title: Cleft palate caused by perfluorooctane sulfonate is caused mainly by extrinsic factors.
abstract: Perfluorooctane sulfonate (PFOS) is found ubiquitously in the environment, and is known to cause developmental toxicity, including cleft plate (CP). The aim of the present study was to elucidate the mechanism of CP associated with in utero exposure to PFOS in mice. We first examined whether the concentration of PFOS in fetal serum was related to susceptibility to CP. We compared palatogenesis following the administration of various concentrations of PFOS to dams. We conducted histological examination on gestational day (GD) 15 and 18, and alizarin red/alcian blue staining of fetal heads on GD18. Finally, we cultured palatal shelves (PSs) of GD14 fetuses, which had not yet made contact with each other, for 48h, to examine whether the shelves maintained the ability to fuse. The incidence of CP increased from 7.3% with a fetal serum concentration of PFOS of 110.7+/-13.4microg/ml (13mg/kg) to 78.3% with 138.6+/-0.9microg/ml (20mg/kg). PFOS at 50mg/kg on GD11-15 caused CP at a rate of 6.1%, meanwhile PFOS at 20mg/kg on GD1-17 caused a CP rate of 89.3%. Failure of palatal shelf elevation was observed with 20mg/kg PFOS. PFOS at 20mg/kg on GD1-17 and 50mg/kg on GD11-15 inhibited mandibular growth to the same extent, even though the rate of CP was different. Explants exposed to PFOS 20mg/kg and Tween 20 showed 94% (34/36) and 100% (31/31) fusion, respectively. We demonstrated that increasing the oral dose of PFOS from 13 to 20mg/kg resulted in a significant increase in CP even though there was only a small increase in serum concentration of PFOS. PFOS prevented elevation of the PSs above the tongue because their growth/fusion potential was maintained. Mandibular hypoplasia did not seem to play a critical role in the pathogenesis of CP.
authors.affiliation: Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida Konoe, Sakyo-ku, Kyoto 6068501, Japan.
authors.forename: Saho
authors.initials: S
authors.lastname: Era
authors.forename: Kouji H
authors.initials: KH
authors.lastname: Harada
authors.forename: Megumi
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Kayoko
authors.initials: K
authors.lastname: Inoue
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Minata
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Saito
authors.forename: Toshiya
authors.initials: T
authors.lastname: Takigawa
authors.forename: Kouhei
authors.initials: K
authors.lastname: Shiota
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000423:Alcian Blue; D017738:Alkanesulfonic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D000653:Amniotic Fluid / Q000378:metabolism; D000818:Animals; D000880:Anthraquinones; D001835:Body Weight / Q000187:drug effects; D002972:Cleft Palate / Q000139:chemically induced* / Q000473:pathology*; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D007202:Indicators and Reagents; D051379:Mice; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy
chemical_list: D017738:Alkanesulfonic Acids; D000880:Anthraquinones; D005466:Fluorocarbons; D007202:Indicators and Reagents; C010078:alizarin; C076994:perfluorooctane sulfonic acid; D000423:Alcian Blue