There is increasing evidence that human pregnancy outcome can be significantly compromised by suboptimal maternal nutritional status. Poor diet results in a maternal-fetal environment in which the teratogenicity of other insults such as alcohol might be amplified. As an example, there is evidence that zinc (Zn) can interact with maternal alcohol exposure to influence the risk for fetal alcohol spectrum disorders (FASD). Studies with experimental animals have shown that the teratogenicity of alcohol is increased under conditions of Zn deficiency, while its teratogenicity is lessened when animals are given Zn supplemented diets or Zn injections prior to the alcohol exposure. Alcohol can precipitate an acute phase response resulting in a subsequent increase in maternal liver metallothionein, which can sequester Zn and lead to decreased Zn transfer to the fetus. Importantly, the teratogenicity of acute alcohol exposure is reduced in metallothionein knockout mice, which can have improved Zn transfer to the conceptus relative to wild-type mice. Consistent with the above, Zn status has been reported to be low in alcoholic women at delivery. Preliminary data from two basic science and clinical nutritional studies that are ongoing as part of the international Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) support the potential role of Zn, among other nutritional factors, relative to risk for FASD. Importantly, the nutrient levels being examined in these studies are relevant to general clinical populations and represent suboptimal levels rather than severe deficiencies. These data suggest that moderate deficiencies in single nutrients can act as permissive factors for FASD, and that adequate nutritional status or intervention through supplementation may provide protection for some of the effects of prenatal alcohol exposure.

Peroxisome proliferator-activated receptor (PPAR) transcription factors are pharmaceutical drug targets for treating diabetes, atherosclerosis, and inflammatory degenerative diseases. The possible mechanism of interaction between the three PPAR isotypes (␣, ␤/␦, and ␥) is not yet clear. However, this is important both for understanding transcription factor regulation and for the development of new drugs. The present study was designed to compare the effects of combinations of synthetic agonists of PPAR␣ [2-[4-[2-[4-cyclohexylbutyl (cyclohexylcarbamoyl), and PPAR␥ (rosiglitazone, ciglitazone) on inflammatory gene regulation in rat primary astrocytes. We measured cyclooxygenase-2 (COX-2) expression and prostaglandin E 2 synthesis in lipopolysaccharide (LPS)-stimulated cells. PPAR␣, PPAR␤/␦, and PPAR␥ knockdown models served to delineate the contribution of each PPAR isotype. Thiazolidinediones enhanced the LPSinduced COX-2 expression via PPAR␥-dependent pathway, whereas L-165041 and GW7647 had no influence. However, the addition of L-165041 potentiated the effect of PPAR␥ activation through PPAR␤/␦-dependent mechanism. On the contrary, PPAR␣ activation (GW7647) suppressed the effect of the combined L-165041/rosiglitazone application. The mechanism of the interplay arising from combined applications of PPAR agonists involves changes in PPAR expression levels. A PPAR␤/␦ overexpression model confirmed that PPAR␤/␦ expression level is the point at which PPAR␥ and PPAR␣ pathways converge in control of COX-2 gene expression. Thus, we discovered that in primary astrocytes, PPAR␥ has a positive influence and PPAR␣ has a negative influence on PPAR␤/␦ expression and activity. A positive/negative-feedback loop is formed by PPAR␤/␦-dependent increase in PPAR␣ expression level. These findings elucidate a novel principle of regulation in the signaling by synthetic PPAR agonists that involves modulating the interaction between PPAR␣, -␤/␦, and -␥ isoforms on the level of their expression.

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J. Neurochem. (2010) 115, 399–410. Abstract Despite the importance of cytosolic phospholipase A2 type IVA (cPLA2) and secretory PLA2 (sPLA2) in physiological and pathological responses of astrocytes in inflammatory conditions, the regulation of the expression of these genes is still unclear. Both genes have peroxisome proliferator‐activated receptors (PPAR) binding sites in their promoters. The role of synthetic PPAR agonists in the regulation of gene expression in naïve and lipopolysaccharide (LPS)‐stimulated rat astrocytes in culture was investigated. Exposure to LPS resulted in a time‐dependent, fourfold transient increase of sPLA2 expression, with maximum at 4 h; cPLA2 expression was notably increased after 16‐h LPS stimulation. Using selective PPARα, PPARβ/δ, and PPARγ agonists, we found that expression of both cPLA2 and sPLA2 is under PPAR control, but with different isotypes sensitivity. In naïve astrocytes, all three PPAR agonists significantly suppressed the expression of sPLA2, while only PPARα and PPARγ activation suppressed cPLA2 expression. Astonishingly, simultaneous addition of LPS with PPAR agonists evoked the opposite effect. All three PPAR agonists induced potentiation of cPLA2 expression level. Potentiation of sPLA2 expression was induced only by simultaneous addition of LPS with PPARγ agonist. By knockdown of PPARα, PPARβ/δ, and PPARγ, we confirmed the involvement of PPAR‐dependent pathways. The important novelty of our findings is that both sPLA2 and cPLA2 are under dichotomous control of PPARs: suppression in naïve control cells, but induction in LPS‐stimulated astrocytes.