@article{mu_rider_hwang_hoy_leblanc_2005, title={Covert signal disruption: Anti-ecdysteroidal activity of bisphenol a involves cross talk between signaling pathways}, volume={24}, ISSN={["1552-8618"]}, DOI={10.1897/04-063r.1}, abstractNote={AbstractBisphenol A is a key industrial chemical used in the manufacture of polycarbonate plastics and other products. Several recent reports ascribe toxicological properties to this compound that have been attributed to the disruption of endocrine‐related processes. In the present study, the toxicity of bisphenol A was definitively characterized in the water flea (Daphnia magna) in an effort to discern whether this compound may elicit endocrine toxicity in an invertebrate species and to establish the mechanism by which this toxicity is elicited. The ability of bisphenol A to interfere with two ecdysteroid‐dependent physiological processes—molting and embryonic development—was evaluated. Bisphenol A elicited antiecdysteroidal activity as indicated by its prolongation of the intermolt period and interference with embryonic development. This apparent antiecdysteroidal activity was not due to reduced availability of endogenous ecdysteroid nor due to ecdysteroid‐receptor antagonism. The ability of bisphenol A to elicit antiecdysteroidal activity by functioning as a juvenoid hormone was next evaluated. Bisphenol A, alone, did not elicit juvenoid activity. However, bisphenol A did enhance the activity of the crustacean juvenoid hormone methyl farnesoate. A definitive assessment of the effects of bisphenol A on the reproductive capacity of daphnids revealed a concentration‐response relationship that extended at least one order of magnitude below exposure levels that were overtly toxic to the maternal organisms. These results demonstrate that bisphenol A is chronically toxic to daphnids, probably through its ability to interfere with ecdysteroid/juvenoid regulated processes. However, effects are elicited at levels that are not likely to pose environmental concern.}, number={1}, journal={ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY}, author={Mu, XY and Rider, CV and Hwang, GS and Hoy, H and LeBlanc, GA}, year={2005}, month={Jan}, pages={146–152} }
 @article{mu_leblanc_2004, title={Cross communication between signaling pathways: Juvenoid hormones modulate ecdysteroid activity in a crustacean}, volume={301A}, ISSN={["2471-5646"]}, DOI={10.1002/jez.a.104}, abstractNote={AbstractMethyl farnesoate is a juvenoid hormone that regulates a variety of processes in crustaceans including male sex determination among daphnids (Branchiopoda, Cladocera). The synthetic juvenoids pyriproxyfen and fenoxycarb mimic the action of methyl farnesoate in daphnids. In the present study we tested the hypothesis that juvenoids also can regulate ecdysteroid activity in a crustacean (Daphnia magna). Methyl farnesoate, pyriproxyfen, and fenoxycarb all disrupted ecdysteroid‐regulated aspects of embryo development in daphnids. Exposure of ecdysteroid‐responsive cells to 20‐hydroxyecdysone reduced cell proliferation and increased mRNA levels of the ecdysone receptor and its partner protein ultraspiracle. Co‐treatment of cells with the juvenoid pyriproxyfen attenuated all of these ecdysteroid mediated responses. While juvenoids functioned as anti‐ecdysteroids in both intact embryos and in cultured cells, 20‐hydroxyecdysone showed no evidence of acting as an anti‐juvenoid. The combined effects of pyroproxyfen with the ecdysteroid synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone were evaluated in an effort to discern whether the action of the juvenoids were additive with those of know anti‐ecdysteroids. The anti‐ecdysteroid effects of pyriproxyfen were non‐additive with those of either anti‐ecdysteroid. Rather, joint effects conformed to a model of synergy. These results demonstrated that juvenoids elicit anti‐ecdysteroidal activity in a crustacean through a unique mechanism of action. A model involving receptor partner deprivation is proposed that explains the synergistic interactions observed. J. Exp. Zool. 301A:793–801, 2004. © 2004 Wiley‐Liss, Inc.}, number={10}, journal={JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY}, author={Mu, XY and Leblanc, GA}, year={2004}, month={Oct}, pages={793–801} }
