Science Inventory

Tributyltin disrupts fin development in Fundulus heteroclitus from both PCB-sensitive and resistant populations: Investigations of potential interactions between AHR and PPARγ

Citation:

Crawford, K., B. Clark, W. Heiger-Bernays, S. Karchner, M. Hahn, D. Nacci, AND J. Schlezinger. Tributyltin disrupts fin development in Fundulus heteroclitus from both PCB-sensitive and resistant populations: Investigations of potential interactions between AHR and PPARγ. AQUATIC TOXICOLOGY. Elsevier Science Ltd, New York, NY, 218:105334, (2020). https://doi.org/10.1016/j.aquatox.2019.105334

Impact/Purpose:

Some persistent compounds found in the environment cause toxicity through the peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor (RXR) pathway, but these effects are not well understood in wild organisms. Furthermore, the PPAR pathway may be affected by signaling in the arylhydrocarbon receptor (AHR) pathway, and the effects of combined exposure to environmental mixtures that intereact with both pathways is not well known. This paper describes developmental exposure studies that will contribute to our understanding of the effects associated with persistent pollutants that act through these toxic mechanisms. Here we exposed embryonic fish to model chemicals that act through these pathways and assessed their survival, development, and gene expression. We found that exposure to one compound affected fin development, and gene expression analyses helped demonstrate interaction among the pathways. The results demonstrate the value of integrating chemical, biological, and molecular techniques to assess the effects and mechanisms of chemical stress in wild fish populations. Ultimately these studies can contribute to better understanding of how multiple adverse outcome pathways may interact, especially in the case of exposure to environmental mixtures.

Description:

Tributyltin (TBT) and dioxin-like polychlorinated biphenyls (PCBs) are environmental contaminants that are highly toxic to fish and co-occur in New Bedford Harbor (NBH), an estuarine Superfund site located in Massachusetts, USA. Atlantic killifish (Fundulus heteroclitus) that reside in NBH (and other highly contaminated sites along the east coast of the United States) have developed resistance to activation of the aryl hydrocarbon receptor (AHR) pathway and the toxicity of dioxin-like chemicals, such as 3,3′,4,4′,5-pentachlorobiphenyl, PCB126. In many biological systems, TBT disregulates adipose and bone development via the PPARγ-RXR pathway; AHR activation also disrupts adipose and bone homeostasis, potentially through molecular crosstalk between AHR and PPARγ. However, little is known about how co-exposure and the interaction of these pathways modulate the toxicological effects of these contaminants. Here, we tested the hypotheses that TBT would induce teratogenesis in killifish via activation of PPARγ and that PCB126 co-exposure would suppress PPARγ pathway activation in PCB-sensitive killifish from a reference site (Scorton Creek, SC, PCB-sensitive) but not in PCB-tolerant NBH killifish. Killifish embryos from both populations exposed to TBT (50 and 100¿nM) displayed caudal fin deformities. TBT did not change the expression of pparg or its target genes related to adipogenesis (fabp11a and fabp1b) in either population. However, expression of osx/sp7, an osteoblast marker gene, and col2a1b, a chondroblast marker gene, was significantly suppressed by TBT only in SC killifish. An RXR-specific agonist, but not a PPARγ-specific agonist, induced caudal fin deformities like those observed in TBT-treated embryos. PCB126 did not induce caudal fin deformities and did not exacerbate TBT-induced fin deformities. Further, PCB126 increased expression of pparg in SC embryos and not NBH embryos, but did not change the expression of fabp1b. Taken together, these results suggest that in killifish embryos the PPARγ pathway is regulated in part by AHR, but is minimally active at least in this early life stage. In killifish, RXR activation, rather than PPARγ activation, appears to be the mechanism by which TBT induces caudal fin teratogenicity, which is not modulated by AHR responsiveness.