Sulphur dioxide (SO₂) is a toxic air pollutant with deleterious effects on the respiratory, cardiovascular, endocrine and reproductive systems. SO₂, being freely diffusible, can cross the placenta and reach the fetal system. Previous studies have reported the association between SO₂ exposure and adverse pregnancy and fetal outcomes without much emphasis on its molecular aspects. The present study has investigated the adverse consequences of SO₂ derivatives on the two key trophoblast functions critical for placentation: invasion and fusion. SO₂ exposure inhibited the fusogenic potential of BeWo cells, as well as the invasion and migratory ability of the extravillous HTR8/SVneo cells. A molecular insight revealed dysregulated endoplasmic reticulum stress, with an altered epigenetic state as seen by histone modifications following SO₂ exposure. Collectively, our findings revealed the harmful effect of SO₂ and its consequences on the placental function. We therefore elucidated the detrimental impact of SO₂ exposure on trophoblast cells and the possible health consequences that may contribute to pregnancy-related complications as a result of compromised placental function. KEY POINTS: Sulphur dioxide (SO₂) derivatives severely impaired trophoblasts migration, invasion and its ability of fusogenic differentiation. SO₂ derivatives appear to affect trophoblast cell interactions, thereby affecting its 3D organization and its capacity to form spheroids. Mechanistic insight into these events indicates SO₂ derivatives mediated the induction of endoplasmic reticulum stress and inflammation, as well as altered histone-3 markers. We therefore conclude that SO₂ exposure has a detrimental effect on placental trophoblast cells. Long-term exposure during pregnancy may result in an adverse outcome.