The goal of this research is to study the effect of benzo-alpha-pyrene (BαP) as a pollutant on the plasma levels of cortisol, thyroxin (T4), and triiodothyronine (T3) hormones, and the T3/T4 ratio in the yellowfin sea bream, Acanthopagrus latus. The BαP (50 mg kg-1) in vegetable oil was peritoneally injected. Blood samples were obtained from the treated and control groups after 3 and 72 hr, respectively. The amounts of cortisol, T3, and T4 were measured using the ELISA techniques. The results showed that during both the 3 and 72 hr BαP exposures, the T4 hormone levels significantly decreased, although the cortisol levels increased (P<0.05). However, the T3 hormone levels and T3/T4 ratios compared with their control groups showed a significant difference just after 72 hr (P<0.05). The disruptive effects of the BαP exposure on T4 was stronger than that on the T3, being more evident in long-term stress. Thus, the BαP exerts a significant effect on the thyroid endocrine system and consequently on fish metabolism and growth.

The fetus is prenatally exposed to a mixture of organochlorine pesticides (OCPs), mercury (Hg), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and selenium (Se) through maternal seafood consumption in real-life scenario. Prenatal exposure to these contaminants and nutrients has been suggested to affect thyroid hormone (TH) status in newborns, but the potential relationships between them are unclear and the joint effects of the mixture are seldom analyzed. The aim of the study is to investigate the associations of prenatal exposure to a mixture of OCPs, Hg, DHA, EPA and Se with TH parameters in newborns. 228 mother-infant pairs in Shanghai, China were included. We measured 20 OCPs, total Hg, DHA, EPA and Se in cord blood samples as exposure variables. The total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) levels and the FT3/FT4 ratio in cord serum were determined as outcomes. Using linear regression models, generalized additive models and Bayesian kernel machine regression, we found dose-response relationships of the mixture component with outcomes: among the contaminants, p,p'-DDE was the most important positive predictor of TT3, while HCB was predominantly positively associated with FT3 and the FT3/FT4 ratio, indicating different mechanisms underlying these relationships; among the nutrients, EPA was first found to be positively related to the FT3/FT4 ratio. Additionally, we found suggestive evidence of interactions between p,p'-DDE and HCB on both TT3 and FT3, and EPA by HCB interactions for TT3, FT3 and FT3/FT4 ratio. However, the overall effects of the mixture on thyroid hormone parameters were not significant. Our result suggests that prenatal exposure to p,p’-DDE, HCB and EPA as part of a mixture might affect thyroid function of newborns in independent and interactive ways. The potential biological mechanisms merit further investigation.

Perfluorooctanesulfonic acid (PFOS) is a persistent anthropogenic chemical that can affect the thyroid hormone system in humans and animals. In adults, thyroid hormones (THs) are regulated by the hypothalamic-pituitary-thyroid (HPT) axis, but also by organs such as the liver and potentially the gut microbiota. PFOS and other xenobiotics can therefore disrupt the TH system at various locations and through different mechanisms. To start addressing this, we exposed adult male rats to 3 mg PFOS/kg/day for 7 days and analysed effects on multiple organs and pathways simultaneously by transcriptomics. This included four primary organs involved in TH regulation, namely hypothalamus, pituitary, thyroid, and liver. To investigate a potential role of the gut microbiota in thyroid hormone regulation, two additional groups of animals were dosed with the antibiotic vancomycin (8 mg/kg/day), either with or without PFOS. PFOS exposure decreased thyroxine (T4) and triiodothyronine (T3) without affecting thyroid stimulating hormone (TSH), resembling a state of hypothyroxinemia. PFOS exposure resulted in 50 differentially expressed genes (DEGs) in the hypothalamus, 68 DEGs in the pituitary, 71 DEGs in the thyroid, and 181 DEGs in the liver. A concomitant compromised gut microbiota did not significantly change effects of PFOS exposure. Organ-specific DEGs did not align with TH regulating genes; however, genes associated with vesicle transport and neuronal signaling were affected in the hypothalamus, and phase I and phase II metabolism in the liver. This suggests that a decrease in systemic TH levels may activate the expression of factors altering trafficking, metabolism and excretion of TH. At the transcriptional level, little evidence suggests that the pituitary or thyroid gland is involved in PFOS-induced TH system disruption.

