Gestational Exposure to Perchlorate in the Rat: Thyroid Hormones in Fetal Thyroid Gland, Serum, and Brain

Gilbert, Mary E.; Hassan, Iman; Wood, Carmen R.; O’Shaughnessy, Katherine L; Spring, Stephanie; Thomas, Susan E.; Ford, Jermaine

doi:10.1093/toxsci/kfac038

Cited by 17 publications

(21 citation statements)

References 59 publications

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“…Serum T4 and T3 were analyzed by liquid chromatography with tandem mass spectrometry using an AB Sciex (Framingham, Massachusetts) Exion AC UHPLC-Qtrap 6500+ Linear Ion Trap LC/ MS/MS system as previously described (19). The lower limit of quantitation (LLOQ) for each analyte was set to the concentration of the lowest calibration standard that gave an acceptable ion ratio, and acceptable recovery of ±30% of the spike amount; the lower limit of quantification (LLOQ) for both T4/T3 were 0.1 ng/ml (100 pg/ml).…”

Section: Serum Thyroid Hormone Quantificationmentioning

confidence: 99%

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Thyroid hormone action controls multiple components of cell junctions at the ventricular zone in the newborn rat brain

O’Shaughnessy

McMichael²,

Sasser³

et al. 2023

Front. Endocrinol.

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Thyroid hormone (TH) action controls brain development in a spatiotemporal manner. Previously, we demonstrated that perinatal hypothyroidism led to formation of a periventricular heterotopia in developing rats. This heterotopia occurs in the posterior telencephalon, and its formation was preceded by loss of radial glia cell polarity. As radial glia mediate cell migration and originate in a progenitor cell niche called the ventricular zone (VZ), we hypothesized that TH action may control cell signaling in this region. Here we addressed this hypothesis by employing laser capture microdissection and RNA-Seq to evaluate the VZ during a known period of TH sensitivity. Pregnant rats were exposed to a low dose of propylthiouracil (PTU, 0.0003%) through the drinking water during pregnancy and lactation. Dam and pup THs were quantified postnatally and RNA-Seq of the VZ performed in neonates. The PTU exposure resulted in a modest increase in maternal thyroid stimulating hormone and reduced thyroxine (T4). Exposed neonates exhibited hypothyroidism and T4 and triiodothyronine (T3) were also reduced in the telencephalon. RNA-Seq identified 358 differentially expressed genes in microdissected VZ cells of hypothyroid neonates as compared to controls (q-values ≤0.05). Pathway analyses showed processes like maintenance of the extracellular matrix and cytoskeleton, cell adhesion, and cell migration were significantly affected by hypothyroidism. Immunofluorescence also demonstrated that collagen IV, F-actin, radial glia, and adhesion proteins were reduced in the VZ. Immunohistochemistry of integrin αvβ3 and isoforms of both thyroid receptors (TRα/TRβ) showed highly overlapping expression patterns, including enrichment in the VZ. Taken together, our results show that TH action targets multiple components of cell junctions in the VZ, and this may be mediated by both genomic and nongenomic mechanisms. Surprisingly, this work also suggests that the blood-brain and blood-cerebrospinal fluid barriers may also be affected in hypothyroid newborns.

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Section: Serum Thyroid Hormone Quantificationmentioning

confidence: 99%

“…All samples were stored at -80°C until analysis. THs were isolated by solid phase extraction and analyzed by LC/MS/MS as previously described (19) for N=5 control and N=5 PTU exposed samples. The LLOQ for total T4 and reverse T3 (rT3) were 0.01 ng/g and total T3 0.05 ng/g.…”

Section: Brain Hormone Quantificationmentioning

confidence: 99%

Thyroid hormone action controls multiple components of cell junctions at the ventricular zone in the newborn rat brain

O’Shaughnessy

McMichael²,

Sasser³

et al. 2023

Front. Endocrinol.

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“…The process of neural cell differentiation is supported by micronutrients, such as iodine and zinc ( 34 ). Perchlorate is an environmental contaminant that interferes with iodine uptake into the thyroid to affect brain development ( 35 ). The animal experiment we carried out fully screened for the effects of these confounding factors.…”

Section: Discussionmentioning

confidence: 99%

Effects of maternal iodine nutritional status on neurodevelopmental and cognitive function of rat offspring

Guo

et al. 2022

Front. Nutr.

