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. 2015 Oct 15:414:42-52.
doi: 10.1016/j.mce.2015.07.013. Epub 2015 Jul 17.

Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus

Viktoria Y Topper  1 , Deena M Walker  2 , Andrea C Gore  3
Affiliations

Sexually dimorphic effects of gestational endocrine-disrupting chemicals on microRNA expression in the developing rat hypothalamus

Viktoria Y Topper et al. Mol Cell Endocrinol. .

Abstract

This study examined developmental changes and sexual dimorphisms in hypothalamic microRNAs, and whether gestational exposures to environmental endocrine-disrupting chemicals (EDCs) altered their expression patterns. Pregnant rat dams were treated on gestational days 16 and 18 with vehicle, estradiol benzoate, or a mixture of polychlorinated biphenyls. Male and female offspring were euthanized on postnatal days (P) 15, 30, 45, or 90, and microRNA and mRNA targets were quantified in the medial preoptic nucleus (MPN) and ventromedial nucleus (VMN) of the hypothalamus. MicroRNAs showed robust developmental changes in both regions, and were sexually dimorphic in the MPN, but not VMN. Importantly, microRNAs in females were up-regulated by EDCs at P30, and down-regulated in males at P90. Few changes in mRNAs were found. Thus, hypothalamic microRNAs are sensitive to prenatal EDC treatment in a sex-, developmental age-, and brain region-specific manner.

Keywords: Endocrine-disrupting chemicals (EDCs); Hypothalamus; Medial preoptic nucleus (MPN); MicroRNA; Polychlorinated biphenyls (PCBs); Ventromedial nucleus (VMN).

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Figures

Figure 1
Figure 1
Developmental profiles of the 8 microRNAs in the MPN of female and male rats are shown. Main effects of age, sex, and treatment are indicated above the panels. Post-hoc analyses of significant age effects are indicated as: a, P15 vs P30; b, P15 vs P45; c, P15 vs P90; d, P30 vs P45; e, P30 vs P90 (all p < 0.05). Post-hoc analyses for significant age x treatment interactions are indicated as *p < 0.05, A1221 vs. DMSO at the same age; +p < 0.05, EB vs. DMSO at the same age. Abbreviation: Trt, Treatment.
Figure 2
Figure 2
Developmental profiles of the 8 microRNAs in the VMN of female and male rats are shown. Main effects of age, sex, and treatment are indicated above the panels. Post-hoc analyses for significant age effects are indicated as: a, P15 vs P30; b, P15 vs P45; c, P15 vs P90; e, P30 vs P90; f, P45 vs P90 (all p < 0.05). Post-hoc analyses for significant age x treatment interactions are indicated as *p < 0.05, A1221 vs. DMSO at the same age; +p < 0.05, EB vs. DMSO at the same age. Abbreviations: Trt, Treatment.
Figure 3
Figure 3
Developmental profiles of mRNAs in the MPN that were significantly affected by age, treatment, or had age x treatment interactions, in female (A, B) and male (C, D, E) rats. Main effects of age and treatment are indicated above the panels. Post-hoc analyses for age are indicated as b, P15 vs P45; c, P15 vs P90; d, P30 vs P45; e, P30 vs P90; f, P45 vs P90 (all p < 0.05). A significant age x treatment interaction was found only for male Ppara expression at P15 (*, p < 0.05 A1221 vs. DMSO). Abbreviations: Trt, Treatment.
Figure 4
Figure 4
Developmental profiles of mRNAs in the VMN that were significantly affected by age, treatment, or had age x treatment interactions, in female (A – D) and male (E, F) rats. Main effects are indicated below the panels. Post-hoc analyses for age are indicated as: a, P15 vs P30; b, P15 vs P45; c, P15 vs P90; d, P30 vs P45; e, P30 vs P90; f, P45 vs P90 (all p < 0.05). Age x treatment interaction were found for Lepr and Clock at P45 in females, and for Ar and Clock at P90 in males (*p < 0.05, A1221 vs. DMSO at the same age; +p < 0.05, EB vs. DMSO at the same age). Abbreviations: Trt, Treatment.
Figure 5
Figure 5
Cytoscape analysis of microRNAs, genes, and hormones for the three treatment groups in the females, collapsed across development, in the MPN (A–C) and VMN (D–F). Abbreviations: E2, estradiol, T, testosterone.
Figure 6
Figure 6
Cytoscape analysis of microRNAs, genes, and hormones for the three treatment groups in the males, collapsed across development, in the MPN (A–C) and VMN (D–F). Abbreviations: E2, estradiol, T, testosterone.
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