All Three Trimester Binge Alcohol Exposure Causes Fetal Cerebellar Purkinje Cell Loss in the Presence of Maternal Hypercapnea, Acidemia, and Normoxemia: Ovine Model

Ramadoss, Jayanth; Lunde, Emilie R.; Piña, Kevin B.; Chen, Wei‐Jung A.; Cudd, Timothy A.

doi:10.1111/j.1530-0277.2007.00422.x

Cited by 32 publications

(46 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The results from this study confirm the earlier findings (Cudd et al 2001; Parnell et al 2007; Ramadoss et al 2007; West et al 2001; Washburn et al 2013) that alcohol exposure leads to maternal acidemia, hypercapnea and hypoxemia and fetal acidemia and hypercapnea but not fetal hypoxemia. Alcohol exposure in human clinical cases is known to result in mixed respiratory and metabolic acidosis (Lamminpaa and Vilska 1991; Sahn et al 1975; Zehtabchi et al 2005) and in animal models, acidemia has been described as a candidate mechanism for alcohol-induced developmental neuronal injury and altered amino acid homeostasis (Ramadoss et al 2007, 2008; Cudd et al 2001).…”

Section: Discussionsupporting

confidence: 91%

Effects of l-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol

et al. 2014

Self Cite

View full text Add to dashboard Cite

Not much is known about effects of gestational alcohol exposure on maternal and fetal cardiovascular adaptations. This study determined whether maternal binge alcohol exposure and L-glutamine supplementation could affect maternal-fetal hemodynamics and fetal regional brain blood flow during the brain growth spurt period. Pregnant sheep were randomly assigned to one of four groups: saline control, alcohol (1.75–2.5 g/kg body weight), glutamine (100 mg/kg body weight) or alcohol + glutamine. A chronic weekend binge drinking paradigm between gestational days (GD) 99 and 115 was utilized. Fetuses were surgically instrumented on GD 117 ± 1 and studied on GD 120 ± 1. Binge alcohol exposure caused maternal acidemia, hypercapnea, and hypoxemia. Fetuses were acidemic and hypercapnic, but not hypoxemic. Alcohol exposure increased fetal mean arterial pressure, whereas fetal heart rate was unaltered. Alcohol exposure resulted in ~40 % reduction in maternal uterine artery blood flow. Labeled microsphere analyses showed that alcohol induced >2-fold increases in fetal whole brain blood flow. The elevation in fetal brain blood flow was region-specific, particularly affecting the developing cerebellum, brain stem, and olfactory bulb. Maternal L-glutamine supplementation attenuated alcohol-induced maternal hypercapnea, fetal acidemia and increases in fetal brain blood flow. L-Glutamine supplementation did not affect uterine blood flow. Collectively, alcohol exposure alters maternal and fetal acid–base balance, decreases uterine blood flow, and alters fetal regional brain blood flow. Importantly, L-glutamine supplementation mitigates alcohol-induced acid–base imbalances and alterations in fetal regional brain blood flow. Further studies are warranted to elucidate mechanisms responsible for alcohol-induced programming of maternal uterine artery and fetal circulation adaptations in pregnancy.

show abstract

Section: Discussionsupporting

confidence: 91%

Effects of l-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Efforts to successfully prevent or ameliorate the teratogenic effects of ethanol have been impeded, at least in part, by a limited understanding of the mechanisms by which ethanol damages the developing brain (9). A series of reports from our laboratory have established in an ovine model system that maternal ethanol consumption results in a decrease in maternal and fetal arterial pH (11,33,39). Acidemia was hypothesized to be a mechanism underlying the teratogenic effects of ethanol (16), even before fetal alcohol syndrome was described by Jones et al (17).…”

Section: Ramadoss J Lunde Er Ouyang N Chen W-j Cudd Tamentioning

confidence: 98%

“…The total number of fetal cerebellar Purkinje cells was estimated using unbiased stereological cell-counting techniques, as described previously (39). In brief, the microscope (Nikon Optiphot; Garden City, NY) used in this study had a ϫ40 objective lens with a 1.4 numerical aperture condenser.…”

Section: Subjectsmentioning

confidence: 99%

Acid-sensitive channel inhibition prevents fetal alcohol spectrum disorders cerebellar Purkinje cell loss