Short-chain chlorinated paraffins (SCCPs) are ubiquitous in the environment and might cause adverse environmental and human health effects. Little is known about the relative toxicity of different SCCP compounds especially during development. The objective of this study was to characterize and compare effects of seven SCCP groups at environmentally relevant levels, using a zebrafish (Danio rerio) model. Observations on malformation, survival rates at 96 h post fertilization (hpf), and hatching rates at 72 hpf indicated that the C10- groups (C10H18Cl4, 1,2,5,6,9,10-C10H16Cl6 and C10H15Cl7) were more toxic than the C12- groups (C12H22Cl4, C12H19Cl7 and 1,1,1,3,10,12,12,12-C12H18Cl8) and Cereclor 63L. The C10- groups were also more potent than C12- groups and Cereclor 63L in decreasing thyroid hormone levels. Among the three compounds within the C10- group, the compounds with less chlorine content had stronger effects on sub-lethal malformations but less effects on triiodothyronine (T3) and tetraiodothyronine (T4). Only C10H18Cl4 significantly decreased the mRNA expression of tyr, ttr, dio2 and dio3 at a dose-dependent manner suggesting that the specific mode of actions differ with different congeners. The mechanisms of disruption of thyroid status by different SCCPs could be different. C10H18Cl4 might inhibit T3 production through the inhibition effect on dio2. These results indicate that SCCP exposure could alter gene expression in the hypothalamic-pituitary-thyroid (HPT) axis and thyroid hormone levels. The mechanisms of disruption of thyroid status by different SCCPs could be different. Our results on the relative developmental toxicities of SCCPs will be useful to reach a better understanding of SCCP toxicity supporting environmental risk evaluation and regulation and used as a guidance for environmental monitoring of SCCPs in the future.

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants (FRs) in China for decades, even after they were identified as persistent organic pollutants. In this study, serum samples were collected from 172 adults without occupational exposure who were residents of a well-known FR production region (Laizhou Bay, north China), and PBDE congeners were measured to assess their occurrence, congener profile and influencing factors in serum. Moreover, the relationships between serum concentrations of PBDEs and thyroid/liver function indicators were analyzed to evaluate whether human exposure to PBDEs would lead to thyroid/liver injury. All 8 PBDE congeners were detected at higher frequencies and serum concentrations than those found in general populations. The median levels of ∑PBDEs, BDE-209 and ∑₃₋₇PBDEs (sum of tri-to hepta-BDEs) were 64.5, 56.9 and 7.2 ng/g lw (lipid weight), respectively, which indicated that deca-BDE was the primarily produced PBDE in Laizhou Bay and that the lower brominated BDEs were still ubiquitous in the environment. Gender was a primary influencing factor for some BDE congeners in serum; their levels in female serum samples were significantly lower than those in male serum samples. Serum PBDE levels showed a downward trend with increased body mass index (BMI), which might reflect the increasing serum lipid contents. Serum levels of some BDE congeners were significantly positively correlated with certain thyroid hormones and antibodies, including free triiodothyronine (fT3), total triiodothyronine (tT3), total thyroxine (tT4) and thyroid peroxidase antibody (TPO-Ab). Levels of some congeners were significantly negatively correlated with some types of serum lipid, including cholesterol (CHOL), low density lipoprotein (LDL) and total triglyceride (TG). Other than serum lipids, only two liver function indicators, total protein (TP) and direct bilirubin (DBIL), were significantly correlated with certain BDE congeners (BDE-100 and BDE-154). Our results provide new evidence on the thyroid-disrupting and hepatotoxic effects of PBDEs.

