Progesterone receptor membrane component 1 inhibits tumor necrosis factor alpha induction of gene expression in neural cells.

Progesterone membrane receptor component 1 (Pgrmc1) is a cytochrome b5-related protein with wide-ranging functions studied most extensively in non-neural tissues. We previously demonstrated that Pgrmc1 is widely distributed in the brain with highest expression in the limbic system. To determine Pgrmc1 functions in cells of these regions, we compared transcriptomes of control siRNA-treated and Pgrmc1 siRNA-treated N42 hypothalamic cells using whole genome microarrays. Our bioinformatics analyses suggested that Pgrmc1 plays a role in immune functions and likely regulates proinflammatory cytokine signaling. In follow-up studies, we showed that one of these cytokines, TNFα, increased expression of rtp4, ifit3 and gbp4, genes found on microarrays to be among the most highly upregulated by Pgrmc1 depletion. Moreover, either Pgrmc1 depletion or treatment with the Pgrmc1 antagonist, AG-205, increased both basal and TNFα-induced expression of these genes in N42 cells. TNFα had no effect on levels of Rtp4, Ifit3 or Gbp4 mRNAs in mHippoE-18 hippocampal control cells, but Pgrmc1 knock-down dramatically increased basal and TNFα-stimulated expression of these genes. P4 had no effect on gbp4, ifit3 or rtp4 expression or on the ability of Pgrmc1 to inhibit TNFα induction of these genes. However, a majority of the top upstream regulators of Pgrmc1 target genes were related to synthesis or activity of steroids, including P4, that exert neuroprotective effects. In addition, one of the identified Pgrmc1 targets was Nr4a1, an orphan receptor important for the synthesis of most steroidogenic molecules. Our findings indicate that Pgrmc1 may exert neuroprotective effects by suppressing TNFα-induced neuroinflammation and by regulating neurosteroid synthesis.

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.

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.