Covert signal disruption: Anti‐ecdysteroidal activity of bisphenol a involves cross talk between signaling pathways

Abstract

Bisphenol 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.

Crustacean Molting: Regulation and Effects of Environmental Toxicants

“…Several studies have reported effects of environmental chemicals that are consistent with interference with ecdysteroid signaling, though a precise mechanism of action was not established. The chemicals 4-nonylphenol [69], propiconazole [70], and bisphenol A [71], have elicited effects in crustaceans consistent with anti-ecdysteroidal activity. The fungicides propiconazole [72] and fenarimol [73] inhibit cytochromeP450 (CYP) enzymes that are critical to ecdysteroid synthesis.…”

“…The 4-Nonylphenol is an antagonist of the insect ecdysteroidreceptor in vitro [62]. Bisphenol A was proposed to elicit anti-ecdysteroidal activity through a receptor cross-talk mechanism [71,74]. Thus, it is mechanistically plausible that all of these compounds elicit toxicity to crustaceans via perturbations in ecdysteroid signaling.…”

Crustacean endocrine toxicology: a review

“…The chemicals 4-nonylphenol (Shurin and Dodson 1997;LeBlanc et al 2000), propiconazole (Kast-Hutcheson et al 2001), and bisphenol A (Mu et al 2005), have elicited effects in crustaceans consistent with anti-ecdysteroidal activity. The fungicides propiconazole (Ronis et al 1998) and fenarimol (Williams et al 2000) inhibit cytochrome P450 (CYP) enzymes that are critical to ecdysteroid synthesis.…”

A critical analysis of the biological impacts of plasticizers on wildlife

“…Bisphenol A inhibits reproduction and development rates with an NOEC of 1000 mg l 21 (Brennan et al 2006) and affected intermolt duration at 9000 mg l 21 (Mu et al 2005). In the marine copepods A. tonsa and Tigriopus japonicus, BPA has been shown to inhibit development at 100 and 0.1 mg l…”

“…In the D. melanogaster BII cell line, BPA was shown to act as an ecdysteroid antagonist, but only at a high exposure concentration of 22.8 mg l 21 (Dinan et al 2001). Studies combining BPA with other chemicals have shown interactive effects, affecting the number of embryo abnormalities and offspring emergence (Mu et al 2005;Wang et al 2005). In summary, for studies in aquatic arthropods, BPA appears to interfere with their hormone systems-possibly by affecting the synthesis of HSPs and/or by interfering with the ecdysone receptor itself-and causes adverse effects at concentrations in the low mg l 21 range.…”