Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) impairs Postnatal Testis Development in Mice: The Microtubule Cytoskeleton as a Sensitive Target

Abstract

Tetrabromobisphenol A-bis(2,3-dibromopropyl ether) (TBBPA-BDBPE), a widely used flame retardant, has been frequently detected in various environmental compartments, but its health hazard remains largely unknown. Here, we investigated the adverse effects of TBBPA-BDBPE (50 and 1000 μg/kg/day) on postnatal testis development in CD-1 mice and the underlying mechanism. Following the first week of maternal exposure, neonatal mice in the high-dose group exhibited reduced seminiferous tubule area, fewer Sertoli cells and germ cells, and damaged microtubules in Sertoli cells; even microtubule damage was also observed in the low-dose group. When exposure extended to adulthood, male offspring in the high-dose group presented more remarkable alterations in reproductive parameters, including reduced sperm count; in the low-dose group, microtubule damage was also observable, along with blood−testis barrier impairment. Further molecular docking analysis and tubulin polymerization assay indicated that TBBPA-BDBPE could interact with tubulin and disrupt its polymerization. Moreover, we observed attenuated microtubules in mouse Sertoli cells in vitro (TM4) following TBBPA-BDBPE treatment, suggesting that TBBPA-BDBPE impaired testis development possibly by interfering with tubulin dynamics. This study not only highlights the male reproductive hazard of TBBPA-BDBPE but also greatly improved the understanding of the molecular mechanism for male reproductive toxicity of chemicals.

Bioaccumulation and Male Reproductive Toxicity of the New Brominated Flame Retardant Tetrabromobisphenol A-Bis(2,3-dibromo-2-methylpropyl ether) in Comparison with Hexabromocyclododecane

“…Similar to our results, previous studies reported that HBCD below the dose of 10 mg/kg/d had no obvious effects on conventional end points in one-generation or two-generation reproductive toxicity guideline-compliant test. , Our study highlights testicular alterations at the molecular and cellular levels caused by HBCD, including reduced microtubule amounts and exfoliated spermatocytes. In fact, reduced microtubule amount and exfoliated spermatocytes were also observed in mice treated with TBBPA or TBBPA-BDBPE in our previous studies. , Moreover, the effects of TBBPA-DBMPE on most parameters are generally comparable with those of TBBPA and TBBPA-BDBPE. Although both TBBPA and TBBPA-BDBPE caused no alterations in conventional reproductive end points, the treated testes became susceptible to chemical-induced spermatogenic stress or to the extended exposure to the late reproductive age, displaying severe reproductive damage. , Therefore, we are concerned about the effects of a longer-term exposure to TBBPA-DBMPE on male reproduction in mammals.…”

“…As shown in Figure , mice were administrated with TBBPA-DBMPE or HBCD from PND 0 referring to our previous studies. − After exposure for 7 days, we investigated the effects of TBBPA-DBMPE or HBCD on testicular development and the key molecular events in male pups, considering the first week after birth as a critical period for rapid testis development. Additionally, we measured the concentrations of TBBPA-DBMPE and HBCD in the livers of pups to confirm the accessibility of these chemicals in suckling pups.…”

“…We chose oral administration (via drinking water) of the chemicals to reduce the stress on experimental animals and the workload. To reach the doses of approximately 50 and 1000 μg/kg/d, the corresponding concentrations of target chemicals in drinking water were set as 150 and 3000 ng/mL, respectively, according to our previous experience. ,, Specifically, TBBPA-DBMPE or HBCD was dissolved in DMSO to prepare stock solutions and further diluted in the drinking water (0.1%, vol/vol) to reach the concentrations of 150 and 3000 ng/mL. Twenty litters, each with one dam and ten newborn pups (at least six males), were randomly assigned into four groups ( n = 5) and were given 0.1% DMSO (solvent control, aliased as CON), 150 ng/mL TBBPA-DBMPE (TD-50), 3000 ng/mL TBBPA-DBMPE (TD-1000), and 150 ng/mL HBCD (HB-50) in drinking water.…”

“…Several studies reported that high doses of HBCD exerted reproductive toxicity in mamals, despite its effects at environmentally relevant doses remaining unkown. ,, Additionally, other brominated flame retardants, such as polybrominated diphenyl ethers and TBBPA, have also been reported to have adverse reproductive effects on laboratory animals. , Recently, we found that both TBBPA and TBBPA-bis­(2,3-dibromopropyl ether) (TBBPA-BDBPE) at low doses disrupted postnatal testis development in mice and thereby resulted in some molecular and cellular changes of testes in adulthood. − Moreover, the male mice treated with TBBPA became susceptible to busulfan-induced spermatogenic stress, resulting in severe adverse reproductive outcomes . TBBPA-DBMPE shares similar structural and chemical properties with TBBPA and TBBPA-BDBPE, thus we hypothesize that TBBPA-DBMPE is capable of disrupting testis development in mammals and leads to male subfertility in adulthood, especially at the life stage when male fertility begins to decline.…”

Critical Review of Pd-Catalyzed Reduction Process for Treatment of Waterborne Pollutants

“…Rapid industrialization has led to an exponential increase in the discharge of various pollutants into the environment, particularly in bodies of water. Halogenated organics, such as polychlorinated biphenyls, organic flame retardants, vinyl chloride, halogenated phenols, heavy metals, and oxylate ions (NO 3 – /NO 2 – , BrO 4 – /BrO 3 – , ClO 4 – /ClO 3 – ), are the most frequently detected pollutants in the water environment, posing lasting and significant public health concerns. To provide clean drinking water and eliminate ecological risks, various water treatment technologies have been proposed, including physical adsorption, biochemical processing, and chemical transformation. , These technologies, either individually or in combination, form the foundation of the water purification process for treating industrial wastewater, municipal sewage, and raw water to achieve a sustainable environment and safe drinking water.…”