Polybrominated diphenyl ethers (PBDEs) are flame retardants and the congener 2, 2′, 4, 4′-tetrabromodiphenyl ether (PBDE-47) is capable of inducing thyroid endocrine disruption and developmental toxicity. However, little is known about whether developmental PBDE-47 exposure-elicited alterations in semen quality is associated with thyroid hormones (THs) perturbation. In this research, we sought to explore the impacts of gestational and lactational PBDE-47 exposure on adult sperm quantity and motility, and its link with THs levels. For this purpose, female Sprague-Dawley rats were administered environmentally relevant PBDE-47 levels (0.1, 1.0, 10 mg/kg/day) by oral gavage from prepregnancy through lactation cessation to achieve early-life exposure of offspring and to mimic the actual exposure. Sperm quantity and motility together with serum THs levels from male offspring were determined on postnatal day 88. In utero and lactational exposure to PBDE-47 boosted the weight gain while reduced the relative testis weight in adult male offspring. These were accompanied with the reductions in sperm counts (total and living sperm counts), the percentage of progressive sperm motility, sperm velocities (curvilinear velocity, straight-line velocity and average path velocity), motion path (beat cross frequency, linearity and wobble) and linear motile sperm parameters (count, motility and concentration). Further studies identified that the levels of serum triiodothyronine (T₃) were increased by PBDE-47 exposure and negatively associated with those differential semen parameters on quantity and motility. Collectively, our results indicate that exposure to low-level PBDE-47 during early-life development impairs semen quality in adult rats, which could be mediated partially by abnormal T₃ levels.

Prenatal fine particulate matter (PM₂.₅) exposure has been associated with impaired offspring neurodevelopment; however, the association of PM₂.₅ exposure during preconception with offspring’s neurodevelopment and factors responsible for this association are still unclear. This study estimated the associations of PM₂.₅ exposure during preconception and the first trimester with offspring neurodevelopment and evaluated whether maternal thyroid hormones mediate these associations. We recruited 1329 mother-child pairs between 2013 and 2015 in Wuhan, China. PM₂.₅ exposure levels of each woman during the 3 months preconception and the first trimester were estimated using land-use regression models. Offspring neurodevelopment characterized by mental developmental index (MDI) and psychomotor developmental index (PDI) were measured at 24 months of age. Maternal serum levels of free thyroxine (FT3), free triiodothyronine (FT4), and thyroid-stimulating hormone (TSH) during early pregnancy were measured of a subset of the 1329 women (551 women). Generalized estimation equation and general linear regression models were used to estimate the associations between maternal PM₂.₅ exposure, thyroid hormones, and offspring neurodevelopment. After adjusting for potential confounders, we found that either among all participants or the subset, PM₂.₅ exposure during preconception and the first trimester was negatively associated with offspring PDI. Double increment in the first trimester PM₂.₅ exposure was significantly associated with 3.43 and 6.48 points decrease in offspring MDI. In the subset, each doubling of PM₂.₅ exposure during preconception and the first trimester was significantly associated with 7.93 and 8.02 points decrease in maternal FT4 level, respectively. Increased maternal FT4, in turn, was associated with increased PDI (β = 16.69, 95% CI: 5.39, 27.99). About 7.7% (95% CI: 2.0%–19.4%) and 8.6% (95% CI: 3.0%, 22.1%) of the effect of PM₂.₅ exposure during preconception on offspring PDI was mediated through maternal FT4 and the FT4/FT3 ratio, respectively.

Prior human studies have explored effects of phthalate exposures on thyroid function, but the underlying biological mechanisms remain poorly unclear. We aimed to explore the associations between phthalate exposures and thyroid function among a potentially susceptible population such as patients with thyroid nodules, and further to assess the mediating role of oxidative stress. We measured eight phthalate metabolites, three oxidative stress biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-prostaglandin F₂α (8-isoPGF₂α) and 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA)] in urine and three thyroid function biomarkers [thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4)] in serum among 214 patients with thyroid nodules. Multivariate regression models were applied to assess the associations among urinary phthalate metabolites, oxidative stress and thyroid function biomarkers. The potential mediating role of oxidative stress was explored by mediation analysis. We observed that multiple urinary phthalate metabolites were associated with altered FT4 and increased oxidative stress biomarkers (all FDR-adjusted P ≤ 0.05). Meanwhile, we found that 8-isoPGF₂α was negatively associated with FT3/FT4 among patients with benign thyroid nodules (FDR-adjusted P = 0.08). The mediation analysis indicated that 8-isoPGF₂α mediated the associations of urinary MEHHP and %MEHP with FT3/FT4, with 55.6% and 32.6% proportion of the mediating effects, respectively. Our data suggest that lipid peroxidation may be an intermediate mechanism involved in the effects of certain phthalate exposures on altered thyroid function among patients with benign thyroid nodules.

No information is available on the long-term effects on thyroid and growth hormones of children exposed to phthalate-tainted products, despite the infamous 2011 Taiwan phthalate episode. We investigated estimated daily intake levels and their long-term effects on serum thyroid and growth hormone levels in children.We recruited 166 children (2–18 years old) in three visits who provided specimens and filled out a questionnaire from the Risk Assessment of Phthalate Incident in Taiwan (RAPIT) project study from 2012 to 2016. Morning spot urine samples were analyzed for nine phthalate metabolites. Serum thyroid (triiodothyronine [T₃], thyroxine [T₄], and free T₄) and growth hormone (insulin-like growth factor-1 [IGF-1] and its binding protein 3 [IGF-BP3]) levels were measured. A generalized estimating equation model was used to evaluate associations between phthalate metabolite levels and children’s thyroid and growth hormone levels.The median metabolite levels of monomethyl phthalate (MMP), Σdibutyl phthalate (DBP), and Σdi-(2-ethylhexyl) phthalate (DEHP) at visits 1, 2, and 3 were 6.59, 10.5, and 21.0 ng/mL, 0.15, 0.24, and 0.20 nmol/mL, and 0.15, 0.17, and 0.12 nmol/mL, respectively. After adjusting for potential confounding factors, we found that levels of urinary MMP were negatively associated with T₃ (β = −0.013, p = 0.047), T₄ (β = −0.016, p = 0.006), free T₄ (β = −0.012, p = 0.002), and IGF-BP3 (β = −0.025, p = 0.003). Urinary mono-ethyl phthalate (MEP) was negatively associated with IGF-1 (β = −0.027, p = 0.029) and IGF-BP3 (β = −0.016, p = 0.018). In addition, serum free T₄ was positively associated with urinary mono-2-ethyl-5-hydroxy hexyl phthalate (MEHHP) (β = 0.016, p = 0.043), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) (β = 0.015, p = 0.024), and ΣDEHPm (β = 0.019, p = 0.020).Our findings support the hypothesis that specific phthalates disturb the hemostasis of thyroid and growth hormone levels in children exposed to phthalate-tainted products.

Triphenyl phosphate (TPHP; CAS # 115-86-6), a commonly used plasticizer and flame retardant, has been reported in wild birds and identified as a potential high-risk chemical. We exposed Japanese quail (Coturnix japonica) by in ovo injection, and once hatched, orally each day for 5 days to safflower oil (controls) or TPHP dissolved in vehicle at low (5 ng TPHP/g), mid (50 ng TPHP/g), or high (100 ng TPHP/g) nominal TPHP doses. The low TPHP dose reflected concentrations in wild bird eggs, with mid and high doses 10x and 20x greater to reflect potential increases in environmental TPHP concentrations in the future. Despite no effects on mRNA expression in thyroid-related genes, TPHP exposure enhanced thyroid gland structure in high TPHP males, but in females, suppressed thyroid gland structure and activity (all TPHP females), and circulating free triiodothyronine (high TPHP females only). Consistent with thyroidal changes, and compared to controls, mid and high TPHP chicks experienced significantly reduced resting metabolic rate (≤13%) and growth (≤53%); mid TPHP males and high TPHP females were significantly smaller. The observed thyroidal effects and suppressed growth and metabolic rate of the quail chicks suggest that TPHP may adversely affect the health of wild birds.