Cocaine as a cause of congenital malformations of vascular origin: Experimental evidence in the rat

Abstract

Cocaine hydrochloride was administered to pregnant Sprague-Dawley rats as a single intraperitoneal dose or as two doses 1-4 hours apart. A single dose administered on day 16 of gestation was teratogenic in a dose-dependent manner, with 40 mg/kg being a no-effect dose and 50 mg/kg the lowest teratogenic dose; 80 mg/kg was lethal to the dam. Forty-eight hours after exposure to a teratogenic dose on day 16 of pregnancy, the fetuses showed severe hemorrhage and edema in the their extremities, particularly the footplates, tail, genital tubercle, and upper lip/nose. When the fetuses were examined on day 21 of gestation, the main externally visible malformations were reduction deformities of the limbs and tail. When two doses of cocaine were administered 1-4 hours apart, the incidence of affected fetuses increased as the time interval between the two doses decreased. Two doses of cocaine administered 2 hours apart were not teratogenic on day 9, 10, 11, 12, 13, or 14 of gestation but did induce reduction deformities on days 15, 16, 17, 18, or 19. The same dose administered 1 hour apart was teratogenic on days 14-19. In general, cocaine administration on gestational days 14, 15, or 16 induced more severe and more widespread hemorrhage and edema than administration on days 17, 18, or 19. In the latter cases, damage was restricted to the distal parts of the hindlimb digits and the tail. The results show that in the rat cocaine is only teratogenic during the late organogenic or postorganogenic period.(ABSTRACT TRUNCATED AT 250 WORDS)

Cocaine differentially inhibits neuronal differentiation and proliferation in vitro.

“…Our findings of significant inhibition of PC-12 neuronal differentiation upon exposure to moderate to high cocaine levels suggest that cocaine may have direct effects on brain development, in addition to vascular side effects ( 16,17) that could contribute to the adverse neurodevelopmental outcomes. An alteration in neuronal differentiation could alter subsequent processes of synaptogenesis during the critical period of cell differentiation and rapid axonal and dendritic expansion.…”

“…Hypoxic ischemic insult secondary to systemic vascular side effects of cocaine could have contributed to these findings and have been reported in humans ( 1,17). Future animal studies must carefully control for vascular side effects, as in the Anderson-Brown study, to generate useful data on direct actions of cocaine in neural tissues.…”

“…Animal studies suggest that cocaine disturbs central nervous system development (1 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], but the mechanism of effect may be related to indirect vascular side effects of cocaine, Receivedfor publication I March 1993 and in revisedform 15 November 1993. rather than direct effects on cell growth and differentiation (16,17).…”

The Search for Congenital Malformations in Newborns With Fetal Cocaine Exposure

“…Some studies report no increases in congenital abnormalities in rats or mice. 40 -42 Other studies in both species, however, have indicated that prenatal cocaine exposure may be teratogenic in a dose-dependent manner, resulting in abnormalities of the limbs, [43][44][45] cardiovascular, 43,46 genitourinary, 43,44,47,48 and central nervous systems. 43,44,46,47,49 Some human reports have likewise noted anomalies of the genitourinary 3,10,11,13,20,21 and cardiovascular systems, 1,8,14 -16 skull defects, 14 limb defects and intestinal atresias, 6,13,20,21,50 and a variety of central nervous system lesions 4,5,7,9,13,[51][52][53][54][55][56] in infants exposed to cocaine in utero.…”

An update on amniotic bands sequence

“…This is the case of exome sequencing; however, it has successfully identified mutations in predominantly Mendelian phenotypes with high penetration alleles, whereas ABS may be caused by a combination of DNA variants, so it is necessary to perform a family-wide analysis and assess functional pathways that may be involved in ABS development to select the variants that should be validated by Sanger sequencing and, therefore, replicate the sequencing method in the family or the control population. 27,71 • Black population 73 • Unplanned or unintended pregnancy 16,27 • Smoking (> 15 cigarettes/day) 27,[70][71][72][73][74] • Exposure to cocaine 75,76 • Alcohol abuse 28 • High glycemic index in the diet 77 • Living in an attitudinal zone > 2000 meters above sea level 29,78 Obstetric factors • Nulliparity 15,21,26,71,73 • Multiparity…”