BMS-189453, a Novel Retinoid Receptor Antagonist, Is a Potent Testicular Toxin

Abstract

BMS-189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha, beta, and gamma. In Sprague Dawley rats at daily oral doses of 15, 60, or 240 mg/kg for 1 month, BMS-189453 produced increases in leukocyte counts, alkaline phosphatase and alanine aminotransferase levels, and marked testicular degeneration and atrophy at all doses. Significant overt signs of toxicity and deaths occurred at 240 mg/kg, whereas body-weight and food-consumption decreases occurred at 60 and 240 mg/kg. When BMS-189453 was administered to male rats at daily doses ranging from 12.5 to 100 mg/kg for 1 week, only minimal testicular changes occurred at all doses, shortly after the dosing period. However, after a 1-month drug-free observation period, marked testicular atrophy was evident at all doses. BMS-189453 was then administered at doses of 2, 10, or 50 mg/kg to male rats for 1, 3, or 7 consecutive days. Dose- and duration-dependent testicular toxicity that occurred after a 1-month observation period did not recover, and, in some cases, was more severe 4 months after the last dose. In rabbits administered BMS-189453 at oral doses of 2, 10, or 50 mg/kg for 1 week, testicular degeneration and atrophy were evident in the high-dose group at 1 month following treatment. These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated.

Retinoic acid signalling specifies intermediate character in the developing telencephalon

“…Soluble WNT3A, mouse frizzled receptor 8 protein (mFrz8CRD-IgG) and control condition media were generated as described (Gunhaga et al, 2003). All-trans retinoic acid (Sigma) and BMS189453 (Chen et al, 1995;Schulze et al, 2001) were used at 100 nM. Cyclopamine (Incardona et al, 1998) was used at 1 µM.…”

“…Heparin acrylic beads (Sigma) were soaked in PBS (control) or mouse recombinant FGFR4 (R&D Systems). AG 1-X2 resin converted to formate form were soaked in DMSO (control), all-trans retinoic acid (1 mM) or the synthetic retinoid BMS-189453 (Chen et al, 1995;Schulze et al, 2001) (4 mM). The beads were inserted into the prospective prosencephalon of HH stage 10-11 chick embryos and placed in contact with the neural ectoderm.…”

“…Thus, telencephalic cells appear to be exposed to RA signals at the time they begin to acquire intermediate character. To examine whether RA signalling is required for the specification of cells of an intermediate character, we exposed stage 14 I explants to the RAR antagonist BMS-1895453 (BMS453) (100 nM) (Chen et al, 1995;Schulze et al, 2001). Under these conditions, the generation of MEIS2 + cells was blocked (0% compared with 22±6% in untreated stage 14 I explants, P<0.01), the number of PAX6 + cells (7±3%) was reduced, and a small number of NKX2.1 + cells (5±3%) also appeared, but the growth of the explants was not affected (Fig.…”

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

“…RA signaling restricts the cardiac progenitor pool, and exposure of the anterior lateral plate mesoderm of zebrafish embryos to the RA antagonist BMS-189453 causes uncommitted lateral mesodermal cells to become myocardial progenitors [15,16]. RA signaling also regulates anterior-posterior polarisation of the heart [17].…”

As the world grows: contraception in the 21st century

“…BMS-189453 is a synthetic retinoid that acts as a panantagonist of all three RARs (RARα, RARβ, and RARγ). Rats and rabbits treated orally with low doses of BMS-189453 for only one week exhibited profound testicular toxicity within one month after cessation of treatment and minimal systemic toxicity (87). In contrast to the reversibility observed upon restoration of vitamin A to the diet, the effects of the pan-RAR antagonist were reported to be irreversible (87).…”