Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – part II: how can key events of relevant adverse outcome pathways be addressed in toxicological assessments?

Marty, Sue; Beekhuijzen, Manon; Charlton, Alex; Hallmark, Nina; Hannas, Bethany R.; Jacobi, Sylvia; Melching-Kollmuß, Stephanie; Sauer, Ursula G.; Sheets, Larry P.; Strauss, Volker; Urbisch, Daniel; Botham, Philip A.; Ravenzwaay, Bennard van

doi:10.1080/10408444.2021.1910625

Cited by 16 publications

(11 citation statements)

References 168 publications

(282 reference statements)

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“…407 (optional), 408, 414, 421, 422, and 443 . However, the analysis of additional TH and metabolites in plasma and further matrixes (e.g., brain, thyroid) may help to assess the TH disturbance as a cause of adverse effects observed in these studies. , Different analytical methods (chromatographical, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA)) are accepted, if certain quality criteria are met: a coefficient of variation (CV) below 25%, demonstrated repeatability between days and performance in the matrix . The new xLC-MS/MS method for the analysis of total TH metabolites in plasma presented here complies with these quality criteria .…”

Section: Discussionmentioning

confidence: 99%

A Novel and Fast Online-SPE-LC-MS/MS Method to Quantify Thyroid Hormone Metabolites in Rat Plasma

Hindrichs,

Walk,

Melching-Kollmuss

et al. 2023

Chem. Res. Toxicol.

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Since the focus in regulatory toxicology has drifted toward the identification of endocrine disruptors, the improvement in determination of alterations in the thyroid hormone system has become more important. THs are involved in several molecular processes important for a proper pre-and postnatal development so that disturbances can inter alia lead to incorrect brain maturation and/or disturbed metabolic processes (thermogenesis or lipolysis). In this publication, a new automated online solid-phase extraction (SPE)-liquid chromatography (LC)-tandem mass spectrometry (MS/MS, xLC-MS/MS) is introduced which simultaneously analyzes total T4, T3, rT3, T2, and T1. Method validation parameters are presented, and the method was positively verified by analyzing control and PTU-treated rat plasma samples (time points day 7, 14, and 28) for their total TH content. The obtained results were compared to published results by using a radioimmunoassay method. The automated SPE system ensures a consistent unified sample preparation, and this method overall showed sufficient specificity and accuracy to detect the given analytes in rat plasma. For the preparation of 50 μL of rat plasma, the following LOQs were established: 0.020 nM for T1, 0.029 nM for T2, 0.023 nM for rT3 and T3, and 3.22 nM for T4. This method is suitable to assess the identification of mechanisms leading to adverse effects, such as disturbed TH metabolism and regulation.

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Section: Discussionmentioning

confidence: 99%

A Novel and Fast Online-SPE-LC-MS/MS Method to Quantify Thyroid Hormone Metabolites in Rat Plasma

Hindrichs,

Walk,

Melching-Kollmuss

et al. 2023

Chem. Res. Toxicol.

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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%

“…Indirect (TSH-mediated) neoplastic changes of the thyroid gland in rodents are generally accepted to have little human relevance, acknowledging interspecies differences in the physiology of thyroid hormone homeostasis affecting the vulnerability to perturbation (Meek et al, 2003;Bartsch et al, 2018;Foster et al, 2021). But there are also safety concerns related to a decreased and potentially insufficient supply of TH, especially during pregnancy with direct health implications for the developing offspring (Noyes et al, 2019;O'Shaughnessy and Gilbert, 2020;Marty et al, 2021). However, evidence of a relevant risk for human health is still limited and therefore uncertain (Crivellente et al, 2019).…”

Section: Introductionmentioning

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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“…E. Gilbert et al, 2022;M. E. Gilbert et al, 2021;Kortenkamp et al, 2017;O'Shaughnessy et al, 2019) and whether this can also be expected in humans (Choksi et al, 2003;ECHA et al, 2018;EFSA, 2020;Jahnke et al, 2004;Marty et al, 2021;O'Shaughnessy, Wood, et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…It has been and still is accepted that rat thyroid tumors are of limited relevance to humans (Bartsch et al, 2018; Foster et al, 2021). Nevertheless, histopathological effects or thyroid hormone changes occurring in animal studies (M. Gilbert et al, 2017; O'Shaughnessy, Kosian, et al, 2018; O'Shaughnessy, Wood, et al, 2018) are important with regard to potential effects on neurological development of the offspring (M. Gilbert et al, 2017; M. E. Gilbert et al, 2022; M. E. Gilbert et al, 2021; Kortenkamp et al, 2017; O'Shaughnessy, Kosian, et al, 2018; O'Shaughnessy et al, 2019) and whether this can also be expected in humans (Choksi et al, 2003; ECHA et al, 2018; EFSA, 2020; Jahnke et al, 2004; Marty et al, 2021; O'Shaughnessy, Wood, et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Boscalid shows increased thyroxin‐glucuronidation in rat but not in human hepatocytes in vitro

Wiemann¹,

Melching-Kollmuß

Hambruch

et al. 2023

J of Applied Toxicology

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The fungicide boscalid induces thyroid histopathological and hormone effects in the rat, secondary to liver enzyme induction. To assess the human relevance of liver enzyme induction presumably leading to thyroid hormone disruption, a species comparative in vitro study on T4‐glucuronidation was conducted. Currently, no guidelines how to evaluate Phase II induction are in place. Therefore, we investigated the optimal conditions to evaluate Phase I and Phase II induction potential of boscalid in primary rat (PRH) and human (PHH) hepatocytes. Endpoints included mRNA gene expression and enzyme activities (cytochrome P450 isozymes [CYPs] and uridine diphosphate‐glucuronosyltransferases [UGTs]), measured after 3 (D3) and 7 (D7) days of exposure to reference compounds and to 5, 10, and 20 μM boscalid, focusing on T4‐glucuronidation. Basal CYP activities and T4 glucuronidation were similar or higher on D7 than D3. The highest induction responses of CYPs were on D3, whereas UGT induction and T4‐glucuronidation increases were highest on D7. Boscalid induced CYP1A, CYP2B, and CYP3A mRNA and/or increased related activities in PRH and PHH. Species differences in the induction pattern of UGT genes by reference inducers (ß‐naphthoflavone [BNF], 5‐pregnen‐3ß‐ol‐20‐one‐16α‐carbonitirile [PCN], rifampicin [RIF], and phenobarbital [PB]) and boscalid were seen: UGT1A1, UGT1A3, and UGT1A9 were predominantly induced in PHH, while UGT2B1 was predominantly induced in PRH. Basal activity levels for T4‐glucuronidation were very low in humans and an order of magnitude higher in rat, for this reason increases in activities were assessed as delta activity to the control. Significant increases in T4‐glucuronidation occurred with boscalid in rat but not in human hepatocytes.

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Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – part II: how can key events of relevant adverse outcome pathways be addressed in toxicological assessments?

Cited by 16 publications

References 168 publications

A Novel and Fast Online-SPE-LC-MS/MS Method to Quantify Thyroid Hormone Metabolites in Rat Plasma

A Novel and Fast Online-SPE-LC-MS/MS Method to Quantify Thyroid Hormone Metabolites in Rat Plasma

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

Boscalid shows increased thyroxin‐glucuronidation in rat but not in human hepatocytes in vitro

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