 @article{mu_leblanc_2004, title={Synergistic interaction of endocrine-disrupting chemicals: Model development using an ecdysone receptor antagonist and a hormone synthesis inhibitor}, volume={23}, ISSN={["1552-8618"]}, DOI={10.1897/03-273}, abstractNote={AbstractEndocrine toxicants can interfere with hormone signaling through various mechanisms. Some of these mechanisms are interrelated in a manner that might result in synergistic interactions. Here we tested the hypothesis that combined exposure to chemicals that inhibit hormone synthesis and that function as hormone receptor antagonists would result in greater‐than‐additive toxicity. This hypothesis was tested by assessing the effects of the ecdysteroid‐synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone on ecdysteroid‐regulated development in the crustacean Daphnia magna. Both compounds were individually characterized for effects on the development of isolated embryos. Fenarimol caused late developmental abnormalities, consistent with its effect on offspring‐derived ecdysone in the maturing embryo. Testosterone interfered with both early and late development of embryos, consistent with its ability to inhibit ecdysone provided by maternal transfer (responsible for early developmental events) or de novo ecdysone synthesis (responsible for late developmental events). We predicted that, by decreasing endogenous levels of hormone, fenarimol would enhance the likelihood of testosterone binding to and inhibiting the ecdysone receptor. Indeed, fenarimol enhanced the toxicity of testosterone, while testosterone had no effect on the toxicity of fenarimol. Algorithms were developed to predict the toxicity of combinations of these two compounds based on independent joint action (IJA) alone as well as IJA with fenarimol‐on‐testosterone synergy (IJA+SYN). The IJA+SYN model was highly predictive of the experimentally determined combined effects of the two compounds. These results demonstrate that some endocrine toxicants can synergize, and this synergy can be accurately predicted.}, number={4}, journal={ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY}, author={Mu, XY and LeBlanc, GA}, year={2004}, month={Apr}, pages={1085–1091} }
 @article{mu_rider_leblanc_2002, title={Abstracts from the Eleventh International Symposium on Pollutant Responses in Marine Organisms (PRIMO 11) - Endocrine disrupters}, volume={54}, number={3-5}, journal={Marine Environmental Research}, author={Mu, X. Y. and Rider, C. V. and Leblanc, G. A.}, year={2002}, pages={741–754} }
 @article{mu_leblanc_2002, title={Developmental toxicity of testosterone in the crustacean Daphnia magna involves anti-ecdysteroidal activity}, volume={129}, ISSN={["0016-6480"]}, DOI={10.1016/S0016-6480(02)00518-X}, abstractNote={Testosterone has been shown to cause developmental arrest of embryonic daphnids (Daphnia magna). The present study was undertaken to determine whether this toxicity might be due to anti-ecdysteroidal activity associated with testosterone. The effect of testosterone on molt frequency of early instar daphnids was first evaluated to determine whether testosterone interfered with this ecdysteroid-regulated process. Molt frequency was delayed by exposure to testosterone and this effect was mitigated by co-exposure to the ecdysteroid 20-hydroxyecdysone. Testosterone exposure concentrations that interfered with molting also elicited developmental abnormalities among neonatal organisms produced by maternal organisms that were continuously exposed to testosterone or among embryos that were removed from unexposed mothers and exposed directly to the hormone. Embryos were significantly protected against the developmental toxicity of testosterone by co-exposure to 20-hydroxyecdysone. Taken together, these results demonstrated that the embryo toxicity of testosterone to daphnids is due largely to its ability to interfere with ecdysteroid control of development. Experiments next were conducted to determine whether testosterone interfered with ecdysteroidal activity by acting as an ecdysone receptor antagonist or by reducing endogenous ecdysone levels. Testosterone significantly antagonized the action of 20-hydroxyecdysone in an ecdysone-responsive cell line. Testosterone had no discernable effect on endogenous ecdysone levels in daphnids. These results demonstrated that (1) ecdysteroids regulate critical processes in daphnid embryo development, (2) testosterone elicits embryo toxicity to daphnids by interfering with ecdysteroid activity, and (3) ecdysteroid receptor antagonism could be one mechanism by which testosterone elicits these effects.}, number={2}, journal={GENERAL AND COMPARATIVE ENDOCRINOLOGY}, author={Mu, XY and LeBlanc, GA}, year={2002}, month={Nov}, pages={127–133} }
