The impact of maternal cyanotoxin ingestion on the development and function of the stress axis in
offspring. Anthropogenic activities and global warming have increased water eutrophication, which caused a
significant increase in the frequency in cyanobacterial harmful algal blooms in freshwaters. This dramatically
elevated the production and release of hazardous cyanotoxins, mainly microcystins (MCs), of which MC leucine
arginine (MC-LR) is the most abundant and toxic form. Accidental, and sub-chronic exposure to environmental
levels of MCs is almost inevitable, through ingestion, inhalation, and/or dermal contact with MC-contaminated
drinking water. Evidence indicate that MCs disrupt the mammalian stress response, which in mammals is under
the control of the hypothalamus-pituitary-adrenal (HPA) axis. Stressors activate hypothalamic paraventricular
nucleus (PVN) neurons to release the neurohormone corticotropin-releasing hormone, which stimulates
adrenocorticotropic hormone release from the pituitary to activate release of glucocorticoids from the adrenals.
We and others showed that disrupted HPA activity to be linked to promoting anxiety and depression. Our studies
in male mice found that sub-chronic ingestion of non-lethal MC-LR levels caused maladaptive HPA activation
that may lead to stress-related mental health conditions, such as anxiety and depression. We also found that
peripheral correlates of HPA function, such as metabolic activity and microbiome were MC-LR sensitive.
Together these data formed the premise that sub-chronic ingestion of non-lethal MC-LR levels causes significant
changes in HPA activation in mice. Unlike studies focused on adult animals, prenatal sub-chronic MC-LR effects
on the HPA development and function in the offspring have not been studied in detail. In this proposal, we will
test the hypothesis that sub-chronic maternal ingestion of non-lethal MC-LR levels disrupts embryonic HPA
development and HPA functions in the adult offspring. Aim 1 will determine that sub-chronic maternal ingestion
of non-lethal MC-LR levels disrupts the development of brain regions that control stress axis in embryos, while
aim 2 will determine that sub-chronic maternal ingestion of non-lethal MC-LR levels disrupts HPA functions in
the adult offspring. This proposal will determine the impact of maternal ingestion of MC-LR on HPA development
and function in the offspring. This allows for the evaluation of how in utero cHAB toxins in freshwater sources
affect the homeostasis and health of the offspring, which is of clinical significance given that it is well-established
that disrupted HPA function underlies anxiety and depression.
