Paternal Nicotine/Ethanol/Caffeine Mixed Exposure Induces Offspring Rat Dysplasia and Its Potential “GC-IGF1” Programming Mechanism

Abstract

Clinical and animal studies suggest that paternal exposure to adverse environments (bad living habits and chronic stress, etc.) has profound impacts on offspring development; however, the mechanism of paternal disease has not been clarified. In this study, a meta-analysis was first performed to suggest that paternal exposure to nicotine, ethanol, or caffeine is a high-risk factor for adverse pregnancy outcomes. Next, we created a rat model of paternal nicotine/ethanol/caffeine mixed exposure (PME), whereby male Wistar rats were exposed to nicotine (0.1 mg/kg/d), ethanol (0.5 g/kg/d), and caffeine (7.5 mg/kg/d) for 8 weeks continuously, then mated with normal female rats to obtain a fetus (n = 12 for control group, n = 10 for PME group). Then, we analyzed the changes in paternal hypothalamic–pituitary–adrenal (HPA) axis activity, testicular function, pregnancy outcomes, fetal serum metabolic indicators, and multiple organ functions to explore the mechanism from the perspective of chronic stress. Our results demonstrated that PME led to enhanced paternal HPA axis activity, decreased sperm quality, and adverse pregnancy outcomes (stillbirth and absorption, decreased fetal weight and body length, and intrauterine growth retardation), abnormal fetal serum metabolic indicators (corticosterone, glucolipid metabolism, and sex hormones), and fetal multi-organ dysfunction (including hippocampus, adrenal, liver, ossification, and gonads). Furthermore, correlation analysis showed that the increased paternal corticosterone level was closely related to decreased sperm quality, adverse pregnancy outcomes, and abnormal offspring multi-organ function development. Among them, the decreased activity of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis may be the main mechanism of offspring development and multi-organ dysfunction caused by PME. This study explored the impact of common paternal lifestyle in daily life on offspring development, and proposed the GC-IGF1 programming mechanisms of paternal chronic stress-induced offspring dysplasia, which provides a novel insight for exploring the important role of paternal chronic stress in offspring development and guiding a healthy lifestyle for men.

Unveiling the hidden risk: paternal smoking and alcohol exposure prior to conception as independent factors for allergic rhinitis in children

“…Recently, the rat model, in which the paternal exposure to a combination of nicotine, ethanol, and caffeine demonstrated that such mixed adverse exposure resulted in heightened activity of the hypothalamic pituitary adrenal axis, diminished sperm quality, unfavorable outcomes in pregnancy, abnormal indicators of fetal serum metabolism, and dysfunction in multiple organs in male rats. Notably, the reduced activity of the glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis may serve as the primary mechanism underlying the developmental and multi-organ dysfunction observed in offspring due to paternal mixed exposure ( 44 ).…”

Impacts of Maternal Noise Exposure on Risk of Stillbirth and Oxidative Stress-Induced Neurobehavioral Changes in Offspring

“…It has also been demonstrated that high levels of glucocorticoids adversely affect the uterus and fetus and inhibit the secretion of pituitary luteinizing hormone, estrogen, and progesterone by the ovary. A lack of progesterone during pregnancy can also be attributed to stress hormone-induced inhibitory effects on female reproductive organs, resulting in the symptoms known as "hypothalamic" amenorrhea and fetal loss [21]. Studies have previously shown that noise exposure stimulates HPA axis activity and increased corticosterone production [22].…”