Abstract
This study investigates the in vitro effect of eleven thyroid-active compounds known to affect pituitary and/or thyroid weights in vivo, using the proliferation of GH3 rat pituitary cells in the so-called "T-screen," and of FRTL-5 rat thyroid cells in a newly developed test denoted "TSH-screen" to gain insight into the relative value of these in vitro proliferation tests for an integrated testing strategy (ITS) for thyroid activity. Pituitary cell proliferation in the T-screen was stimulated by three out of eleven tested compounds, namely thyrotropin releasing hormone (TRH), triiodothyronine (T3) and thyroxine (T4). Of these three compounds, only T4 causes an increase in relative pituitary weight, and thus T4 was the only compound for which the effect in the in vitro assay correlated with a reported in vivo effect. As to the newly developed TSH-screen, two compounds had an effect, namely, thyroid-stimulating hormone (TSH) induced and T4 antagonized FRTL-5 cell proliferation. These effects correlated with in vivo changes induced by these compounds on thyroid weight. Altogether, the results indicate that most of the selected compounds affect pituitary and thyroid weights by modes of action different from a direct thyroid hormone receptor (THR) or TSH receptor (TSHR)-mediated effect, and point to the need for additional in vitro tests for an ITS. Additional analysis of the T-screen revealed a positive correlation between the THR-mediated effects of the tested compounds in vitro and their effects on relative heart weight in vivo, suggesting that the T-screen may directly predict this THR-mediated in vivo adverse effect.
Highlights
Endocrine disruption has been the source of considerable debate since 1991 when Ana Soto reported that man-made compounds could act as estrogen mimics (Soto et al, 1991), an observation that was popularized with the publication of Our Stolen Future by Theo Colborne in 1996
The preservation of thyroid-stimulating hormone (TSH)-induced cell proliferation in the FRTL-5 cell line is a property exhibited by only three cell lines that originate from normal rat thyroid follicular epithelium
In vitro pituitary and thyroid cell proliferation assays are not viable substitutes for assessing pituitary and thyroid organ weight change, respectively. This calls into question the use of thyroid hormone-dependent cell proliferation assays and related TR-mediated reporter gene assays as alternative in vitro tests for the in vivo effect of chemicals on the HPT axis
Summary
Endocrine disruption has been the source of considerable debate since 1991 when Ana Soto reported that man-made compounds could act as estrogen mimics (Soto et al, 1991), an observation that was popularized with the publication of Our Stolen Future by Theo Colborne in 1996. An analysis of literature search results in ScopusTM reveals that, in the last decade, the majority of the papers published on endocrine disruption have focused on estrogen rather than on androgen or thyroid hormone disruption This is in contrast to the number of chemicals listed on the Toxnet hazardous substance data bank (HSDB) as of 25 January 2013 which lists 159 chemicals for androgen, 352 chemicals for estrogen, and 924 chemicals for thyroid activity. This is a cause for concern as altered thyroid hormone (TH) levels can cause adverse effects such as decreased fertility and retarded development, especially of the bones and the brain (Poppe and Velkeniers, 2004; Wajner et al, 2009; Göthe et al, 1999; Aronson et al, 1990; Zoeller and Crofton, 2000)
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