 @article{mu_leblanc_2002, title={Environmental antiecdysteroids alter embryo development in the crustacean Daphnia magna}, volume={292}, ISSN={["0022-104X"]}, DOI={10.1002/jez.10020}, abstractNote={AbstractThe role of ecdysteroids in crustacean embryo development and the susceptibility of the developing embryo to the antiecdysteroidal properties of an environmental chemical were evaluated. The agricultural fungicide fenarimol was shown to exhibit antiecdysteroidal activity to the crustacean Daphnia magna by lowering endogenous ecdysone levels and delaying molting in a concentration‐dependent fashion that was mitigated by co‐exposure to exogenous 20‐hydroxyecdysone. Exposure of either gravid maternal organisms or isolated embryos to fenarimol resulted in embryo abnormalities ranging from early partial developmental arrest to incomplete development of antennae and shell spines. Developmental abnormalities were associated with suppressed ecdysone levels in the embryos and the abnormalities could be prevented by co‐exposure to 20‐hydroxyecdysone. Developmental abnormalities caused by the antiecdysteroid were associated with reduced fecundity of the parental organisms. These results demonstrate that ecdysteroids are critical to normal crustacean embryo development and environmental antiecdysteroids can disrupt normal embryo development and compromise the production of viable offspring. Antiecdysteroidal activity may provide a means by which environmental chemicals impact crustacean species while not affecting vertebrates. J. Exp. Zool. 292:287–292, 2002. © 2002 Wiley‐Liss, Inc.}, number={3}, journal={JOURNAL OF EXPERIMENTAL ZOOLOGY}, author={Mu, XY and LeBlanc, GA}, year={2002}, month={Feb}, pages={287–292} }
 @article{leblanc_mu_rider_2000, title={Embryotoxicity of the alkylphenol degradation product 4-nonylphenol to the crustacean Daphnia magna}, volume={108}, ISSN={["0091-6765"]}, DOI={10.2307/3434824}, abstractNote={Laboratory studies have suggested that some alkylphenols and pesticides elicit developmental toxicity to crustaceans. The purpose of the present study was to evaluate the possibility that the alkylphenol degradation product 4-nonylphenol is embryotoxic to the crustacean Daphnia magna through its known ability to interfere with the metabolic elimination of testosterone. Direct exposure of maternal daphnids to testosterone caused developmental abnormalities in neonates that consisted of partial arrest of early embryonic development and abnormalities in shell spine and first antennae development. Exposure of maternal daphnids to concentrations of 4-nonylphenol also produced developmental abnormalities though the profile of abnormalities was distinct from that observed throughout the testosterone concentration-response curve. Thus, 4-nonylphenol is a developmental toxicant in daphnids, but its toxicity is not consistent with that elicited by elevated testosterone accumulation. Further experiments demonstrated that testosterone was directly toxic to developing embryos, and the maternal organism can serve as the vector for this toxicity. In contrast, neither direct embryo exposure nor early maternal exposure to 4-nonylphenol elicited embryotoxicity consistent with that observed during continuous maternal and gestational exposure. Thus, 4-nonylphenol is not directly embryotoxic at these exposure levels, but rather toxicity is mediated by maternal influences during gestation. The threshold concentration for the occurrence of developmental abnormalities ( approximately 44 microg/L) indicates that typical environmental concentrations of 4-nonylphenol pose no imminent hazard with respect to developmental toxicity. However, these effects do occur at sufficiently low levels to warrant evaluation of the relative susceptibility of other crustacean species to this previously uncharacterized mode of toxicity.}, number={12}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={LeBlanc, GA and Mu, XY and Rider, CV}, year={2000}, month={Dec}, pages={1133–1138} }