Gene expression profiling to examine the thyroid hormone‐disrupting activity of hydroxylated polychlorinated biphenyls in metamorphosing amphibian tadpole

Abstract

Hydroxylated polychlorinated biphenyls are the metabolites produced from parent compounds by the drug-metabolizing enzyme cytochrome P450. These compounds are suspected to disrupt postembryonic neural development in the brains of mammals including humans. We studied the effects of these compounds on thyroid hormone function in the brain by using metamorphosing tadpoles of the African clawed toad (Xenopus laevis) as a model for mammalian postembryonic development. The metamorphosis assay revealed that these compounds inhibit thyroid hormone-induced metamorphosis. Genome-wide gene expression analysis in the brain following short-term exposure demonstrated that delayed metamorphosis could partially be caused by disruption of thyroid hormone-induced gene expression. Furthermore, we associated the terms of functional ontology with the genes, whose expression was disrupted by these compounds. We suggest that the use of a genome-wide analysis coupled with bioinformatics might provide an overview of the molecular mechanism underlying thyroid-disrupting activities in vivo.

A screening assay for thyroid hormone signaling disruption based on thyroid hormone-response gene expression analysis in the frog Pelophylax nigromaculatus

“…Due to the lack of complex interaction of cofactors with TRs, however, these in vitro bioassays are not potent enough to detect the TH signaling disrupting effects of chemicals in vivo (Zoeller et al, 2007). For example, Ishihara et al (2011) reported that 5-500 nmol/L OH-PCBs caused an alteration of TH-response gene expression as well as a delay of T3-induced vertebrate development, demonstrating TH signaling disrupting activity, but no TH signaling disrupting activity was observed in a T3-dependent reporter gene assay in vitro. Therefore, it is necessary to develop simple and rapid in vivo screening methods that can sufficiently detect TH signaling disrupting activity (Coady et al, 2010;Shi, 2009).…”

Thyroid and reproduction in amphibians and reptiles

“…Reproduction in amphibians is disrupted by laboratory and environmental exposure to a large array of pharmaceutical, agricultural, and industrial chemicals (see Norris, 2011, 2024; Orton & Tyler, 2015; Trudeau et al, 2020). Anthropogenic estrogenic endocrine‐disruptive chemicals, including bisphenyl A (Iwamuro et al, 2003), nonylphenols (Christensen et al, 2005; McGuire et al, 2021; Park et al, 2010), octylphenols (Haselman et al, 2016; McGuire et al, 2021), and polycarbonated bisphenyls (Gutleb et al, 2000; Ishibara et al, 2011; Lehigh Shirey et al, 2006) caused feminization and shifts in sex ratios in anurans. Furthermore, these anthropogenic estrogenic chemicals inhibited thyroid function and metamorphosis.…”

Detailed Review Paper on the State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocrine Disruptors

“…Similarly, Ishihara et al used gene expression profiling to examine the thyroid hormone-disrupting activity of hydroxylated PCBs in metamorphosing amphibian tadpole. 561 They concluded that genomewide gene expression analysis in Xenopus brain following short-term exposure could be coupled with bioinformatics to provide an overview of the molecular mechanisms underlying thyroid-disrupting activities in vivo.…”