Sex‐specific endocrine‐disrupting effects of three halogenated chemicals in Japanese medaka

Abstract

Several halogenated chemicals are found in an array of products that can cause endocrine disruption. Human studies have shown that endocrine responses are sex specific, with females more likely to develop hypothyroidism and males more likely to have reproductive impairment. The objective of this study was to assess sex differences on thyroid and estrogenic effects after exposure of Japanese medaka (Oryzias latipes, SK2MC) to halogenated compounds. This strain is an excellent model for these studies as sex can be determined non-destructively a few hours postfertilization. Medaka embryos were exposed to sublethal concentrations of Tris(1,3-dichloro-2-propyl) phosphate (TDCPP, 0.019 mg/L), perfluorooctanoic acid (PFOA, 4.7 mg/L) and its next generation alternative, perfluorobutyric acid (PFBA, 137 mg/L). Methimazole (inhibits thyroid hormone synthesis) and the thyroid hormone triiodothyronine served as reference controls. Fish were exposed throughout embryo development until 10 days postfertilization. Females displayed significantly larger swim bladders (which are under thyroid hormone control) after exposure to all chemicals with the exception of triiodothyronine, which caused the opposite effect. Females exposed to TDCPP and PFOA had increased expression of vitellogenin and exposure to PFOA upregulated expression of multiple thyroidrelated genes. Upregulation of estrogenic-regulated genes after exposure to TDCPP, PFOA and methimazole was only observed in males. Overall, our results suggest that females and males show an estrogenic response when exposed to these halogenated chemicals and that females appear more susceptible to thyroid-induced swim bladder dysfunction compared with males. These results further confirm the importance of considering sex effects when assessing the toxicity of endocrine-disrupting compounds.

Effect of thyroid hormone‐disrupting chemicals on swim bladder inflation and thyroid hormone‐related gene expression in Japanese medaka and zebrafish

“…Recently, Dang et al (2021) reviewed the influence of thyroid hormone-disrupting chemicals on fish, including Japanese medaka and zebrafish. They noted that studies have shown changes in the expression of thyroid-related genes, such as thyroid stimulating hormone subunit beta (tshβ), thyroid hormone receptor alpha (trα), and beta (trβ), after exposure to the following chemicals: 2,2 0 ,4,4 0tetrabromodiphenyl ether in zebrafish (Chan & Chan, 2012), TDCPP in Japanese medaka (Godfrey et al, 2019) and in zebrafish (Wang et al, 2013), and 2-ethylhexyl-4-methoxycinnamate (EHMC) in Japanese medaka (Lee et al, 2019) and in zebrafish (Chu et al, 2021).…”

“…Although exposure to TDCPP and EHMC causes changes in the expression of thyroid-related genes in both Japanese medaka and zebrafish, the reports then specified that, after exposure to TDCPP, trα and tshβ are upregulated in Japanese medaka (Godfrey et al, 2019) and zebrafish (Wang et al, 2013), and after exposure to EHMC, trα and trβ are upregulated in Japanese medaka (Lee et al, 2019) but downregulated in zebrafish (Chu et al, 2021). These results indicate that our understanding of how thyroid hormonedisrupting chemicals change the expression of genes related to thyroid hormone in Japanese medaka and zebrafish remains incomplete.…”

“…ERGO (EndocRine in Guideline Optimisation) group in EURION (European Cluster to Improve Identification of Endocrine Disruptors) have been using this approach in addition to the eye and brain development in zebrafish to examine the effects of thyroid hormone disruption (Baumann et al, 2019; Holbech et al, 2020; Knapen et al, 2020). Godfrey et al (2017, 2019) have reported that exposure of Japanese medaka and zebrafish to 3,3′,5‐triiodo‐ l ‐thyronine (T3), methimazole, tris(1,3‐dichloro‐2‐propyl) phosphate (TDCPP), perfluorooctanoic acid, or heptafluorobutanoic acid (PFBA) induces absence of swim bladder inflation, though it should be noted that Godfrey et al (2017) observed the presence or absence of swim bladder inflation in zebrafish at 6 days post fertilization and that they used only a single concentration of each test chemical. It is known that in zebrafish the swim bladder becomes inflated at approximately 2 days after hatching (5 days after fertilization) (Horie, Yamagishi, et al, 2017), meaning the effects of chemicals on swim bladder inflation can be investigated within 120 h after fertilization.…”

“…They noted that studies have shown changes in the expression of thyroid‐related genes, such as thyroid stimulating hormone subunit beta ( tshβ ), thyroid hormone receptor alpha ( trα ), and beta ( trβ ), after exposure to the following chemicals: 2,2′,4,4′‐tetrabromodiphenyl ether in zebrafish (Chan & Chan, 2012), TDCPP in Japanese medaka (Godfrey et al, 2019) and in zebrafish (Wang et al, 2013), and 2‐ethylhexyl‐4‐methoxycinnamate (EHMC) in Japanese medaka (Lee et al, 2019) and in zebrafish (Chu et al, 2021). Although exposure to TDCPP and EHMC causes changes in the expression of thyroid‐related genes in both Japanese medaka and zebrafish, the reports then specified that, after exposure to TDCPP, trα and tshβ are upregulated in Japanese medaka (Godfrey et al, 2019) and zebrafish (Wang et al, 2013), and after exposure to EHMC, trα and trβ are upregulated in Japanese medaka (Lee et al, 2019) but downregulated in zebrafish (Chu et al, 2021). These results indicate that our understanding of how thyroid hormone‐disrupting chemicals change the expression of genes related to thyroid hormone in Japanese medaka and zebrafish remains incomplete.…”

“…These results indicate that our understanding of how thyroid hormone‐disrupting chemicals change the expression of genes related to thyroid hormone in Japanese medaka and zebrafish remains incomplete. One of the reasons for this incomplete understanding is that various timings have been used in previous studies examining the expression of thyroid‐related genes in both Japanese medaka (Godfrey et al, 2019: TDCPP, 10 days post fertilization; Lee et al, 2019: EHMC, adult fish) and in zebrafish (Wang et al, 2013: TDCPP, 6 days post fertilization; Chu et al, 2021: EHMC, adult fish). Thus, coordinated studies examining expression of thyroid‐related genes at the time of swim bladder inflation.…”