The effects of marginal maternal vitamin A status on penta-brominated diphenyl ether mixture-induced alterations in maternal and conceptal vitamin A and fetal development in the Sprague Dawley rat.
BACKGROUND
Polybrominated diphenyl ether (PBDE) toxicity in rodents can be associated with disruptions in endocrine signaling. We previously reported that the penta-BDE mixture, DE-71, disrupts thyroid hormones and vitamin A metabolism in rats during lactation, and that this disruption is amplified in animals fed diets marginal in vitamin A. The ability of the DE-71 to disrupt vitamin A metabolism during the prenatal period has not been evaluated. While penta-BDE mixtures are not strong teratogens in pregnant animals fed standard commercial laboratory diets, we hypothesized that they could be teratogenic under conditions of marginal vitamin A status.


METHODS
rats were fed diets containing 0.4 retinyl equivalents (RE, marginal) or 4.0 RE (adequate) of vitamin A per gram of diet. Pregnant animals were exposed to DE-71 (0, 6, 18, 60, or 120 mg/kg) from gestation days (GD) 6-11.5, or on GD 6-19.5.


RESULTS
DE-71 treatment resulted in dose-responsive reductions in maternal thyroid hormone and markers of vitamin A metabolism, with the latter reduction amplified in marginal vitamin A dams. Fetuses from marginal vitamin A, DE-71-exposed dams exhibited a dose-responsive increase in liver retinol binding protein levels. DE-71 treatment did not result in gross malformations; however, consistent with our hypothesis, GD 20 fetal weights were lower, and skeletal ossification was less when DE-71 exposure occurred concomitant with a marginal vitamin A status. For several endpoints, observable effects were evident at the lowest dose tested, consistent with a dose-response trend.


CONCLUSIONS
The results of this study support the concept that marginal vitamin A status enhances the disruptive effects of DE-71 during prenatal development.
Ellis-Hutchings
Robert G
RG
Department of Nutrition, University of California-Davis, Davis, CA, USA. REllis-hutchings@dow.com
Cherr
Gary N
GN
Hanna
Lynn A
LA
Keen
Carl L
CL
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D000284:Administration, Oral; D000821:Animal Feed; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005411:Flame Retardants / Q000633:toxicity*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D055768:Halogenated Diphenyl Ethers / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D018811:Maternal Exposure / Q000009:adverse effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood; D014801:Vitamin A / Q000008:administration & dosage* / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000150:complications* / Q000503:physiopathology
D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; C000607072:Rara protein, mouse; C000607073:Rara protein, rat; C518457:Rbp1 protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D054840:Retinol-Binding Proteins, Cellular; D013963:Thyroid Hormones; D014801:Vitamin A; C086401:pentabromodiphenyl ether