title: Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin may alter LH release patterns by abolishing sex differences in GABA/glutamate cell number and modifying the transcriptome of the male anteroventral periventricular nucleus.
abstract: Developmental exposure to arylhydrocarbon receptor (AhR) ligands abolishes sex differences in a wide range of neural structures and functions. A well-studied example is the anteroventral periventricular nucleus (AVPV), a structure that controls sex-specific luteinizing hormone (LH) release. In the male, testosterone (T) secreted by the developing testes defeminizes LH release mechanisms; conversely, perinatal AhR activation by 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) blocks defeminization. To better understand developmental mechanisms altered by TCDD exposure, we first verified that neonatal TCDD exposure in male rats prevented the loss of AVPV GABA/glutamate neurons that are critical for female-typical LH surge release. We then used whole genome arrays and quantitative real-time polymerase chain reaction (QPCR) to compare AVPV transcriptomes of males treated neonatally with TCDD or vehicle. Our bioinformatics analyses showed that TCDD enriched gene sets important for neuron development, synaptic transmission, ion homeostasis, and cholesterol biosynthesis. In addition, upstream regulatory analysis suggests that both estrogen receptors (ER) and androgen receptors (AR) regulate genes targeted by TCDD. Of the 23 mRNAs found to be changed by TCDD at least 2-fold (p<0.05), most participate in the functions identified in our bioinformatics analyses. Several, including matrix metallopeptidase 9 and SRY-box 11 (Sox11), are known targets of E2. CUG triplet repeat, RNA binding protein 2 (cugbp2) is particularly interesting because it is sex-specific, oppositely regulated by estradiol (E2) and TCDD. Moreover, it regulates the post-transcriptional processing of molecules previously linked to sexual differentiation of the brain. These findings provide new insights into how TCDD may interfere with defeminization of LH release patterns.
authors.affiliation: Department of Veterinary and Animal Sciences, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States.
authors.forename: Javier
authors.initials: J
authors.lastname: Del Pino Sans
authors.affiliation: Department of Veterinary and Animal Sciences, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States.
authors.forename: Kelsey J
authors.initials: KJ
authors.lastname: Clements
authors.affiliation: Department of Veterinary and Animal Sciences, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Suvorov
authors.affiliation: Department of Veterinary and Animal Sciences, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States.
authors.forename: Sudha
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Department of Veterinary and Animal Sciences, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States.
authors.forename: Hillary L
authors.initials: HL
authors.lastname: Adams
authors.affiliation: Department of Veterinary and Animal Sciences, 661 North Pleasant Street, University of Massachusetts Amherst, Amherst, MA 01003, United States. Electronic address: spetersen@vasci.umass.edu.
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Petersen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D018698:Glutamic Acid / Q000378:metabolism; D007032:Hypothalamus, Anterior / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D059467:Transcriptome / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007986:Luteinizing Hormone
keywords: AVPV; Cugbp2; LH; Mmp9; Sox11; defeminization