Toxic effect of PBDE-47 on thyroid development, learning, and memory, and the interaction between PBDE-47 and PCB153 that enhances toxicity in rats

Abstract

Polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) are widespread environmental contaminants. There are potential interactive effects between PBDEs and PCBs, as these compounds share similar structures. The developmental neurotoxicity of 2, 2', 4, 4'-tetrabromodiphenyl ether (PBDE-47) and the interaction of PBDE-47 with 2, 2', 4, 4', 5, 5'-hexachlorobipheny (PCB153) were investigated herein, as the dominant congener forms of PBDEs and PCBs, respectively. SD rats were exposed to a single oral dose of PBDE-47 (1, 5, and 10 μg/g) and/or PCB153 (5 μg/g) on post-natal day (PND) 10. Concentrations of PBDE-47, triiodothyronine (T(3)), thyroxine (T(4)), and thyroid-stimulating hormone (TSH) in serum; organ-to-body weight ratios; as well as long-term learning and memory were measured in 2-month-old rats. The present study found that some doses of PBDE-47 decreased the organ-to-body weight ratios of the thyroid and uterus, decreased the concentration of T(4) in serum, and increased the organ-to-body weight ratio of the ovaries (p < 0.05). PCB153 could increase the action of PBDE-47 during combined exposure, but this interaction was not found between PBDE-47 and PCB153. In a Morris water maze experiment, the latency periods were significantly prolonged and time ratios were obviously depressed in all PBDE-47-treated groups compared to the control (p < 0.05); furthermore, significant interactions between PBDE-47 and PCB153 were observed (p < 0.05). In conclusion, PBDE-47 may depress thyroid development as well as the long-term learning and memory capabilities in adult rats exposed to PBDE-47 on PND 10. PCB153 can interact with PBDE-47, resulting in an increase in developmental neurotoxicity.

Developmental Exposure to Polybrominated Diphenyl Ethers and Neurodevelopment

“…Effects did not vary by sex or mouse strain [40] and appeared to worsen with age, such that PBDE-related effects on altered spontaneous behavior and reduced habituation capabilities were more pronounced as the animals aged [34,36,37,38]. Effects on neurodevelopment were corroborated by others who found that in mice, perinatal PBDE exposure was associated with impaired learning and poorer functioning on memory tasks [41,42,43,44], altered locomotor activity, increased hyperactivity [45,46,47,48,49] and increased impulsivity, particularly in adult animals [50]. In rats, similar detrimental effects on attention and learning were also observed [43,51].…”

“…In vitro models have shown that PBDE congeners, as well as their hydroxylated metabolites have the potential to bind to thyroid hormone receptors [75,76] and animal models indicate that PBDEs may have a direct effect on the thyroid gland [44,77]. …”

“…Oxidative stress in response to PBDE exposure has been observed to cause neuronal death due to apoptosis [32,44,102,103,104]. Additionally, PBDEs and PBDE metabolites have been shown to disrupt vital intracellular and extracellular signaling mechanisms in the brain including calcium homeostasis and protein kinase C [105].…”

A mechanistic view of polybrominated diphenyl ether (PBDE) developmental neurotoxicity

“…In a follow-up study (Fischer et al 2008), exposure of mice to BDE-99 together with methylmercury enhanced the toxicity of the former in a more than additive manner. Another in vivo study by He et al (2011) showed that concomitant exposures of rats to low doses of BDE-47 and PCB-153 on postnatal day 10 had a synergistic effect on serum T 4 levels and behaviour in the Morris maze. Also in rats, exposure to DE-71 and to Fox River mix (a mixture of several Aroclor formulations containing multiple PCB congeners) during pregnancy, caused an additive effect on dopamine neurochemistry and on circulating T4 levels in developing pups (Dreiem et al 2010; Miller et al 2012).…”

“…A lack of correlation between PBDE exposure and T 4 or TSH blood levels was also reported by Chevrier et al (2011b), Eggesbo et al (2011), Gascon et al 2011), Shy et al (2012), and Kim et al (2012a; 2012b). In addition, adverse developmental effects of PBDEs in animals have also been observed in the absence of significant thyroid hormone alterations (Branchi et al 2005; Gee et al 2008; He et al 2011; Costa, Giordano, et al, unpublished; Table 1). Thus, overall, there is some evidence that PBDEs, mostly through their hydroxylated metabolites, can alter thyroid hormone homeostasis; however, whether this occurs in humans, and whether this is an important contributor to their developmental neurotoxicity remains to be determined.…”