 2006;Le Page et al 2006;Lee et al 2006;Linderoth et al 2006;Lyssimachou et al 2006). However, these data also raise a number of questions that urgently need answers regarding the potential effects of estrogen mimics on embryonic and adult neurogenesis in fish.…”

Toxicity of the aromatase inhibitor letrozole to Japanese medaka (Oryzias latipes) eggs, larvae and breeding adults

“…Kawahara and Yamashita (2000) reported that medaka eggs incubated with an AI resulted in no abnormal sex ratios. In a more recent study (Kuhl and Brouwer, 2006), the results demonstrated that immersion exposure to AIs alone did not result in any female-to-male inversions of medaka, even though aromatase activity was inhibited. Therefore, altered aromatase activity levels are not a requirement for sex inversion in fish (Kuhl and Brouwer, 2006).…”

“…In a more recent study (Kuhl and Brouwer, 2006), the results demonstrated that immersion exposure to AIs alone did not result in any female-to-male inversions of medaka, even though aromatase activity was inhibited. Therefore, altered aromatase activity levels are not a requirement for sex inversion in fish (Kuhl and Brouwer, 2006). However, as far as we know, alteration of the genotypic sex ratio in fish has never been reported.…”

Lack of a heritable reproductive defect in the offspring of male rainbow trout exposed to the environmental estrogen 17α-ethynylestradiol

“…Exposures at this time are known to cause significant detrimental impacts on physiology, anatomy and, most importantly, reproductive success (Jobling et al, 1998, 2002; Scholz and Gutzeit, 2000; van den Belt et al, 2003; Balch et al, 2004; Nash et al, 2004; Mills and Chichester, 2005; Kuhl et al, 2005; Campbell et al, 2006; Kuhl and Brouwer, 2006; Kidd et al, 2007; Maunder et al, 2007; Woodling et al, 2006). Although less frequently studied, exposure during later intervals of the life history also exhibit detrimental reproductive effects (van den Belt et al, 2002; Schultz et al, 2003; Brown et al, 2007).…”

“…Environmental release of estrogenic substances are a concern due to their known ability to significantly affect fishes through induced developmental abnormalities of the gonads and brain, which ultimately results in impaired reproductive success (Jobling et al, 1998; Janz, 2000; Jobling et al, 2002; Kuhl et al, 2005; Campbell et al, 2006; Kuhl and Brouwer, 2006; Filby et al, 2007; Cheshenko et al, 2008). The body of scientific evidence amassed evaluating environmental estrogen exposure in fishes indicates a strong likelihood for long lasting reproductive effects, some of which could ultimately be felt at the population level (Jobling et al, 1998; van den Belt et al, 2003; Nash et al, 2004; Kidd et al, 2007; Schafers et al, 2007).…”