Figure 8

Proposed mechanisms and hypotheses linking maternal Cd exposure to altered neurodevelopment. We propose that maternal Cd exposure increases retinoic acid (RA) synthesis and/or degradation in the fetal brain. This leads to aberrant Hox expression, altered (early onset of) myelination, and altered behavior. Aberrant Hox expression may explain the previously known role of Cd as a teratogen. Additionally, we propose that maternal Cd exposure damages the mitochondria in the fetal brain and therefore impacts energy production in the brain. Metabolites produced during this process may have feedback on RA production. Finally, we propose that maternal Cd exposure alters levels of essential trace elements, which is sensed by the body as a state of malnutrition and may lead to a hypoxic environment during development due to the significantly reduced levels of iron in circulation. This also alters energy production in the brain and may explain the enlarged proportional brain weights at birth, consistent with the phenomenon known as “brain-sparing”. These hypotheses lay the foundation for future mechanistic work to elucidate molecular pathways occurring at each arrow. Data described here or in Hudson et al.15 that support the hypotheses are italicized in smaller text below the corresponding hypothesis in each box.