Moderate prenatal ethanol exposure in the rat promotes kidney cell apoptosis, nephron deficits, and sex‐specific kidney dysfunction in adult offspring

Abstract

Alcohol during pregnancy can impair fetal development and result in offspring with neurodevelopmental deficits. Less is known about how low to moderate alcohol exposure can affect other organs, such as the kidney. Here, the effects of moderate ethanol exposure throughout pregnancy on kidney development were examined using a rat model. Rats were fed a liquid diet containing 6% ethanol (vol/vol) or control (0% ethanol) throughout pregnancy. Kidneys were collected at embryonic day (E) 20 or postnatal day (PN) 30 and total glomerular (nephron) number determined using unbiased stereology. Kidney function was examined in offspring at 8 and 19 months. At E20, fetuses exposed to ethanol had fewer nephrons with increased apoptosis. Alcohol exposure caused kidney dysregulation of pro‐ (Bax) and anti‐ (Bcl‐2) apoptotic factors, and reduced expression of the cell proliferation marker, Ki67. Prenatal alcohol decreased expression of Gdnf and Tgfb1, important regulators of branching morphogenesis, in male fetuses. At PN30, kidney volume and nephron number were lower in offspring exposed to prenatal alcohol. Urine flow and osmolality were normal in offspring exposed to alcohol however sodium excretion tended to be lower in females prenatally exposed to alcohol. Findings suggest exposure to moderate levels of alcohol during pregnancy results in impaired kidney development and leads to a permanent nephron deficit. Although the impact on adult kidney function was relatively minor, these data highlight that even at moderate levels, alcohol consumption during pregnancy can have deleterious long‐term outcomes and should be avoided.

Associations of maternal periconceptional alcohol consumption with offspring prehypertension/hypertension at age 6 years: the Growing Up in Singapore Towards healthy Outcomes prospective mother-offspring cohort study

“…The increased kidney growth found in children of mothers with high alcohol consumption (≥1.9 g/day) in our cohort could be the result of low nephron endowment at birth which is compensated postnatally by increased glomerular and tubular hypertrophy. Research on animal models of prenatal alcohol exposure suggests maternal alcohol, even at low-to-moderate levels during pregnancy can result in low nephron endowment in the offspring [27–29]. Increased kidney cell apoptosis and suppression of branching morphogenesis could be potential mechanisms through which alcohol exposure influences renal development [29,30].…”

“…Journal of Hypertension www.jhypertension.com influences renal development [29,30]. Low nephron number is linked to increased BP [27,28] and the increase in BP of children at age 6 years in the high QAC and FAC groups could be the result of maternal alcohol consumption resulting in a nephron deficit at birth and subsequent postnatal renal hypertrophy.…”

Fetal Programming Is Deeply Related to Maternal Selenium Status and Oxidative Balance; Experimental Offspring Health Repercussions

“…Moreover, since the kidney is the second organ implicated in EtOH metabolism and it is highly related to CVD generated by the IR-process [ 176 ], different authors have described renal programming problems after maternal EtOH exposure during gestation in their offspring, such as nephron malformations, which could compromise renal hemodynamic functions and cardiovascular function, since a low nephron endowment is considered a risk factor for the development of kidney disease in adulthood [ 177 , 178 , 179 , 180 , 181 ]. In this context, Akison et al [ 180 ] showed that maternal EtOH exposure during pregnancy results in impaired kidney development and leads to a permanent nephron deficit, which has an impact on the adult kidney function. He et al [ 182 ] also found that prenatal EtOH exposure leads to fetal kidney dysplasia and adult glomerulosclerosis in the offspring rats, and that the intrauterine programming alteration of IGF-1 might be involved in fetal-originated glomerulosclerosis.…”

Introduction to a special issue on kidney development and disease

“…A series of original research articles in this issue further support the importance of DOHaD renal research. Prof. Karen Moritz, an ongoing collaborator of John's, presents their latest experimental findings regarding the long‐term adverse impact of maternal ethanol intake on rat offspring nephron number and kidney function; even moderate ethanol exposure was shown to be detrimental (Akison et al, 2020). In a rabbit model of maternal hypertension, Monash colleague and collaborator Prof. Kate Denton describes methodologies for the in utero high‐resolution ultrasound assessment of fetal growth trajectories, including helpful assessments of fetal kidney size (Coombs, Walton, Maduwegedera, Flower, & Denton, 2020).…”