Prenatal PCBs disrupt early neuroendocrine development of the rat hypothalamus
- Center for Molecular and Cellular Toxicology, Division of Pharmacology and Toxicology, University of Texas at Austin, Austin, TX 78712 (United States)
Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; or estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor {alpha} (ER{alpha}) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ER{alpha}, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA{sub B} receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGF{alpha}. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function.
- OSTI ID:
- 21535268
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 252, Issue 1; Other Information: DOI: 10.1016/j.taap.2011.01.012; PII: S0041-008X(11)00022-6; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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ADULTS
APOPTOSIS
ESTRADIOL
FEMALES
GENES
HYPOTHALAMUS
MALES
NUCLEI
POLYCHLORINATED BIPHENYLS
POLYMERASE CHAIN REACTION
RATS
RECEPTORS
SEX
AGE GROUPS
ANIMALS
AROMATICS
BODY
BRAIN
CENTRAL NERVOUS SYSTEM
CHLORINATED AROMATIC HYDROCARBONS
ESTRANES
ESTROGENS
GENE AMPLIFICATION
HALOGENATED AROMATIC HYDROCARBONS
HORMONES
HYDROXY COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
PROTEINS
RODENTS
STEROID HORMONES
STEROIDS
VERTEBRATES