Sex-specific enhanced behavioral toxicity induced by maternal exposure to a mixture of low dose endocrine-disrupting chemicals.

Humans are increasingly and consistently exposed to a variety of
endocrine disrupting chemicals (EDCs), chemicals that have been linked
to neurobehavioral disorders such as ADHD and autism.
Many of such EDCs have been shown to adversely influence brain
mesocorticolimbic systems raising the potential for cumulative toxicity.
As such, understanding the effects of developmental exposure to
mixtures of EDCs is critical to public health protection. Consequently,
this study compared the effects of a mixture of four EDCs to their
effects alone to examine potential for enhanced toxicity, using
behavioral domains and paradigms known to be mediated by
mesocorticolimbic circuits (fixed interval (FI) schedule controlled
behavior, novel object recognition memory and locomotor activity) in
offspring of pregnant mice that had been exposed to vehicle or
relatively low doses of four EDCs, atrazine (ATR - 10mg/kg),
perfluorooctanoic acid (PFOA - 0.1mg/kg), bisphenol-A (BPA - 50μg/kg),
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD - 0.25μg/kg) alone or combined
in a mixture (MIX), from gestational day 7 until weaning. EDC-treated
males maintained significantly higher horizontal activity levels across
three testing sessions, indicative of delayed habituation, whereas no
effects were found in females. Statistically significant effects of MIX
were seen in males, but not females, in the form of increased FI
response rates, in contrast to reductions in response rate with ATR, BPA
and TCDD, and reduced short term memory in the novel object recognition
paradigm. MIX also reversed the typically lower neophobia levels of
males compared to females. With respect to individual EDCs, TCDD
produced notable increases in FI response rates in females, and PFOA
significantly increased ambulatory locomotor activity in males.
Collectively, these findings show the potential for enhanced behavioral
effects of EDC mixtures in males and underscore the need for animal
studies to fully investigate mixtures, including chemicals that converge
on common physiological substrates to examine potential mechanisms of
toxicity with full dose effect curves to assist in interpretations of
relevant mechanisms.

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