Nakayama, S. F. | Search bioRxiv

bioRxiv2022

TRIAC disrupts cerebral thyroid hormone action via a negative feedback loop and heterogenous distribution among organs

3,3,5-triiodothyroacetic acid (TRIAC) is a metabolite of endogenous thyroid hormones (THs) that can bind to and activate TH receptors. As TRIAC was previously detected in sewage effluent, we aimed to investigate exogenous TRIACs potential for endocrine disruption. We administered either TRIAC or 3,3,5-triiodo-L-thyronine (LT3) to both euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC alleviated growth retardation, suppressed the hypothalamus-pituitary-thyroid (HPT) axis, and upregulated TH-responsive genes in the pituitary gland, liver, and heart. We observed that, unlike LT3, TRIAC does not upregulate the expression of TH-responsive genes in the cerebrum. Measurement of organ-specific TRIAC levels suggested that TRIAC was not efficiently trafficked into the cerebrum. Furthermore, by analyzing euthyroid mice, we found that cerebral TRIAC levels did not increase despite TRIAC administration at higher concentrations, whereas serum and cerebral TH levels were substantially decreased. Hence, TH-responsive genes in the cerebrum appear to be downregulated by TRIAC. In summary, TRIAC administration decreases circulating TH levels by suppressing the HPT axis, while the consequent attenuation of TH actions was compensated by TRIAC in peripheral tissues but not in the cerebrum due to the relative impermeability of the blood-brain barrier towards TRIAC. We verified that exogenous TRIAC disrupts TH actions in the cerebrum. This disruption is apparently due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogenous distribution of TRIAC among different organs. Our findings indicate that environmental TRIAC poses a potential neurodevelopmental risk.

ecology↗

bioRxiv2019

Estrogenic action by tris(2,6-dimethylphenyl) phosphate, an impurity in resorcinol bis flame retardant formulations, impairs the development of female reproductive functions

BackgroundDevelopmental exposure to environmental chemicals with estrogen-like activity has been suspected to permanently impair womens health. ObjectivesIn this study, we used a mouse model to evaluate whether a chemical having putative estrogen-like action detected by in vitro study, namely tris(2,6-dimethylphenyl) phosphate (TDMPP) impairs sexual differentiation of the brain. MethodsTo induce developmental exposure, TDMPP was administered subcutaneously to dams from gestational day 14 to parturition and to pups from postnatal day 0 to 9 at two different doses (TDMPP-high and TDMPP-low groups, respectively). To compare the results between TDMPP and typical estrogen exposures, 17{beta}-estradiol was administered at two different doses on the same treatment schedule (E2-low and E2-high groups, respectively). A vehicle control group was formed by administering an equivalent volume of sesame oil to dams and to pups. ResultsAlthough there was no specific impairment in female ovary morphology, precocious puberty, detected by vaginal opening, and irregular estrous cycles, detected by vaginal cytology after sexual maturation, were found in TDMPP- and E2-treated groups, but not in the vehicle control group. In addition, lower lordosis response during reproductive behavioral tests was found in TDMPP- or E2-treated groups. To further clarify whether TDMPP directly affects sexual differentiation of the brain, we evaluated the transfer of TDMPP into the brain and the formation of sexual dimorphic nuclei. We detected a certain amount of TDMPP and its metabolites in the mouse brain after treatment, and masculinization of sexual dimorphic nuclei in the hypothalamus of female mice, suggesting the direct impact of TDMPP in developing brain. DiscussionTaken together, the experimental evidence demonstrates that TDMPP directly enters the fetal and neonatal brain, inducing changes of sex-related brain structures, and impairing female reproductive functions.

pharmacology and toxicology↗