Binge toluene exposure in pregnancy and pre-weaning developmental consequences in rats

Abstract

The persistent rate of abuse of inhaled organic solvents, especially among women of child-bearing age, raises the risk for teratogenic effects of maternal toluene abuse. In this study, timed-pregnant Sprague Dawley rats were exposed from Gestation Day (GD) 8 to GD20 to 12,000 or 8,000 parts per million (ppm) toluene, or 0 ppm (controls) for 30 min twice daily, 60 min total daily exposure. Pups were assessed from postnatal day (PN) 4 to PN21 using a developmental battery measuring growth (i.e., body weight), maturational milestones (e.g., eye opening & incisor eruption), and biobehavioral development (e.g., negative geotaxis & surface righting). Pups exposed in utero to 12,000 ppm or 8,000 ppm toluene weighed significantly less than the non-exposed control pups beginning at PN4 and PN12 (respectively) until PN21. Toluene resulted in significant increases in an index of poor perinatal outcome, specifically a composite of malformations, defined “runting” and neonatal death. No significant delays were observed in reaching maturational milestones. The results reveal that brief, repeated, prenatal exposure to high concentrations of toluene can cause growth retardation and malformations in rats. A comparison of the present, conservative results with findings in previous studies implies that binge patterns of toluene exposure in pregnant rats modeling human solvent abuse can result in developmental and morphological deficits in offspring. These results do not exclude the possibility that maternal toxicity as well as teratogenic effects of toluene may contribute to outcomes. The results suggest that abuse of inhaled organic solvents like toluene may result in similar early developmental outcomes in humans.

Prenatal toluene exposure impairs performance in the Morris Water Maze in adolescent rats

“…The reduced weight gain in dams after exposure to 12,000-ppm toluene vapor, similar to one of our previous reports (Bowen & Hannigan, 2013), suggests that a toluene-induced maternal toxicity or under-nutrition during pregnancy may have contributed to the current growth restrictions observed in pups at PN1. One the other hand, in another prior study using identical toluene exposures in pregnant rats we reported significant reductions in fetal growth without effects on maternal weight gain (Bowen et al, 2009).…”

“…Abuse of inhalants like toluene while pregnant can lead to a constellation of physical anomalies and developmental disabilities in the offspring collectively referred to as “Fetal Solvent Syndrome” (FSS; Toutant and Lippmann, 1979, Hannigan and Bowen, 2010, Bowen and Hannigan, 2013). The signs of FSS in children include premature birth, low birth weight (Ahmed and Jaakkola, 2007), skeletal and other facial anomalies (Jones and Balster, 1998), and impaired cognitive development (Laslo-Baker et al, 2004), outcomes sharing similarities with Fetal Alcohol Spectrum Disorders (FASD; Pearson et al, 1994, Wilkins-Haug, 1997).…”

“…Rats exposed prenatally to repeated abuse levels of toluene display similar outcomes, including the gross skeletal abnormalities (Bowen et al, 2009) and behavioral disruptions (Batis et al, 2010, Bowen and Hannigan, 2013). The patterns of behavioral effects of toluene may also parallel those of prenatal alcohol exposure that are mediated by alterations in hippocampal function, including disruptions in spatial performance (Berman and Hannigan, 2000, Brolese et al, 2014, Elibol-Can et al, 2014).…”

Migration of toluene through different plastic laminated films into food simulants

“…Toluene is one of the most widely used aromatic solvents but is a known carcinogen and teratogen (Bowen & Hannigan, 2013). It is toxic furthermore to the liver and to the hematological and immune systems.…”

Long-Term Behavioral Consequences of Prenatal Binge Toluene Exposure in Adolescent Rats

“…In previous work examining prenatal binge toluene exposure, repeated 15 min (8,000 or 12,000 ppm) exposure twice a day (30 min total per day) from Gestation Day 8 (GD8) through GD20 produced significant increases in total minor and gross malformations, including reduced body weight, soft tissue anomalies (e.g., missing eyes), and skeletal abnormalities (shortened and/or missing digits and missing limbs, reduced skeletal ossification), "runting" and fetal or postnatal death [8,51]. Growth deficits were more prevalent when repeated exposures to high concentrations were increased to 30 min binge exposures in rats [11] and mice [51]. This pattern of prenatal exposure to toluene also resulted in a higher incidence of gross morphological anomalies including shortened and/or missing digits and missing limbs [12].…”