Prenatal caffeine exposure-induced adrenal developmental abnormality in male offspring rats and its possible intrauterine programming mechanisms

Abstract

Glucocorticoid (GC) is a major factor for fetal tissue maturation and fate decision after birth. We previously demonstrated that prenatal caffeine exposure (PCE) suppressed fetal adrenal steroidogenesis and resulted in adrenal dysplasia. However, whether these changes play a role until adulthood and its intrauterine programming mechanisms remain unknown. In the present study, a rat model of intrauterine growth retardation (IUGR) was established by PCE, male fetuses and adult offspring were sacrificed at postnatal day (PD) 1, PD7, PD35, PD100 and PD168, respectively. Results showed that the PCE fetal weight decreased and the IUGR rate increased, while the serum corticosterone (CORT) level increased but the insulin-like growth factor 1 (IGF1) level decreased. Fetal adrenal exhibited an enhanced GC-activation system (11β-hydroxysteroid dehydrogenases/corticoid receptors/CCAAT/enhancer binding proteins), an inhibited IGF1 pathway and steroid synthesis function. After birth, the serum CORT levels in the PCE offspring were increased in the early period followed by falling in the later stage, while the serum IGF1 level change was the opposite and was accompanied by an obvious catch-up growth. Furthermore, the adrenal GC-activation system was inhibited but the IGF1 signaling pathway was enhanced, resulting in a compensatory increase of adrenal steroidogenesis, and the expression of steroidal synthetase was consistent with that of the IGF1 signaling pathway. Based on these findings, we proposed "two-programming mechanisms" for PCE-induced adrenal abnormality: the "first programming" mechanism is a lower function of adrenal steroidogenesis, and prenatal and postnatal adrenal structural and functional abnormalities triggered by the intrauterine GC-IGF1 axis programming-mediated by the GC-activation system that acts as "the second programming" mechanism.

The Effects of High Peripubertal Caffeine Exposure on the Adrenal Gland in Immature Male and Female Rats

“…The zona fasciculata is most frequently affected by noxious compounds [29], and chemically-induced toxicity causes impaired steroidogenesis, leading to excess steroid precursors and cytoplasmic vacuolation in the adrenal cortical cells of the zona fasciculata [29]. Similarly, we observed histological distortion of the adrenal cortex including cloudy swellings and some vacuolation within the cells of the zona fasciculata, dilation of some blood sinusoids, and more dilated intercellular spaces in the cortex in the caffeine-fed groups, particularly the females (Figure 4A) (Table 1), consistent with previous data on caffeine exposure of adult and fetal animals [8,9,10]. During puberty, there is marked expansion of the zona fasciculata [26], which constitutes the main bulk of the adrenal cortex.…”

“…On the other hand, prenatal caffeine exposure has been reported to reduce adrenal cortical area by half in male rat offspring [9]. However, we observed no difference in adrenal cortical or medullary area between caffeine-fed and control males (Figure 3), whereas in the caffeine-fed females, cortical and medullary areas increased in spite of the reduced absolute weights of the adrenals.…”

“…The adrenal gland is the earliest and fastest-developing organ [22,23] and concentrates caffeine more than any other organ [24], suggesting that there could be a high risk of caffeine toxicity to this organ. It has been reported that prenatal exposure to caffeine significantly restricts growth of the adrenals, particularly of the cortical area [9,10]. As puberty is another crucial phase for neuroendocrine transformation, including adrenal cortical maturation [25], it could be anticipated that peripubertal exposure to caffeine would reduce growth of the adrenals.…”

“…Clinical and experimental studies suggest that caffeine affects the function and morphology of the adrenal glands. For instance, prenatal exposure of rats to caffeine inhibits glucocorticoid production and reduces the size of the adrenal cortical zone in male offspring; it also leads to a disorganized arrangement of cells and cellular swelling [8,9]. In contrast, in adult humans and animals, high doses of caffeine elevate glucocorticoid levels in a stress-like pattern of endocrine responses [6,7].…”

Age-Characteristic Changes of Glucose Metabolism, Pancreatic Morphology and Function in Male Offspring Rats Induced by Prenatal Ethanol Exposure

“…In our previous researches, we have demonstrated that PEE could induce fetal over-exposure to maternal glucocorticoids in utero (26, 55, 56), which further increased the GR expression [e.g., hippocampus (56) and adrenals (26)] and decreased IGF1 expression [e.g., adrenals (26), and liver (28)] of multiple fetal organs, and thus resulted in their developmental programming alterations. In addition, in other IUGR models induced by prenatal exposure to xenobiotics [such caffeine (57), nicotine (58)], we have also found the fetal over-exposure to maternal glucocorticoids, and the alterations of GR expression in multiple fetal organs, accompanied with related developmental programming changes. In the present study, we found that the contents of pancreatic insulin and proinsulin were lower, and the expression levels of INS1, INS2 and ISL1 mRNA were decreased in the PEE group, furthermore, the GR mRNA expression level was increased but the expression level of IGF1 mRNA was decreased.…”