Developmental toxicity of the PBDE metabolite 6-OH-BDE-47 in zebrafish and the potential role of thyroid receptor β

Abstract

6-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-BDE-47) is both a polybrominated diphenyl ether (PBDE) flame retardant metabolite and a marine natural product. It has been identified both as a neurotoxicant in cell-based studies and as a developmental toxicant in zebrafish. Hydroxylated PBDE metabolites are also considered thyroid hormone disruptors due to their structural similarity to endogenous thyroid hormones. The purpose of this study was to evaluate the effects of 6-OH-BDE-47 on a developmental pathway regulated by thyroid hormones in zebrafish. Morphological measurements of development (head trunk angle, otic vesicle length, and eye pigmentation) were recorded in embryos at 30 hours post fertilization (hpf) and detailed craniofacial morphology was examined in 4 day old larvae using cartilage staining. Exposure to 6-OH-BDE-47 resulted in severe developmental delays. A 100 nM concentration resulted in a 26% decrease in head trunk angle, a 54% increase in otic vesicle length, and a 42% decrease in eye pigmentation. Similarly, altered developmental morphology was observed following: Thyroid Receptor β morpholino knockdown;, exposure to the thyroid hormone triiodothyronine (T3) and to thyroid disrupting chemicals (TDC; iopanoic acid and propylthiouracil). The threshold for lower jaw deformities and craniofacial cartilage malformations was at doses greater than 50 nM. Of interest, these developmental delays and effects were rescued by microinjection of TRβ mRNA during the 1–2 cell stage. These data indicate that OH-BDEs can adversely affect early life development of zebrafish and suggest they may be impacting thyroid hormone regulation in vivo through downregulation of the thyroid hormone receptor.

Benzotriazole ultraviolet stabilizers alter the expression of the thyroid hormone pathway in zebrafish (Danio rerio) embryos

“…Embryonic exposure to multiple chemicals (e.g. difenoconazole and 6-hydroxy-2, 2 0 , 4, 4 0 -tetrabromodiphenyl ether) appears to perturb the expression of thrb and results in abnormal development in zebrafish (Liang et al, 2015;Macaulay et al, 2015). These results Table S3.…”

Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions

“…The impact of PTU on eye development, opsin expression and pigmentation in fish has been demonstrated previously (Gan and Novales Flamarique, 2010;Macaulay et al, 2015;Raine et al, 2010). Effects of the PTUrelated compound phenylthiourea have also been reported (Bohnsack et al, 2011;Li et al, 2012), and these authors describe reduced eye size and cellular changes after treatment with this commonly used inhibitor of pigmentation in zebrafish larvae.…”

“…Recent studies revealed the adverse effect of PTU on the zebrafish thyroid system (Schmidt and Braunbeck, 2011) and embryonic development (Jomaa, 2014). Also effects of PTU on fish eye development have been reported (Macaulay et al, 2015;Raine and Hawryshyn, 2009), which makes it an interesting candidate for the current project. Due to its presence in the environment and biota (Environment Canada, 2013;Kitamura et al, 2002), TBBPA was chosen as exposure chemical in the present study as representative for a thyroid action disruptor.…”

Parental dietary seleno-L-methionine exposure and resultant offspring developmental toxicity

“…From a compilation of our preliminary trial, investigations in our laboratory and selected studies from the literature (Dong et al, 2012; Dong et al, 2014; Dong et al, 2013; Holm et al., 2005; Lemly, 1997c; Macaulay et al, 2015; Villalobos et al, 2000), phenotypic responses were formulated as pre-defined categories to evaluate embryo alterations using a simple frequency analysis (presence/absence). These categories included: mortality; hatching time/success; craniofacial abnormality , change in size and/or shape of the jaw and specifically ocular deformities , agenesis, edema, asymmetry, pigment loss or irregularities; pericardial and abdominal (Pc/Ab) edema , swelling of pericardial cavity (Pc) and/or a clear space between the long axis of the body and the dorsal margin of the yolk sac (Ab); notochord malformation; spleen color , lack or change in color; gall bladder color , lack or change in color; blood pooling ; and, at or after hatch, swim bladder noninflation , partially inflated or uninflated in post-hatch individuals; other altered phenotypes, i.e.…”