Abstract
Thyroid hormones (TH) regulate biological processes implicated in neurodevelopmental disorders and can be altered with environmental exposures. Developmental exposure to the dioxin-like compound, 3,3’,4,4’-tetrachloroazobenzene (TCAB), induced a dose response deficit in serum T4 levels with no change in 3,5,3’- triiodothyronine or thyroid stimulating hormone. Female Sprague-Dawley rats were orally gavaged (corn oil, 0.1, 1.0, or 10 mg TCAB/kg/day) two weeks prior to cohabitation until post-partum day 3 and male offspring from post-natal day (PND)4-21. At PND21, the high dose showed a deficit in body weight gain. Conventional neuropathology detected no neuronal death, myelin disruption, or gliosis. Astrocytes displayed thinner and less complex processes at 1.0 and 10 mg/kg/day. At 10 mg/kg/day, microglia showed less complex processes, unbiased stereology detected fewer hippocampal CA1 pyramidal neurons and dentate granule neurons (GC) and Golgi staining of the cerebellum showed diminished Purkinje cell dendritic arbor. At PND150, normal maturation of GC number and Purkinje cell branching area was not observed in the 1.0 mg/kg/day dose group with a diminished number and branching suggestive of effects initiated during developmental exposure. No effects were observed on post-weaning behavioral assessments in control, 0.1 and 1.0mg/kg/day dose groups. The demonstrated sensitivity of hippocampal neurons and glial cells to TCAB and T4 deficit raises support for considering additional anatomical features of brain development in future DNT evaluations.
Highlights
The complexity of the nervous system and the ability to examine endpoints reflecting integrated functions has lead to a reliance on neurobehavioral evaluations in neurotoxicity assessments and are prominent within standard developmental neurotoxicity (DNT) studies
We demonstrated that developmental exposure to TCAB induced a dose response deficit in serum T4 levels in the dam and weanling pup that was not accompanied by a decrease in T3 or increase in thyroid stimulating hormone (TSH)
DNT-related neurobehavioral and neuropathological assessments lacked sensitivity to detect changes induced by developmental exposure to TCAB and hypothyroxinemia with serum T4 deficits of approximately 60%
Summary
The complexity of the nervous system and the ability to examine endpoints reflecting integrated functions has lead to a reliance on neurobehavioral evaluations in neurotoxicity assessments and are prominent within standard developmental neurotoxicity (DNT) studies. Severe TH dysfunction in the rat induced by known goitrogens can produce anatomical effects on brain development and functional changes in startle reactivity, auditory acuity, and spatial learning [26] While such effects have established an expected characteristic profile for developmental TH disruption, a broad and relatively severe effect on the TH system including T4, T3, and TSH, appears to be required. While TCAB could have direct effects upon the developing nervous system, the significant level of T4 deficit observed focused our evaluation on endpoints to detect changes that would be hypothesized to occur based on available data from developmental exposure to known goitrogens as well as standard developmental neurotoxicity assessments. Using a developmental exposure regimen for TCAB encompassing gestational and lactational periods, we examined numerous neurobehavioral endpoints and anatomical features of brain development [36,37,38,39,40,41,42] that have been previously associated with developmental deficits in TH
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