Citation:

Gilbert, M., J. Goodman, J. Gomez, A. Johnstone, AND R. Ramos. Adult Hippocampal Neurogenesis is Impaired by Transient and Moderate Developmental Thyroid Hormone Disruption. NEUROTOXICOLOGY. Elsevier B.V., Amsterdam, Netherlands, 59:9-21, (2017).

Impact/Purpose:

The EPA must evaluate the risk of exposure of the developing brain to chemicals with the potential to disrupt thyroid hormone (TH) homeostasis. One of the primary concerns of TH disruptors is the effect on cognitive function. The hippocampus is a brain region critical for learning and memory and known to be a target of TH insufficiency. Although typically a process relegated to the developing brain, neurogenesis continues in maturity in only two brain regions, the hippocampus and the olfactory bulb, with new neurons added to these areas throughout life. In the hippocampus, a significant fraction of these newly born neurons integrate into the existing hippocampal circuitry to support learning and memory, modulate affect, and stand ready to respond to brain injury. Neurogenesis is impaired in models of adult onset hypothyroidism following severe TH insult, has not been investigated at lower levels of TH insufficiency, or in adult offspring following a developmental TH insult. The present study was designed to examine: 1) dose- and time- dependent changes in brain and hippocampal weight and volume following developmental TH disruption; 2) adult hippocampal neurogenesis after moderate degrees of TH insufficiency beginning in adulthood; 3) persistent effects of developmental TH insufficiency on adult neurogenesis. Varying degrees of TH insufficiency were induced by administration of the TH synthesis inhibitor, propylthiouracil (PTU 0, 3, 10 ppm) in the drinking water of pregnant rats. In contrast to previous reports in high dose models, we found that moderate levels of TH insufficiency limited to adulthood did not affect adult neurogenesis. However, in adult offspring of developmental hypothyroid dams, a significant reduction in cell proliferation was seen in the neurogenic niche of the adult hippocampus. This impairment was accompanied by a reduction in hippocampal volume, an effect that was not detected at this low dose in the neonate, but which emerged in adulthood. Additional TH insult imposed on the adult after perinatal TH compromise did not produce further decrements in neurogenesis. These data suggest a direct effect of developmental hypothyroidism on the size or proliferative capacity of the neural stem cell population, and that the expression of that deficit remains and may not be readily detected until adulthood. Learning deficits associated with modest TH insufficiency may in part be the result of a disruption of this neurogenic process. This same neurogenic process also plays an important role in the formation of functional neural networks in the developing brain, and in the mature brain during learning. Impairment of neurogenesis at low levels of TH insufficiency may underlie some of the neurological deficiencies in offspring following maternal TH insufficiency. Moreover, our data also reveal that these processes can be impaired in the absence of change in other common metrics of developmental neurotoxicity (i.e., body weight, brain weight, brain volume) used to identify TH-disrupting chemicals. Better characterization of the consequences of moderate degrees of developmental TH insufficiency will not only provide insight into the role of TH in brain development, but serve to identify molecular substrates of TH action that are critical for the development of sensitive assays and endpoints for detection of dysfunction.

Description:

Severe thyroid hormone (TH) deprivation during development impairs neurogenesis throughout the brain. The hippocampus also maintains a capacity for neurogenesis throughout life which is reduced in adult-onset hypothyroidism. This study examined hippocampal volume in the neonate and adult hippocampal neurogenesis after developmental and adult-onset TH insufficiency. Pregnant rat dams were administered 0, 3, or 10 ppm of propylthiouracil (PTU) via drinking water from gestational day (GD) 6 until weaning. PTU at the high dose reduced body, brain, hippocampal weights on postnatal day (PN) 14, 21 and 78. Sub-regional analysis revealed decrements in hippocampal volumes at 10 but not 3 ppm PTU on PN23. In Experiment 2, one pair of adult male offspring of 0 and 3ppm-teated dams was placed on 3 ppm PTU from PN60, while a 2nd pair remained on control water. Adult neurogenesis was assessed by bromodeoxyuridine (BrdU, 50mg/kg, ip, 2X daily, X5 days) starting on PN90. Brains from animals perfused 1 and 28 days later were processed for immunohistochemistry. Although no volume changes were seen in neonates at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency reduced BrdU+ve cells at 1-day with no further reduction at 28-days post-BrdU, indicative of a selective effect on cell proliferation. This was supported by fewer cells staining for the proliferative marker, Ki67. Adult only PTU did not impair neurogenesis or exacerbate effects seen with developmental exposure. A reduced capacity for neurogenesis may contribute to cognitive deficits evident in adults following moderate degrees of developmental TH insufficiency.

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