Developmental exposure to the brominated flame retardant DE-71 reduces serum thyroid hormones in rats without hypothalamic-pituitary-thyroid axis activation or neurobehavioral changes in offspring

Abstract

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants for which human exposure remains ubiquitous. This is of concern since these chemicals can perturb development and cause adverse health effects. For instance, DE-71, a technical mixture of PBDEs, can induce liver toxicity as well as reproductive and developmental toxicity. DE-71 can also disrupt the thyroid hormone (TH) system which may induce developmental neurotoxicity indirectly. However, in developmental toxicity studies, it remains unclear how DE-71 exposure affects the offspring’s thyroid hormone system and if this dose-dependently relates to neurodevelopmental effects. To address this, we performed a rat toxicity study by exposing pregnant dams to DE-71 at 0, 40 or 60 mg/kg/day during perinatal development from gestational day 7 to postnatal day 16. We assessed the TH system in both dams and their offspring, as well as potential hearing and neurodevelopmental effects in prepubertal and adult offspring. DE-71 significantly reduced serum T4 and T3 levels in both dams and offspring without a concomitant upregulation of TSH, thus inducing a hypothyroxinemia-like effect. No discernible effects were observed on the offspring’s brain function when assessed in motor activity boxes and in the Morris water maze, or on offspring hearing function. Our results, together with a thorough review of the literature, suggest that DE-71 does not elicit a clear dose-dependent relationship between low serum thyroxine (T4) and effects on the rat brain in standard behavioral assays. However, low serum TH levels are in themselves believed to be detrimental to human brain development, thus we propose that we lack assays to identify developmental neurotoxicity caused by chemicals disrupting the TH system through various mechanisms.

Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food

“…The median (range) concentrations of the most abundant BDE-47 and -153 increased from 0.35 ng/g lipid (0.25-0.60) to 0.50 ng/g lipid (0.20-0.80) and from 0.33 ng/g lipid (0.22-0.52) to 0.65 ng/g lipid (0.39-1.0), respectively after 12 months. Similar results were reported by Rantakokko et al (2015) as referenced by Jansen et al (2017). Jansen et al (2018) analysed serum samples that were collected between 2012 and 2014 from 63 patients before and 1 year after bariatric surgery for BDE-47, -99, -100, -153 and -209 as well as other POPs.…”

“…In male pups, no changes in the follicular epithelium, follicular morphology, stroma or c-cells were evident in thyroid glands on PND16. However, a dose-dependent increase in minimal vacuolation of follicular colloid was noted (statistically significant higher incidence at 60 mg/kg bw per day, study 2) (Ramhøj et al, 2022) The LOAEL was 20 mg/kg bw per day.…”

“…Hypertrophy of hepatocytes was localised to the centrilobular areas. No microvesicular vacuolation was observed (Ramhøj et al, 2022). The LOAEL was 20 mg/kg bw per day.…”

“…The studies on biomarkers of inflammation were mostly cross-sectional. Endpoints consisted of a long list of biomarkers related to oxidative stress Yuan et al, 2017), inflammation (Kumar, Lind, Salihovic, van Bavel, Ekdahl, et al, 2014;Schaebel et al, 2017;Yuan et al, 2017;Zota, Geller, et al, 2018), immune system (Kumar, Lind, Salihovic, van Bavel, Ekdahl, et al, 2014) and non-alcoholic fatty liver disease (Rantakokko et al, 2015, Midya et al, 2022, as full listed in Table 30 and Appendix D. The large variation in biomarkers between studies and mostly cross-sectional study designs preclude an integrative assessment of the evidence at this stage. In the only prospective study in this group, liver injury and hepatocellular apoptosis was assessed in relation to prenatal BDE-47 and -153 levels by Midya et al (2022) using a collaborative network of six ongoing, population-based prospective birth cohort studies from six European countries (France, Greece, Lithuania, Norway, Spain and the UK; HELIX study, n = 1108).…”

“…In the study by Ramhøj et al (2022) previously described in Section 3.1.2.2.1, in which pregnant Wistar rats were exposed by gavage to 0, 20, 40 or 60 mg DE-71/kg bw per day from GD7 to PND14 (study) or to 0, 40 or 60 mg DE-71/kg bw per day from GD 7 to PND 16 (2d. study), DE-71 significantly reduced serum TT4 and TT3 levels in both dams and offspring without a concomitant upregulation of TSH.…”