Transthyretin disruption in developing fish leading to projected decline in fish populationTH displacement from serum TTR leading to decline in fish populationAdriana WebbBY-SA2.7<div style="margin-left:48px; text-align:left"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">- Transthyretin (TTR) is a thyroid distribution protein that transports thyroid hormone to target tissues and helps maintain hormone homeostasis. Several studies have highlighted the ability of environmental contaminants, including PCBs, PBDEs, and PFAS, to competitively bind to TTR in the bloodstream, displacing thyroid hormones and potentially disrupting normal thyroid signaling.</span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">- TTR shown to be disrupted (T4 or T3 displaced) by environmental contaiminents. </span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">- Data from a recent SR focused on collecting thyroid hormone serum binding information across species and lifestages at multiple biological levels were obtained, and a survey of the AOP Wiki was conducted to identify potentially relevant AOPs and MIEs. We standardized and manually mapped the data using corresponding KE information in the AOP Wiki as a source for endpoint terms.</span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">- </span></span><span style="font-size:14px"><span style="font-family:Calibri"><span style="color:black">One such putative AOP that can be developed from this SR data is in developing fish, a population known to be potentially sensitive to TTR-binding compounds.</span></span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:14px"><span style="font-family:Calibri"><span style="color:black">- </span></span></span><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif">Based on publicly available sequence information, differences in the structure of the transthyretin protein are predicted to result in different suseptibility to chemicals acting at this molecular target. </span></span></div>
<div style="margin-left:48px; text-align:left">- <span style="font-family:Calibri,sans-serif; font-size:11pt">We are interested in understanding if competitive TTR binding leads to altered thyroid hormone homeostasis in across fish in developing life stages and if these species demonstrate functional differences following competitive TTR binding.</span></div>
<div style="margin-left:48px; text-align:left"><span style="font-family:Calibri,sans-serif; font-size:11pt">- </span><span style="font-family:Calibri,sans-serif; font-size:11pt">Primary are focused solely on serum/blood concentrations of both T</span><sub style="font-family:Calibri,sans-serif">4 </sub><span style="font-family:Calibri,sans-serif; font-size:11pt">or T</span><sub style="font-family:Calibri,sans-serif">3 . </sub><span style="font-family:Calibri,sans-serif; font-size:11pt">Secondary endpoints focus on functional endpoints and are only of interest when they coincide with primary endpoints.</span></div>
<div style="margin-left:48px; text-align:left"><span style="font-family:Calibri,sans-serif; font-size:11pt">- TTR is present during development in fish but not really in adulthood (only some ancient fish species)</span></div>
<div style="margin-left:48px; text-align:left"><span style="font-family:Calibri,sans-serif; font-size:11pt">- TTR has moderate affinity in developing fish, higher than albumin which has weak affinity (TBG not present in fish at all).</span></div>
<div style="margin-left:48px; text-align:left"><span style="font-family:Calibri,sans-serif; font-size:11pt">- </span><span style="font-size:14px"><span style="font-family:Calibri"><span style="color:black">Thyroid hormone distribution proteins, <strong>albumin</strong>, <strong>transthyretin (TTR), and thyroxine‐binding globulin, </strong></span></span></span><span style="font-size:18.0pt"><span style="font-family:Calibri"><span style="color:black"><span style="font-size:14px">are responsible for transporting thyroid hormone (TH) from the thyroid gland throughout the body to target cells</span> </span></span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:18.0pt"><span style="font-family:Calibri"><span style="color:black"><span style="font-size:14px">- </span></span></span></span><span style="color:black; font-family:Calibri; font-size:14px">Environmental chemicals can competitively bind to TTR, alter hormone homeostasis, and disrupt the thyroid axix.</span></div>
<div style="margin-left:48px; text-align:left"><span style="color:black; font-family:Calibri; font-size:14px">- </span><span style="color:black; font-family:Calibri; font-size:14px">In silico, in vitro, and in vivo evidence suggests TTR-binding may be an MIE of relevance for many environmental chemicals including some PFAS compounds</span></div>
<div style="margin-left:48px; text-align:left"><span style="color:black; font-family:Calibri; font-size:14px">- </span><span style="color:black; font-family:Calibri; font-size:14px">In non-mammalian vertebrates, TTR is important only during developmental stages. </span><span style="color:black; font-family:Calibri; font-size:14px">TTR is</span><strong style="color:black; font-family:Calibri; font-size:14px"> less-important </strong><span style="color:black; font-family:Calibri; font-size:14px">in mammals due to the presence of other distribution proteins. </span><span style="color:black; font-family:Calibri; font-size:14px">Structural differences exist between mammals and non-mammalian vertebrates resulting in different TH affinity.</span></div>
<div style="margin-left:48px; text-align:left"><span style="color:black; font-family:Calibri; font-size:14px">- </span><span style="font-size:14px"><span style="font-family:Calibri">Early life-stages of <strong>fish</strong>, <strong>amphibians</strong>, and <strong>reptiles</strong> are the population potentially </span><u><span style="font-family:Calibri"><strong>most sensitive </strong></span></u><span style="font-family:Calibri">to TTR-binding compounds.</span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:14px"><span style="font-family:Calibri">- <span style="color:black">All vertebrate species with available data demonstrated susceptibility to both PFOS and TBBPA, although the mean effect concentrations were significantly higher in fish and birds than amphibians (vliet et al. 2022)</span></span></span></div>
<div style="margin-left:48px; text-align:left"><span style="font-size:14px"><span style="font-family:Calibri"><span style="color:black">- </span></span></span></div>
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AOPWiki2025-05-22T13:13:362025-05-22T14:01:47