Anti-androgenic activity of novel flame retardants in mixtures: Newly identified contribution from tris(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO)

In recent decades, male infertility has been on the rise, largely attributed to exposure to chemicals with endocrine-disrupting properties. The adverse effects of disrupting androgen actions on the development and reproductive health of children and adolescents have been extensively studied. Flame retardants (FRs), used in consumer products to delay flammability, have been identified as antagonists of the androgen receptor (AR), potentially leading to adverse outcomes in male reproductive health later in life. This study examined the interaction of eight novel FRs with the AR, employing an in vitro AR-dependent luciferase reporter gene assay utilizing MDA-kb2 cells. The investigation revealed the anti-androgenic activity of tris(2,3-dibromopropyl) isocyanurate (TDBP-TAZTO), a frequently detected FR in the environment. Furthermore, TDBP-TAZTO contributed to anti-androgenic activity when combined with six other anti-androgenic FRs. The mixture effects were predicted by three commonly employed models: concentration addition (CA), generalized CA, and independent action, with the CA model showcasing the highest accuracy. This suggests that all FRs act through a similar mechanism, as further confirmed by in silico molecular docking, indicating limited synergy or antagonism. Importantly, in the mixtures, each FR contributed to the induction of anti-androgenic effects at concentrations below their individual effective concentrations in single exposures. This raises concern for public health, especially considering the co-detection of these FRs and their potential co-occurrence with other anti-androgenic chemicals like bisphenols. Therefore, our findings, along with previous research, strongly support the incorporation of combined effects of mixtures in risk assessment to efficiently safeguard population health.