Ramadoss

Lunde²,

Ouyang³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

Self Cite

View full text Add to dashboard Cite

Ethanol is now considered the most common human teratogen. Educational campaigns have not reduced the incidence of ethanol-mediated teratogenesis, leading to a growing interest in the development of therapeutic prevention or mitigation strategies. On the basis of the observation that maternal ethanol consumption reduces maternal and fetal pH, we hypothesized that a pH-sensitive pathway involving the TWIK-related acid-sensitive potassium channels (TASKs) is implicated in ethanol-induced injury to the fetal cerebellum, one of the most sensitive targets of prenatal ethanol exposure. Pregnant ewes were intravenously infused with ethanol (258+/-10 mg/dl peak blood ethanol concentration) or saline in a "3 days/wk binge" pattern throughout the third trimester. Quantitative stereological analysis demonstrated that ethanol resulted in a 45% reduction in the total number of fetal cerebellar Purkinje cells, the cell type most sensitive to developmental ethanol exposure. Extracellular pH manipulation to create the same degree and pattern of pH fall caused by ethanol (manipulations large enough to inhibit TASK 1 channels), resulted in a 24% decrease in Purkinje cell number. We determined immunohistochemically that TASK 1 channels are expressed in Purkinje cells and that the TASK 3 isoform is expressed in granule cells of the ovine fetal cerebellum. Pharmacological blockade of both TASK 1 and TASK 3 channels simultaneous with ethanol effectively prevented any reduction in fetal cerebellar Purkinje cell number. These results demonstrate for the first time functional significance of fetal cerebellar two-pore domain pH-sensitive channels and establishes them as a potential therapeutic target for prevention of ethanol teratogenesis.

show abstract

“…In animal models, acidemia has been described as a candidate mechanism for alcohol-induced developmental neuronal injury and altered amino acid homeostasis (Cudd et al, 2001; Horiguchi et al, 1971; Ramadoss et al, 2007; 2008b). Although the consequence of these repeated bouts of alcohol-induced acidemia on the skeletal growth of the offspring is unknown, acid base imbalance is known to hamper bone development by altering the bone minerals in order to maintain a stable physiological pH (Arnett, 2003; Barzel, 1995; Bergstrom and Ruva, 1960; Bettice and Gamble, 1975; Bushinsky et al, 1986; 1996; 1999; Green and Kleeman, 1991).…”

Section: Introductionmentioning

confidence: 99%

The Role of Acidemia in Maternal Binge Alcohol-Induced Alterations in Fetal Bone Functional Properties

Sawant

Ramadoss

Hogan

et al. 2013

Alcohol Clin Exp Res

Self Cite

View full text Add to dashboard Cite

Background Heavy alcohol consumption during pregnancy negatively impacts the physical growth of the fetus. Though the deleterious effects of alcohol exposure during late gestation on fetal brain development are well documented, little is known about the effect on fetal bone mechanical properties or the underlying mechanisms. The purpose of this study was to investigate the effects of late gestational chronic binge alcohol consumption and alcohol-induced acidemia, a critical regulator of bone health, on functional properties of the fetal skeletal system. Methods Suffolk ewes were mated and received intravenous infusions of saline or alcohol (1.75 g/kg) over 1 hour on 3 consecutive days per week followed by 4 days without treatment beginning on gestational day (GD) 109 and concluding on GD 132 (term= 147 days). The acidemia group was exposed to increased inspired fractional concentrations of CO2 to closely mimic the alcohol-induced decreases in maternal arterial pH seen in the alcohol group. Results Fetal femurs and tibias from the alcohol and acidemia groups were ~3-7% shorter in length compared to the control groups (P<0.05). Three point bending procedure demonstrated that fetal femoral ultimate strength (MPa) for the alcohol group was decreased (P<0.05) by ~24% and ~29% while the acidemia group exhibited a similar decrease (P<0.05) of ~32% and 37% compared to the normal control and saline control groups, respectively. Bone extrinsic and intrinsic mechanical properties including maximum breaking force (N) and normalized breaking force (N/kg) of fetal bones from the alcohol and acidemia groups were significantly decreased (P<0.05) compared to both control groups. Conclusions We conclude that late gestational chronic binge alcohol exposure reduces growth and impairs functional properties of the fetal skeletal system and that the repeated episodes of alcohol-induced maternal acidemia may be at least partially responsible for these effects.

show abstract

All Three Trimester Binge Alcohol Exposure Causes Fetal Cerebellar Purkinje Cell Loss in the Presence of Maternal Hypercapnea, Acidemia, and Normoxemia: Ovine Model

Cited by 32 publications

References 45 publications

Effects of l-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol

Effects of l-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol

Acid-sensitive channel inhibition prevents fetal alcohol spectrum disorders cerebellar Purkinje cell loss

The Role of Acidemia in Maternal Binge Alcohol-Induced Alterations in Fetal Bone Functional Properties

Contact Info

Product

Resources

About