Disruption of the thyroid hormone system and patterns of altered thyroid hormones after gestational chemical exposures in rodents - a systematic review

Abstract

We present a comprehensive overview of changes in thyroxine (T4) and thyroid stimulating hormone (TSH) serum concentrations after pre-gestational, gestational and/or lactation exposures of rodents to various chemicals that affect the thyroid hormone system. We show that T4 and TSH changes consistent with the idealized view of the hypothalamic-pituitary-thyroid (HPT) feedback loop (T4 decrements accompanied by TSH increases) are observed with only a relatively small set of chemicals. Most substances affect concentrations of various thyroid hormones without increasing TSH. Studies of altered T4 concentrations after gestational exposures are limited to a relatively small set of chemicals in which pesticides, pharmaceuticals and industrial chemicals are under-represented. Our risk-of-bias analysis exposed deficits in T4/TSH analytics as a problem area. By relating patterns of T4 - TSH changes to mode-of-action (MOA) information, we found that chemicals capable of disrupting the HPT feedback frequently affected thyroid hormone synthesis, while substances that produced T4 serum decrements without accompanying TSH increases lacked this ability, but often induced liver enzyme systems responsible for the elimination of TH by glucuronidation. Importantly, a multitude of MOA leads to decrements of serum T4. The current EU approaches for identifying thyroid hormone system-disrupting chemicals, with their reliance on altered TH serum levels as indicators of a hormonal mode of action and thyroid histopathological changes as indicators of adversity, will miss chemicals that produce T4/T3 serum decreases without accompanying TSH increases. This is of concern as it may lead to a disregard for chemicals that produce developmental neurotoxicity by disrupting adequate T4/T3 supply to the brain, but without increasing TSH.

Keywords: T4; TSH; endocrine disruptors; systematic review; thyroid stimulating hormone; thyroxine.

Figure 1

Prisma flow.

Figure 2

Summary of T4 – TSH response patterns with chemicals producing T4 decrements and TSH increases in dams and pups. Shown are records for test compounds with corresponding Cadima reference numbers (see Supplementary Material 5 ). Light grey cells show responses in dams, white cells in pups. Windows of exposure were labelled BP (pre-mating/mating periods, before pregnancy), GD (gestational days, GD 0 to birth) and PND (postnatal days from 10 to 30 or after 30) and green horizontal bars depict the duration of the exposure to pregnant dams. The period of thyroid development (GD 9 – GD 17, 30) is shown as an orange bar. Black arrowheads “▼” indicate the timing of blood sampling for T4 and TSH measurements. Blue downward arrowheads stand for T4 decrements, light blue “▼” in pups and dark blue “▼” in dams; orange upwards arrowheads show increases of T4 or TSH, light orange “▲”in pups, dark orange “▲” in dams. The absence of change in hormonal levels is represented by “↔”. Where varying responses occurred, we used “?”. Most of the studies reported dosages of test chemicals as mg/kg bw/d, except for PTU administered via the drinking water where doses were expressed as parts per million (ppm) (indicated next to the chemical name). The asterisk (*) indicates studies where FT4 was measured instead of T4. When the exposure (green horizontal bars) reached “≥ PND 30”, this indicates that the dosing period was prolonged until or beyond the PND 30. When the sampling day was placed on the “≥ PND 30”, this indicates that the sampling took place on the 30 PND or after this day (for more details, see the Supplementary Materials 5–7 ).

Figure 3

Summary of T4 – TSH response patterns with chemicals producing T4 serum decrements with no TSH changes in dams and pups. Symbols and shading as in Figure 2 .

Figure 4

Summary of studies where T4 - TSH changes were not observed in dams and pups at various dosages after gestational and perinatal exposures to test chemicals. List of studies showing as main response the unaffected levels of T4 and TSH. Symbols and shading as in Figure 2 .

Figure 5

Summary of T4/TSH response patterns in dams and pups for chemicals producing inconsistent effects. Symbols and shading as in Figure 2 . (See Supplementary Material 10 for single-dose studies).