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Prenatal exposure to psychosocial stress predicts adverse neurodevelopmental outcomes, particularly during gestation. Mechanisms remain poorly understood. Research links prenatal stress exposures with placental mitochondrial DNA (mtDNA) mutational load, suggesting that disrupted mitochondrial placental function may play a role. We conceptualize that placental mitochondrial biomarkers reflect environmentally-induced oxidation that may contribute to mechanisms influencing neurodevelopment. Furthermore, as maternal stress can impact female and male children differently, this may in part explain sex differences in early childhood neurobehavioral outcomes. This study explores the association between placental mtDNA mutational load and negative affectivity in infants, and whether these associations are modified by maternal lifetime stress and fetal sex. Placenta samples (N\u2009=\u2009394) were collected at delivery and whole mtDNA sequencing was performed to identify gene-specific mutational loads. Mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R) when children were 6.69\u2009\u00b1\u20091.61\u00a0months of age and the Negative Affectivity factor was derived. Multivariable regression analyses were performed to model Negative Affectivity in relation to placental mtDNA mutational load, first adjusting for child sex and maternal age, self-reported race, and education. Lastly, we examined effect modification by maternal stress and fetal sex using cross-product terms and contrast statements. Results showed that higher mutational load in the MT_CYB region was positively associated with increased negative affectivity. Notably, interactions between mtDNA regions (MT_DLOOP and MT_ND), child sex, and maternal stress revealed that girls with higher mutational loads in these regions were at greater risk for increased negative affectivity, particularly under high maternal stress. These findings suggest that placental mtDNA mutational load could serve as a biomarker for neurodevelopmental risk, with sex-specific vulnerabilities influenced by maternal stress. This study underscores the importance of considering both environmental factors and sex differences in understanding early neurodevelopmental trajectories, and the potential of the placenta as a tool for early detection and intervention. Further research is needed to validate these findings and explore their implications for long-term child development.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Highlights<\/jats:bold>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>Increased mutational load in the cytochrome B region of placental mtDNA is associated with higher infant negative affectivity.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Girls exhibited greater sensitivity to mutations in the mitochondrial D-loop and NADH dehydrogenase regions, showing stronger links to negative affectivity compared to boys.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Higher maternal lifetime stress amplified the impact of mitochondrial NADH dehydrogenase mutational load on negative affectivity in girls, highlighting gene-environment interactions.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Findings underscore the placenta's role in integrating environmental and genetic factors that influence early temperament, and its potential role as a future biomarker.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>This is the first study connecting placental mitochondrial DNA mutations with infant temperament in a diverse population, revealing sex-specific and stress-modulated effects.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.1186\/s13293-025-00717-4","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T05:11:46Z","timestamp":1749532306000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Association of placental mitochondrial DNA mutations on infant negative affectivity: modifying effects of maternal lifetime stress and infant sex"],"prefix":"10.1186","volume":"16","author":[{"given":"Agathe M.","family":"de Pins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiao-Hsien Leon","family":"Hsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalind J.","family":"Wright","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly J.","family":"Brunst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,10]]},"reference":[{"issue":"2","key":"717_CR1","doi-asserted-by":"publisher","first-page":"e508","DOI":"10.1038\/tp.2015.3","volume":"5","author":"A Qiu","year":"2015","unstructured":"Qiu A, Anh TT, Li Y, et al. 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