Citation:

OShaughnessy, K., C. Wood, R. Ford, Pat Kosian, M. Hotchkiss, S. Degitz, AND M. Gilbert. Thyroid hormone disruption in the fetal and neonatal rat: Predictive hormone measures and bioindicators of hormone action in the developing cortex- ToxSci. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, , 163-179, (2018). https://doi.org/10.1093/toxsci/kfy190

Impact/Purpose:

Thyroid hormone disruption in the fetal and neonatal rat: Predictive hormone measures and bioindicators of hormone action in the developing cortex. O’Shaughnessy KL, Wood C, Ford RL1, Kosian PA, Hotchkiss, MG, Degitz SJ, Gilbert ME Evaluation of the risk of thyroid disrupting chemicals is a high priority of concern when considering children’s health, as normal brain development is dependent on thyroid hormones (THs). While well accepted that THs are critical for neurodevelopment, there are limited data that address how and my how much lowered TH in the circulation may, or may not, alter hormonal status in the brain. There is also a lack of sensitive downstream apical endpoints indicative of TH related insufficiencies. As such, US EPA and OECD current regulatory/guidance (US EPA/OPP Guidance for Thyroid Assays and OECD Test 421) recommend the use TH measurement in serum as an indicator of the potential neurodevelopmental dysfunction in developing rodents. However, the quantitative relationships between serum hormones and brain hormones, and between brain hormones and brain development, have not been characterized. This data gap poses significant uncertainties for the systematic evaluation of chemical risk of thyroid hormone disrupting chemicals. To address this gap and to aide in interpretation of outcomes of the recommended regulatory/guidance tests, we performed an extensive dose-response analysis with the TPO inhibitor propylthiouracil (PTU). Pregnant rats were dosed with low doses of PTU (dose range 0.1-10 ppm) beginning in early gestation, and the offspring’s serum and brain were assayed for TH concentrations on gestational day 20 (GD20) and postnatal day 14 (PN14) – two time points recommended in EPA guidance documents. The relationship between TH in serum in the dam and offspring; and TH in serum and TH in brain of the fetus and neonate. Given that the primary action of TH in brain is to affect gene transcription of key neurodevelopmental processes, gene expression was interrogated in the cortex as a transcriptional readout of alterations in TH-action. Our results show stage-specific differences in TH regulation of the brain, a potentially important consideration for the interpretation of developmental susceptibility to TH insufficiency. Very few transcriptional changes were evident in the GD20 cortex, despite a significant decrease in brain THs at low doses of PTU. A number of differentially expressed genes were observed in the PN14 cortex, that correlated well with TH decrements in brain tissue. These results show that serum T4 is a good predictor of brain T4, and identify target genes that could potentially serve as a pragmatic readout of TH status in brain. The correlations derived from brain TH and gene expression identify a set of ‘brain bioindicators’ sensitive to alterations in hormonal status in the periphery providing support for the predictive power of serum TH serve as downstream but intermediary markers of potential brain dysfunction.

Description:

Adverse neurodevelopmental consequences remain a primary concern when evaluating the effects of thyroid hormone (TH) disrupting chemicals. Though the developing brain is a known target of TH insufficiency, the relationship between THs in the serum and the central nervous system is not well characterized. To address this issue dose response experiments were performed in pregnant rats, using the goitrogen propylthiouracil (PTU) (dose range 0.1 – 10 ppm). THs were quantified in both the serum and brain of offspring at gestational day 20 (GD20) and postnatal day 14 (PN14), two developmental stages included in OECD and EPA regulatory guideline/guidance studies. From the dose response data, the quantitative relationships between THs in the serum and brain were described. Next, targeted gene expression analyses were performed in the fetal and neonatal cortex, to test the hypothesis that TH action in the developing brain is linked to changes in TH concentration of the tissue. Results show a significant reduction of T4/T3 in the serum and brain of the GD20 fetus in response to low doses of PTU; interestingly, very few genes were significantly different at any dose tested. In the PN14 pup significant reductions of T4/T3 in the serum and brain were also detected; however, twelve transcriptional targets were identified in the neonatal cortex that correlated well with the TH insufficiency within the brain. These results show that serum T4 is a good predictor of brain THs, and offer several target genes that could serve as pragmatic readouts of T4/T3 dysfunction within the PN14 cortex.

URLs/Downloads:

Record Details: