Page 733 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

698 Section |IX Gases, Solvents and Other Industrial Toxicants

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FIGURE 52.4 Possible mechanisms by which BFRs can disrupt thyroid hormone (TH) homeostasis. PBDE is shown as an example of all BFRs.
(1) BFRs as well as their contaminants enter the circulation from the gastrointestinal (GI) tract. (2) BFRs (parent compound as well as metabolites)
can displace thyroxine (T4) from serum binding proteins such as transthyretin (TTR). The resulting free T4 will be subjected to hepatic metabolism
and elimination. (3) Reduced circulating T4 levels trigger the hypothalamic pituitary axis to synthesize and secrete more T4 by thyroid. (4) BFRs
bound to TTR along with T4 will reach target organs including brain, where they can bind to TH receptor to elicit a biological/toxicological
response. (5) After entering liver activate nuclear receptors, BFRs initiate transcription of xenobiotic-metabolizing enzymes for T4 metabolism and
elimination. (6) Influx transporters further increase the T4 uptake and metabolism. (7) Efflux transporters eliminate T4 or its conjugates
from liver into either serum or the bile. Figure is not to scale. Adapted from Kodavanti, P.R.S., Curras-Collazo, M.C., 2010. Neuroendocrine
actions of organohalogens: thyroid hormones, arginine vasopressin, and neuroplasticity. Front. Neuroendo. 31, 479 496 (Kodavanti and
Curras-Collazo, 2010).