Effects of in utero and lactational TCDD exposure on bone development in differentially sensitive rat lines.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a notorious model compound of highly toxic environmental pollutants, polychlorinated dibenzo-p-dioxins (PCDDs). Their toxic effects are mediated via cytosolic aryl hydrocarbon receptor (AHR). We studied the effects of several dose levels of TCDD on developing rat bone after maternal exposure at different times of gestation and lactation in three differentially sensitive rat lines. Rat lines A, B, and C differ in their sensitivity to TCDD due to mutated AHR (Ahr(hw)) in line A and another TCDD-resistance allele (B(hw)) in line B. Line C rats have no resistance alleles. Offspring were analyzed for bone mineral density and geometry by peripheral quantitative computed tomography (pQCT) and for bone biomechanics by three-point bending at mid-diaphysis of tibia and femur and by axial loading at femoral neck. TCDD treatment resulted in bone defects, mainly in offspring of the most sensitive line C at a maternal dose of 1 microg/kg. They included decreased bone length, cross-sectional area of cortex, and bone mineral density. Mechanical testing revealed significantly reduced bending breaking force and stiffness of tibia, femur, and femoral neck. The effects were exposure time-dependent, and earlier exposure caused more severe defects. Gestational exposure alone was not sufficient, but lactational exposure was required to cause the bone defects. Most of the defects were recovered at the age of 1 year. The results indicate that dioxins affect developing bone by interfering with bone growth and mechanical strength and that the effects are mainly reversible. The dioxin-resistance alleles, Ahr(hw) and B(hw) increase the resistance to these defects.
Miettinen
Hanna M
HM
National Public Health Institute, Department of Environmental Health, FIN-70701 Kuopio, Finland. hanna.miettinen@ktl.fi
Pulkkinen
Pasi
P
Jämsä
Timo
T
Koistinen
Jaana
J
Simanainen
Ulla
U
Tuomisto
Jouko
J
Tuukkanen
Juha
J
Viluksela
Matti
M
D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects*; D002460:Cell Line; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D047109:Fetal Development; D007774:Lactation / Q000502:physiology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D012727:Sex Characteristics; D013534:Survival
D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon