| 1. |
- Gilbert, Mary E., et al.
(författare)
-
An animal model of marginal iodine deficiency during development : the thyroid axis and neurodevelopmental outcome
- 2013
-
Ingår i: Toxicological Sciences. - : Oxford University Press. - 1096-6080 .- 1096-0929. ; 132:1, s. 177-195
-
Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormones (THs) are essential for brain development, and iodine is required for TH synthesis. Environmental chemicals that perturb the thyroid axis result in modest reductions in TH, yet there is a paucity of data on the extent of neurological impairments associated with low-level TH disruption. This study examined the dose-response characteristics of marginal iodine deficiency (ID) on parameters of thyroid function and neurodevelopment. Diets deficient in iodine were prepared by adding 975, 200, 125, 25, or 0 µg/kg potassium iodate to the base casein diet to produce five nominal iodine levels ranging from ample (Diet 1: 1000 μg iodine/kg chow, D1) to deficient (Diet 5: 25 µg iodine/kg chow, D5). Female Long Evans rats were maintained on these diets beginning 7 weeks prior to breeding until the end of lactation. Dams were sacrificed on gestational days 16 and 20, or when pups were weaned on postnatal day (PN) 21. Fetal tissue was harvested from the dams, and pups were sacrificed on PN14 and PN21. Blood, thyroid gland, and brain were collected for analysis of iodine, TH, and TH precursors and metabolites. Serum and thyroid gland iodine and TH were reduced in animals receiving two diets that were most deficient in iodine. T4 was reduced in the fetal brain but was not altered in the neonatal brain. Neurobehavior, assessed by acoustic startle, water maze learning, and fear conditioning, was unchanged in adult offspring, but excitatory synaptic transmission was impaired in the dentate gyrus in animals receiving two diets that were most deficient in iodine. A 15% reduction in cortical T4 in the fetal brain was sufficient to induce permanent reductions in synaptic function in adults. These findings have implications for regulation of TH-disrupting chemicals and suggest that standard behavioral assays do not readily detect neurotoxicity induced by modest developmental TH disruption.
|
|
| 2. |
- Bal-Price, Anna, et al.
(författare)
-
Putative adverse outcome pathways relevant to neurotoxicity
- 2015
-
Ingår i: Critical reviews in toxicology. - : Informa UK Limited. - 1040-8444 .- 1547-6898. ; 45:1, s. 83-91
-
Forskningsöversikt (refereegranskat)abstract
- The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways.
|
|
