The thyroid-disrupting effects of long-term perfluorononanoate exposure on zebrafish (Danio rerio)

Abstract

Concentrations of perfluorononanoate (PFNA) suggest an obvious increase in the environment, wildlife, and humans. However, the potential toxicity of PFNA still remains to be fully elucidated. Our present work is directed toward evaluating specific thyroid endpoints, and studying the long-term and the trans-generational effects of PFNA on zebrafish. Zebrafish (Danio rerio) were exposed to different concentrations of PFNA (0, 0.05, 0.1, 0.5, and 1 mg/l) from their early life stages (F(0), 23 day post-fertilization dpf), and the exposure period lasted for 180 days. At the end of the exposure period, thyroid follicle histology and plasma thyroid hormone levels in male zebrafish were evaluated as direct endpoints for the specific thyroid toxicities, while gene expression relative to the hypothalamus-pituitary-thyroid axis was also investigated to study the underlying mechanisms. In addition, offspring embryos (F(1)) from the PFNA exposure parental zebrafish was reared in water either without PFNA or under continual exposure to PFNA for an additional 180 days to investigate effects of multi-generational exposures on the circulating T(3) levels and thyroid-associated gene expression. Our results demonstrate significantly elevated plasma T(3) levels were observed in both F(0) and F(1) adults, as well as PFNA-induced histological changes in the thyroid follicles of F(0) male zebrafish. In the liver, the abundance of gene transcript encoding the protein transthyretin (TTR) was significantly induced, while the expression of UDP-glucuronosyltransferases in F(0) adult males was inhibited. The induced thyroid-disrupting effects also demonstrated a trans-generational effect that was reflected by altered gene expression related to thyroid hormone (TH) synthesis and metabolism in F(1) larvae. Our results provide the first evidence for the thyroid-disrupting effects of long-term PFNA exposure in zebrafish.

Association Between Serum Perfluorinated Chemicals and Thyroid Function in U.S. Adults: The National Health and Nutrition Examination Survey 2007–2010

“…Depression of serum total T 4 , free T 4 , and total T 3 has been reported by several authors in PFOS-exposed rats (5)(6)(7)(8), without the concomitant increase in TSH that would be expected through feedback stimulation, whereas PFOA reduced total T 4 and total T 3 in monkeys (9). In contrast, although there has been no report of perfluorononanoic acid (PFNA) exposure and thyroid hormones in mammals, a recent study demonstrated significantly elevated plasma total T 3 in zebrafish after long-term PFNA exposure (10). Reduced responsiveness of the hypothalamic-pituitary-thyroid axis and displacement of circulating thyroid hormones from their plasma protein binding sites were suggested as potential mechanisms of perfluorodecanoic acid (11).…”

Developmental toxicity of perfluorononanoic acid in mice

“…Fang et al [37][38][39] described the hepatotoxicity of PFNA in rat; while Zhang et al [40,41] further elaborated the transcriptional and proteomic changes in zebrafish liver after chronic exposure to PFNA. Liu et al [42] reported the thyroid-disrupting effects of PFNA in zebrafish. Immunotoxic effects of PFNA in rats and mice have been shown by Fang et al [43,44] and Rockwell et al [45].…”

Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

“…Numerous animal experiments have shown that PFCs impaired thyroid function (Chang et al 2008;Liu et al 2011). For example, depression of serum THs levels has been reported in PFOS-exposed rats and monkeys (Lau et al 2004).…”