Activation of mammalian retinoid X receptors by the insect growth regulator methoprene.

Abstract

We report that methoprene and its derivatives can stimulate gene transcription in vertebrates by acting through the retinoic acid-responsive transcription factors, the retinoid X receptors (RXRs). Methoprene is an insect growth regulator in domestic and agricultural use as a pesticide. At least one metabolite of methoprene, methoprene acid, directly binds to RXR and is a transcriptional activator in both insect and mammalian cells. Unlike the endogenous RXR ligand, 9-cis-retinoic acid, this activity is RXR-specific; the methoprene derivatives do not activate the retinoic acid receptor pathway. Methoprene is a juvenile hormone analog that acts to retain juvenile characteristics during insect growth, preventing metamorphosis into an adult, and it has been shown to have ovicidal properties in some insects. Thus, a pesticide that mimics the action ofjuvenile hormone in insects can also activate a mammalian retinoid-responsive pathway. This finding provides a basis through which the potential bioactivity of substances exposed to the environment may be reexamined and points the way for discovery of new receptor ligands in both insects and vertebrates.With the exception of their role in vision, the manner in which the retinoids exert their biological effects resides in their ability to regulate gene expression. Vitamin A metabolites-i.e., retinoids-play essential roles in many aspects of development, metabolism, and reproduction in vertebrates (1). Some of the end products of vitamin A metabolism have been identified as the molecules responsible for the action of retinoids. Retinol, the major circulating form of retinoid, is converted within cells to all-trans-retinoic acid and 9-cis-retinoic acid (9cRA) (2-4). The retinoic acids function through two classes of receptors: the retinoic acid receptors (RARs), which bind to both atRA and 9cRA, and the retinoid X receptors (RXRs), which bind only to 9cRA. These receptors modulate ligand-dependent gene expression by interacting as RXR/RAR heterodimers or RXR homodimers on specific target-gene DNA sequences known as hormone response elements. In addition to their role in retinoid signaling, RXRs also serve as heterodimeric partners of nuclear receptors for vitamin D, thyroid hormone, and peroxisome proliferators (reviewed in ref. 5).Although both RXR and RAR bind and respond to 9cRA, evolutionarily these receptors are quite distinct. RXR and RAR share only 27% amino acid identity in their ligandbinding domains (6). In addition, at least one homolog of RXR has been identified in insects, called ultraspiracle (7). Like RXR, ultraspiracle serves as a heterodimeric partner to other receptors. For example, the ecdysone receptor requires ultraspiracle as its coreceptor to bind and respond to its ligand, 20-hydroxyecdysone (8). Significantly, however, ultraspiracle does not respond to any of the known retinoids, including 9cRA. These results are consistent with the finding that insectsThe publication costs of this article were defrayed in part by page charge payment. This a...

Two hexameric cyanoprotein subunits from an insect, Riptortus clavatus

“…Although there is evidence that the primary target of JH action is at the plasma membrane in the particular cases of the male accessory gland of D. melanogaster and the ovarian follicular epithelium of Rhodnius prolixus [56Ϫ58], because of its molecular nature as a small, hydrophobic compound, it has been hypothesized that JH influences gene expression similarly as steroid, thyroid and retinoid hormones do. Indeed, Harmon et al [59] have demonstrated that methoprene acid, a derivative of the JHA methoprene, can bind directly to mammalian retinoid X receptors and confers gene activation.…”

Evaluation of wastewater reclamation technologies based on in vitro and in vivo bioassays

“…Degitz et al (2000) reported that 6.25 μg/l all trans retinoic acid could elicit higher teratological rate and mortality of exposed Xenopus laevis. Methoprene acid, a metabolic degradation product of methoprene, a pesticide, and organochlorine pesticides have been shown to bind to members of the retinoic acid receptors (RAR) (Harmon et al, 1995;Lemaire et al, 2005). Although up to now, it is not clear whether the reported increase of teratological rates of Japanese medaka embryos were related to retinoids in the secondary effluent, the above adverse ecological effects should be considered when the secondary effluent from the STPs is used as the main supplementation water source for surface water bodies.…”

Quantitative axial profiles of retinoic acid in the embryonic mouse spinal cord: 9‐Cis retinoic acid only detected after all‐trans‐retinoic acid levels are super‐elevated experimentally

“…Because 9-cis-RA is considered the principal ligand for RXRs, the absence of detectable 9-cis-RA raises the question as to which ligands drive the RXR activation observed by Solomin et al (1998) starting at 11 dpc. One possibility is that 9-cis-RA appears at later stages than assayed by Horton and Maden (1995), another is that 9-cis-RA is present but below the limit of detection, and a third is that RXR activation is driven by other ligands (Eager et al, 1992;Harmon et al, 1995;Kitareewan et al, 1996) or by ligand-independent mechanisms such as phosphorylation (Lefebvre et al, 1995;Rochette-Egly et al, 1995).…”

“…Because retinoid receptors can also be activated by compounds other than retinoids (Eager et al, 1992;Harmon et al, 1995;Kitareewan et al, 1996), and we obtained a prominent peak that is not a retinoid, we assayed other potential ligands, focusing on relevant fatty acids. Arachidonic acid (ARA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) standards were all detectable with our ECD system, but none of these corresponded to any of the peaks in the tissue chromatograms.…”