Gender difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism

Background and Purpose: Dexamethasone is widely used in preterm labor and related diseases. However, prenatal dexamethasone exposure (PDE) can cause multi-organ developmental toxicities in offspring. Our previous study found the occurrence of fetal-originated diseases were associated with adrenal developmental programming alteration in offspring. Here, we investigated the effects of PDE on the adrenal function in offspring and its intrauterine programming mechanism. Experimental Approach: A rat model of PDE was established to observe the alteration of adrenal steroidogenesis in offspring. Further, we confirmed the gender difference of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiment. Key Results: PDE caused a decrease in adrenal steroidogenic function in fetal rats, but decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDE offspring were decreased in males and increased in females, suggesting 11β-HSD2 might mediate gender difference of adrenal function. We further confirmed dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy in adult PDE offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression in AR and ERβ were proved to involve in regulating the gender difference of 11β-HSD2 expression. Conclusion and Implications: This study demonstrated the gender difference in adrenal steroidogenic function of PDE offspring after birth, and elucidates a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

Fetal Programming and Sexual Dimorphism of Mitochondrial Protein Expression and Activity of Hearts of Prenatally Hypoxic Guinea Pig Offspring

Chronic intrauterine hypoxia is a programming stimulus of cardiovascular dysfunction. While the fetal heart adapts to the reduced oxygenation, the offspring heart becomes vulnerable to subsequent metabolic challenges as an adult. Cardiac mitochondria are key organelles responsible for an efficient energy supply but are subject to damage under hypoxic conditions. We propose that intrauterine hypoxia alters mitochondrial function as an underlying programming mechanism of contractile dysfunction in the offspring. Indices of mitochondrial function such as mitochondrial DNA content, Complex (C) I-V expression, and CI/CIV enzyme activity were measured in hearts of male and female offspring at 90 days old exposed to prenatal hypoxia (10.5% O2) for 14 d prior to term (65 d). Both left ventricular tissue and cardiomyocytes exhibited decreased mitochondrial DNA content, expression of CIV, and CI/CIV activity in male hearts. In female cardiomyocytes, hypoxia had no effect on protein expression of CI-CV nor on CI/CIV activity. This study suggests that chronic intrauterine hypoxia alters the intrinsic properties of select respiratory complexes as a programming mechanism of cardiac dysfunction in the offspring. Sex differences in mitochondrial function may underlie the increased vulnerability of age-matched males compared to females in cardiovascular disease and heart failure.

Programming

The author makes several suggestions for how to control the direction taken by an active cognitive process. He proposes a neural/cognitive programming mechanism: traveling waves on cortex. Evidence for traveling waves exists, and interactions of such waves have useful properties. One example is due to Pitts and McCulloch: Why are squares of different sizes seen as examples of squares? If excitation propagates from the corners of a square, waves meet at the diagonals. Squares of different sizes then have a common diagonal representation. Later models include “grassfire models” and “medial axis” models. Experiments suggests that response exists at a “medial axis” halfway between bounding contours, and in this approach “Identity” and “Symmetry” become the same computation. Traveling waves in audition can be used to give the pattern-dependent frequency independent responses seen in some kinds of speech perception.

Prenatal Dexamethasone Exposure Induced Ovarian Developmental Toxicity and Transgenerational Effect in Rat Offspring

Prenatal dexamethasone exposure (PDE) induces multiorgan developmental toxicities in offspring. Here we verified the transgenerational inheritance effect of ovarian developmental toxicity by PDE and explored its intrauterine programming mechanism. Pregnant rats subcutaneously received 0.2 mg/kg/d dexamethasone from gestational day (GD) 9 to GD20. A subgroup was euthanized for fetuses on GD20, and the other group went on to spontaneous labor to produce F1 offspring. The adult F1 females were mated with normal males to produce the F2 and F3 generations. The PDE fetal rats exhibited ovarian mitochondrial structural abnormalities, decreased serum estradiol (E2) levels, and lower expression levels of ovarian steroidogenic factor 1 (SF1), steroidal synthetases, and insulinlike growth factor 1 (IGF1). On postnatal week (PW) 6 and PW12, the PDE F1 offspring showed altered reproductive behavior and ovarian morphology. The serum E2 level and ovarian expression of SF1, steroidal synthetases, and IGF1 were also decreased. The adult F3 offspring showed alterations in reproductive phenotype and ovarian IGF1, SF1, and steroidal synthetase expression similar to those of F1. PDE induces ovarian developmental toxicity and transgenerational inheritance effects. The mechanism by which this toxicity occurs may be related to PDE-induced low-functional programming of fetal ovarian IGF1/SF1 and steroidal synthetases.