First, intermittent exposure to tobacco in the human fetus differs from the continuous nicotine dosing employed in animal models (Slotkin, 2008). Second, there are dramatic differences in brain structure and function http://www.selleckchem.com/products/brefeldin-a.html between rodents and humans (i.e., humans display an enlarged prefrontal cortex, distinct hippocampal structure, and higher density of synaptic connections as compared to rodents). Third, animal studies have primarily focused on perinatal exposure to nicotine alone, whereas human studies necessarily focus on cigarettes and tobacco products, which include nicotine in addition to a numerous other potential neuroteratogens (e.g., arsenic, acetone, and formaldehyde). Finally, the third trimester of human pregnancy corresponds to the postnatal rather than perinatal period in the rodent (Dwyer, McQuown, & Leslie, 2009).

Thus, prior animal studies that have modeled effects of prenatal exposure are not able to provide insight into neural effects of human prenatal exposure in the third trimester. Given these differences, it is critical to investigate effects of MSDP on offspring brain development in humans. Previous comprehensive reviews have summarized studies investigating associations between MSDP and offspring neurobehavioral deficits and disorders from both the human and the animal literatures (Cornelius & Day, 2009; Ernst et al., 2001; Herrmann et al., 2008; Langley et al., 2005; Pauly & Slotkin, 2008).

These reviews have reported relatively consistent links between MSDP and neurobehavioral deficits but highlight the difficulty in establishing causal associations given the number of potentially confounding factors, ethical impossibility of experimental designs in humans, and obstacles in translating findings from animal models to human neurobehavioral outcomes. Previous reviews have also summarized associations between MSDP and offspring neural development with focus on both animal and some human studies (Baler et al., 2008; Blood-Siegfried & Rende, 2010; Dwyer et al., 2009; Shea & Steiner, 2008; Slotkin, 1998). These reviews suggest that dysregulation in the development of receptor, neurotransmitter, and basic synaptic systems by maternal smoking/prenatal nicotine could lead to functional and structural brain changes and neurobehavioral/cognitive impairments in offspring. However, the reviews relied heavily on findings from animal studies and did not provide a comprehensive review of human studies of brain structure and function. Therefore, our aims in the current review are (a) to systematically summarize GSK-3 and critique the small number of human studies of MSDP and brain structure and function and (b) to propose an agenda for future research in this nascent area.