Reproductive consequences of oral arsenate exposure during pregnancy in a mouse model

Abstract

BACKGROUND:The second most common of all structural birth defects, neural tube defects (NTDs), affect approximately 2.6/1,000 births worldwide, and 1/1,000 births in the United States. Of the many environmental agents suspected of being teratogenic, arsenic (As) is capable of inducing NTDs in laboratory animals. METHODS: We evaluated the teratogenicity of oral exposure on embryonic day (E) 7.5 and E:8.5 to As 4.8, 9.6, or 14.4 mg/kg (as sodium arsenate) in an inbred mouse strain, LM/Bc/Fnn, that does not exhibit spontaneous neural tube malformations. Control and arsenic-treated dams (20 per treatment group) were weighed daily, and evaluated for signs of maternal toxicity. Fetuses were evaluated for soft tissue and skeletal malformations. RESULTS: There was no maternal toxicity as evidenced by losses in maternal body weight following As treatment. However, liver weights were lower in all As-treated groups, suggesting hepatotoxicity due to As exposure. The number of litters affected with an NTD (exencephaly) in each treatment group was: 0, 1, 5, and 9 for control, As 4.8, 9.6, or 14.4, respectively, which exhibited a positive linear trend. There was evidence for trends between As dose and the number of litters displaying vertebral (po0.001) and calvarial (po0.01) abnormalities, components of the axial skeleton. Mean fetal weight of all As-treated groups was significantly less than in control. DISCUSSION: In our model, maternal oral treatment with As induced NTDs. It also significantly increased the frequency of axial skeletal anomalies in the offspring exposed in utero, and reduced mean fetal weight, without evidence of maternal toxicity. Birth Defects Res (Part B) 83: 40-47, 2008.

Scientific Opinion on Arsenic in Food

“…Also, mechanistic information may be obtained from experimental studies. Neural tube effects are a consistent finding in experimental studies (Hill et al, 2008), but there are few studies investigating such effects in human populations and no convincing data (Shalat et al, 1996;Brender et al, 2006). Also, findings of aberrant migration and delayed maturation of Purkinje cells following low-dose prenatal arsenic exposure in rats (Dhar et al, 2007) warrant further studies on early human development.…”

“…The authors speculated that this dysregulation might alter disease risk in response to respiratory viral infection (Kozul et al, 2009 Inorganic arsenic has been shown to be embryotoxic and teratogenic in experimental animals; however, most studies have used high parenteral arsenic dosing, which might have involved maternal toxicity (Golub et al, 1998;Wang et al, 2006). Only recently have experimental studies without maternal toxicity shown foetal growth retardation,neurotoxicity and alteration in pulmonary structure following oral dosing at relevant exposure levels, often in the form of arsenate Wang et al, 2006;Hill et al, 2008). Using a mouse model, in utero and early postnatal exposures to arsenic (100 µg/L or less in drinking water in the form of arsenite) were found to alter airway reactivity to methacholine challenge in 28 day old pups (Lantz et al, 2009).…”

Locomotor activity and sensory – motor developmental alterations in rat offspring exposed to arsenic prenatally and via lactation

“…One of the most common fetal malformations in iAs-exposed mice is exencephaly (Hood, 1972;Baxley et al, 1981;Nemec et al, 1998;Hill et al, 2008). Early in gestation, iAs was observed to selectively accumulate in the neuroepithelium (Lindgren et al, 1984) and As 3+ was found to be retained in brain tissue for longer periods of time compared to other valence forms (Vahter and Norin, 1980).…”

Maternal Arsenic Exposure and DNA Damage Biomarkers, and the Associations with Birth Outcomes in a General Population from Taiwan

“…Disrupted placentation [13] and endocrine disturbance [14] have been reported for arsenic-related adverse pregnancy outcomes. Animals treated with high doses of arsenic have reported severe early effects, such as neural tube effects [28]; however, the levels of arsenic exposure relevant to humans await further investigation. DNA damage was reported to be induced by iAs, as shown by increased concentrations of the biomarkers of oxidized DNA adducts (8-oxodG) in the brains of mice [29] and in the urine of women in the early stages of pregnancy [17].…”