Male reproductive toxicity of four bisphenol antioxidants in mice and rats and their estrogenic effect.
Male mice and rats were fed a diet containing four bisphenol antioxidants, 2,2'-methylenebis(4-ethyl-6-tert-butylphenol) (ME), 2,2'-methylenebis(4-methyl -6-tert-butylphenol) (MM), 4,4'-butylidenebis(3-methyl-6-tert-butylphenol) (BM), or 4,4'-thiobis(3-methyl-6-tert-butylphenol) (TM) at levels of 0.06-0.25% for 2 months. BM and TM decreased epididymal, seminal vesicular, prostate and preputial weights, and injured seminiferous tubules in mice in a dose-dependent fashion. BM and TM also reduced sex accessory organ weights and sperm production capacity in rats, but MM and ME were more toxic to rats than BM and TM. ME and MM did not bind ERalpha up to 10(-3) M, while BM and TM competitively bound ERalpha against beta-estradiol (E2). Fifty percent inhibitory concentrations (IC50 s) of BM, TM, and bisphenol A (positive control) against E2-binding were 7.3 x 10(-6) M, 1.8 x 10(-5) M, and 1.4 x 10(-5) M, respectively. When ovariectomized (OVX) mice were sc administered TM at doses of 60 and 300 mg/kg/day for 4 days, or when OVX mice were fed BM in the diet at a level of 0.25% for 2 months, uterine weight was significantly increased. These results suggest that BM and TM are weakly toxic, possibly through an estrogenic mechanism to male reproductive organs in mice as well as rats, while MM and ME may be the direct testicular toxins in rats but not mice.
Takahashi
Osamu
O
Department of Toxicology. Tokyo Metropolitan Research Laboratory of Public Health, 24-1, Hyakunincho 3-chome, 169-0073 Shinjuku-ku, Tokyo, Japan. Osamu_Takahashi@member.metro.tokyo.jp
Oishi
Shinshi
S
D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D001667:Binding, Competitive / Q000187:drug effects; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives* / Q000633:toxicity*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000187:drug effects; D004968:Estrogens, Non-Steroidal; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects; D005837:Genitalia, Male / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D051381:Rats; D011916:Rats, Inbred F344; D012098:Reproduction / Q000187:drug effects*; D013076:Sperm Count; D013737:Testis / Q000187:drug effects / Q000473:pathology; D013739:Testosterone / Q000097:blood; D014599:Uterus / Q000187:drug effects
D000975:Antioxidants; D047628:Estrogen Receptor alpha; D004968:Estrogens, Non-Steroidal; D002084:Butylated Hydroxytoluene; D013739:Testosterone