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ObjectivesThis study aimed to explore the effect of maternal iodine status on the brain development of offspring in rats. Since in human studies, the interference of environmental factors and other nutrients cannot be removed.Materials and methodsA total of 48 female Wistar rats were randomly divided into four groups: low iodine (LI), normal iodine (NI), 10-fold high iodine (10HI), and 50-fold high iodine (50HI). The rats were killed on the 15th day of pregnancy and lactation after collecting 24-h urine. The iodine concentration in 24-h urine, blood, and placenta of pregnant rats, and 24-h urine, milk, blood, and mammary glands of lactating rats was determined by inductively coupled plasma mass spectrometry. The thyroid hormone of pregnant and lactating rats was detected by chemiluminescence. The offspring were subjected to the Morris water maze on the 10th day after birth. Serum was collected to detect the thyroid hormone of offspring. The protein expression of neuroendocrine-specific protein (NSP)-A and brain-derived neurotrophic factor (BDNF) in the offspring brain were studied.ResultsIodine storage in the placenta during pregnancy and mammary glands during lactation was positively correlated with iodine intake, and iodine storage in the placenta and mammary glands in the 50HI group was significantly higher than that in the NI group (P = 0.045 and P = 0.040). Compared with the NI group, the offspring thyroid-stimulating hormone (TSH) level was significantly higher in the 10HI group (P = 0.046), and the FT4 level was significantly lower in the 50HI group (P = 0.032). The Morris water maze showed that LI and 50HI groups required longer time and distance to find the platform than the NI group (P < 0.001). The platform crossing numbers in the LI and 50HI groups decreased significantly (P < 0.001). The expression of NSP-A in offspring brain was lower in the 10HI and 50HI groups than in the NI group (P = 0.026 and P = 0,008). BDNF expression levels were significantly lower in the LI, 10HI, and 50HI groups than in the NI group (P < 0.001).ConclusionMaternal iodine intake affects iodine storage in the placenta and lactating mammary gland, which in turn affects thyroid function and BDNF and NSP-A expression in the offspring.

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“…adenoma or tumor formation in rats (Vansell et al, 2004;Brewer et al, 2007;Mullur et al, 2014). In addition, a decline of maternal T4 even in the absence of an accompanying TSH increase (hypothyroxinemia) during vulnerable prenatal periods has been identified as a critical event associated with an increased risk of adverse neurologic outcomes in rats such as hearing loss (ototoxicity) or structural brain malformations (Hassan et al, 2017;Noyes et al, 2019;O'Shaughnessy and Gilbert, 2020;Marty et al, 2021;Gilbert et al, 2022). Interestingly, human epidemiological studies also linked decreased levels of T4 during pregnancy with neurodevelopmental effects in children (Haddow et al, 1999;Kooistra et al, 2006;Berbel et al, 2009;Ghassabian et al, 2014;Modesto et al, 2015;Korevaar et al, 2016;Levie et al, 2018).…”

Section: Altex Accepted Manuscriptmentioning

confidence: 99%

A rodent thyroid-liver chip to capture thyroid toxicity on organ functional level

Karwelat

Kühnlenz

Steger‐Hartmann

et al. 2022

ALTEX

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Endocrine disruption by environmental chemicals continues to be a concern for human safety. The rat, a widely used model organism in toxicology, is very sensitive to chemical-induced thyroid perturbation, e.g. histopathological alterations in thyroid tissue. Species differences in the susceptibility to thyroid perturbation lead to uncertainty in human safety risk assessments. Hazard identification and characterization of chemically induced thyroid perturbation would therefore benefit from in vitro models addressing different mechanisms of action in a single functional assay, ideally across species. We here introduce a rat thyroid-liver chip that enables simultaneous identification of direct and indirect (liver-mediated) thyroid perturbation on organ-level functions in vitro. A second manuscript describes our work toward a human thyroid-liver chip (Kühnlenz et al., 2022). The presented microfluidic model consisting of primary rat thyroid follicles and liver 3D spheroids maintain a tissue-specific phenotype for up to 21 days. More precisely, the thyroid model exhibits a follicular architecture expressing basolateral and apical markers and secretes T4. Likewise, liver spheroids retain hepatocellular characteristics, e.g. a stable release of albumin and urea, the presence of bile canalicular networks, and the formation of T4-glucuronide. Experiments with reference chemicals demonstrated proficiency to detect direct and indirect mechanisms of thyroid perturbation through decreased thyroid hormone secretion and increased gT4 formation, respectively. Prospectively this rat thyroid-liver chip model, together with its human counterpart, may support a species-specific quantitative in vitro to in vivo extrapolation to improve a data-driven and evidence-based human safety risk assessment with significant contributions to the 3R principles. *

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Gestational Exposure to Perchlorate in the Rat: Thyroid Hormones in Fetal Thyroid Gland, Serum, and Brain

Cited by 17 publications

References 59 publications

Thyroid hormone action controls multiple components of cell junctions at the ventricular zone in the newborn rat brain

Thyroid hormone action controls multiple components of cell junctions at the ventricular zone in the newborn rat brain

Effects of maternal iodine nutritional status on neurodevelopmental and cognitive function of rat offspring

A rodent thyroid-liver chip to capture thyroid toxicity on organ functional level

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