ARTICLES https://doi.org/10.1038/s41593-017-0024-x Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. *e-mail: yaara.yaara@gmail.com; noam.sobel@weizmann.ac.il T errestrial mammals typically rely on their sense of smell to read emotions and communicate socially, and there is growing evidence for meaningful social chemosignaling in humans as well 1–6 . Human social chemosignals can convey information such as age 7 , disease 8 , aggression 9 , happiness 10 and fear 11–14 , and they can act subliminally to influence brain activity 14–16 , hormonal state 17,18 , mate selection 19 , sexual arousal 5 , infant bonding 20 and general psycholog- ical and emotional state 2,3 . Living without these signals, a condition one might term ‘social anosmia’, may constitute an impairment, but one, we speculate, with limited implications. This is because visual and auditory information could make up for the lost chemosignal- ing 21 . In contrast, living with these signals distorted rather than lost, a condition one might term ‘social dysosmia’, could be devas- tating. ASD is characterized by impaired social communication 22 attributed to misreading of emotional cues 23 , but why individuals with ASD misread emotions remains unknown. We hypothesized that a portion of misreading emotions in ASD may be explained by social dysosmia. We investigated this hypothesis by comparing the responses of TD participants and cognitively able participants with ASD to the subliminal presentation of social chemosignals. Results Intact sensory and behavioral substrates for social chemosignal- ing in ASD. We first set out to establish whether the substrates of social chemosignaling remain intact in ASD. Humans constantly and mostly subliminally sample conspecific body odors (BO), and one mechanism for this is unwittingly sniffing one’s own hand after handshaking with a stranger 6 . We tested whether this persists in 18 male participants with ASD (Table 1) and observed a doubling of post-handshake hand-sniffing instances and quadrupling of post- handshake hand-sniffing duration, i.e., a significant change from baseline (P = 0.012), but not significantly different from the behav- ior of previously observed TD participants 6 (χ 2 = 0.11, P = 0.74; Fig. 1a). Under the assumption that hand-sniffing is a BO sampling mechanism, we next asked whether TD and ASD participants could equally explicitly detect and discriminate BOs. In a three-alternative forced-choice (3AFC) task, 18 TD and 16 ASD male participants were asked to identify the odd odor from triplicates containing two BOs from the same individual and one BO from a different indi- vidual (Supplementary Fig. 1). We observed no significant differ- ences between TD and ASD participants in performance of this task (interaction P = 0.72; Fig. 1b). Finally, we collected fear sweat from eight men skydiving 16 and control sweat from eight men walking in a state of calm. Cortisol was significantly higher in the skydiv- ing group, indicating successful fear induction (Methods). We then asked 15 TD and 15 ASD male participants to rate these BOs. Fear sweat was rated as less pleasant, more intense and denoting higher fear than control sweat (all P < 0.01), and there were no differences between TD and ASD participants in these ratings (all interactions P > 0.38; Fig. 1c). Having observed that ASD participants spontane- ously sample chemosignals like TD participants, are equally capable of detecting and discriminating BOs and associate a similar explicit perceptual shift with the smell of fear, we next asked how such social chemosignals influence autonomic arousal and behavior in TD and ASD participants. Altered autonomic responses to the undetected smell of fear in ASD. Whether the smell of fear is a chemical cue capitalized on by the receiver or a chemical signal capitalized on by the sender, it remains a bodily odor with meaningful social value, and its suc- cessful detection confers advantage. Exposure to the smell of fear drives slight but significant alterations in perception of emotionally salient information 24 , slight but significant changes in performance of cognitive tasks 13 , and more robust alterations in autonomic arousal and neural activity in the substrates of emotional process- ing 14,16 . However, the reported effects of the smell of fear mostly materializes in women receivers but not in men receivers 11 . This poses a potential limitation on our intention to study reactions to the smell of fear in cognitively able adults with ASD, which is sig- nificantly more prevalent in men than in women 25 . Nevertheless, we initially set out to test TD and ASD participants using previously applied models. We passively exposed 20 TD and 20 ASD male participants to the volatile bouquet of verified fear sweat (Fig. 2a) or control (collection Altered responses to social chemosignals in autism spectrum disorder Yaara Endevelt-Shapira  *, Ofer Perl, Aharon Ravia  , Daniel Amir, Ami Eisen, Vered Bezalel, Liron Rozenkrantz, Eva Mishor, Liron Pinchover, Timna Soroka, Danielle Honigstein and Noam Sobel  * Autism spectrum disorder (ASD) is characterized by impaired social communication, often attributed to misreading of emo- tional cues. Why individuals with ASD misread emotions remains unclear. Given that terrestrial mammals rely on their sense of smell to read conspecific emotions, we hypothesized that misreading of emotional cues in ASD partially reflects altered social chemosignaling. We found no difference between typically developed (TD) and cognitively able adults with ASD at explicit detection and perception of social chemosignals. Nevertheless, TD and ASD participants dissociated in their responses to sub- liminal presentation of these same compounds: the undetected ‘smell of fear’ (skydiver sweat) increased physiological arousal and reduced explicit and implicit measures of trust in TD but acted opposite in ASD participants. Moreover, two different unde- tected synthetic putative social chemosignals increased or decreased arousal in TD but acted opposite in ASD participants. These results implicate social chemosignaling as a sensory substrate of social impairment in ASD. NATURE NEUROSCIENCE | VOL 21 | JANUARY 2018 | 111–119 | www.nature.com/natureneuroscience 111 © 2017 Nature America Inc., part of Springer Nature. All rights reserved.